WO2006022634A1

WO2006022634A1 - Methods for identifying risk of type ii diabetes and treatments thereof

Info

Publication number: WO2006022634A1
Application number: PCT/US2004/023911
Authority: WO
Inventors: Maria L. Langdown; Matthew Roberts Nelson; Rikard Henry Reneland; Stefan M. Kammerer; Andreas Braun; Carolyn R. Hoyal-Wrightson
Original assignee: Sequenom, Inc.
Priority date: 2004-07-22
Filing date: 2004-07-22
Publication date: 2006-03-02

Abstract

Provided herein are methods for identifying a risk of type II diabetes in a subject, reagents and kits for carrying out the methods, methods for identifying candidate therapeutics for treating type II diabetes, and therapeutic and preventative methods applicable to type II diabetes. These embodiments are based upon an analysis of polymorphic variations in nucleotide sequences within the human genome.

Description

METHODS FOR IDENTIFYING RISK OF TYPE H DIABETES AND TREATMENTS THEREOF

Field of the Invention

[0001] The invention relates to genetic methods for identifying predisposition to type II diabetes, also known as non-insulin dependent diabetes, and treatments that specifically target the disease.

Background

[0002] Diabetes is among the most common of all metabolic disorders, affecting up to 11% of the population by age 70. Type I diabetes (insulin-dependent diabetes) represents about 5 to 10% of this group and is the result of progressive autoimmune destruction of the pancreatic β-cells with subsequent insulin deficiency.

[0003] Type II diabetes (non-insulin dependent diabetes) represents 90-95% of the affected population, more than 100 million people worldwide. Approximately 17 million Americans suffer from type II diabetes, although 6 million don't even know they have the disease. The prevalence of the disease has jumped 33% in the last decade and is expected to rise further as the baby boomer generation gets older and more overweight. The global figure of people with diabetes is set to rise to an estimated 150 to 220 million in 2010, and 300 million in 2025. The widespread problem of diabetes has crept up on an unsuspecting health care community and has already imposed ajhuge burden on health-care systems (Zimmet et al (2001) Nature 414: 782-787).

[0004] Often, the onset of type II diabetes can be insidious, or even clinically unapparent, making diagnosis difficult. Even when the disease is properly diagnosed, many of those treated do not have adequate control over their diabetes, resulting in elevated sugar levels in the bloodstream that slowly destroys the kidneys, eyes, blood vessels and nerves. This late damage is an important factor contributing to mortality in diabetics.

[0005] Type II diabetes is associated with peripheral insulin resistance, elevated hepatic glucose production, and inappropriate insulin secretion (DeFronzo, R. A. (1988) Diabetes 37:667- 687), although the primary pathogenic lesion on type II diabetes remains elusive. Many have suggested that primary insulin resistance of the peripheral tissues is the initial event. Genetic epidemiological studies have supported this view. Similarly, insulin secretion abnormalities have been argued as the primary defect in type II diabetes. It is likely that both phenomena are important in the development of type II diabetes, and genetic defects predisposing to both are likely to be important contributors to the disease process (Rimoin, D.L., et al. (1996) Emery and Rimoin's Principles and Practice of Medical Genetics 3rd Ed. 1: 1401-1402). [0006] Evidence from familial aggregation and twins studies point to a genetic component in the etiology of diabetes (Newman et al. (1987) Diabetologia 30:763-768; Kobberling, J. (1971) Diabetologia 7:46-49; Cook, J. T. E. (1994) Diabetologia 37:1231-1240), however, there is little agreement as to the nature of the genetic factors involved. This confusion can largely be attributed to the genetic heterogeneity known to exist in diabetes.

Summary

[0007] It has been discovered that certain polymorphic variations in human genomic DNA are associated with the occurrence of type II diabetes, also known as non-insulin dependent diabetes. Thus, featured herein are methods for identifying a subject at risk of type II diabetes and/or a risk of type II diabetes in a subject, which comprises detecting the presence or absence of one or more polymorphic variations associated with type II diabetes described herein in a human nucleic acid sample. In an embodiment, two or more polymorphic variations are detected in two or more regions set forth in Table 1 or SEQ ID NO: 1-6. In some embodiments, one or more polymorphic variants are detected in a LOC391238, EIF4G2 or Region A (Region A contains rs214410) locus. In certain embodiments, 3 or more, or 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more polymorphic variants are detected.

[0008] Also featured are nucleic acids that include one or more polymorphic variations associated with occurrence of type II diabetes, as well as polypeptides encoded^" by these nucleic acids. In addition, provided are methods for identifying candidate therapeutic molecules for treating type II diabetes and other insulin-related disorders, as well as methods for treating type II diabetes in a subject by identifying subjects at risk of type II diabetes and treating the subject with a suitable prophylactic, treatment or therapeutic molecule.

[0009] Also provided are compositions comprising a cell from a subject having type II diabetes or at risk of type II diabetes and/or a nucleic acid set forth in Table 1 or SEQ ID NO: 1-6, with a complementary nucleic acid or a RNAi, siRNA, antisense DNA or RNA, or ribozyme nucleic acid designed from a nucleotide sequence in Table 1 or SEQ ID NO: 1-6. In an embodiment, the RNAi, siRNA, antisense DNA or RNA, or ribozyme nucleic acid is designed from a nucleotide sequence in Table 1 or SEQ ID NO: 1-6 that includes one or more type II diabetes associated polymorphic variations, and in some instances, specifically interacts with such a nucleotide sequence. Further, provided are arrays of nucleic acids bound to a solid surface, in which one or more nucleic acid molecules of the array have a nucleotide sequence identified in Figures 1 or 2, or a fragment or substantially identical nucleic acid thereof, or a complementary nucleic acid of the foregoing. Featured also are compositions comprising a cell from a subject having type II diabetes or at risk of type II diabetes and/or a polypeptide from Table 1 or SEQ ID NO: 1-6, with an antibody that specifically binds to the polypeptide. Ia an embodiment, the antibody specifically binds to an epitope in the polypeptide that includes a non-synonymous amino acid modification associated with type II diabetes (e.g., results in an amino acid substitution in the encoded polypeptide associated with type II diabetes). In certain embodiments, the antibody specifically binds to an epitope that comprises an aspartate at position 905 in a PPPlRSA polypeptide, a valine at position 264 in a LOCI 66350/DN AJB 11 polypeptide, a threonine at position 117 in a COPE polypeptide, a threonine at position 247 in a KIAA0141 polypeptide, or a glutamate at position 652 in a Fl 3Al polypeptide.

Brief Description of the Figures

[0010] Figures IA-I C show proximal SNPs in a LOC391238 region in genomic DNA for females, males and combined results, respectively. Figures 2A-2C show proximal SNPs in a EIF4G2 region in genomic DNA for females, males and combined results, respectively. Figures 3 A-3C show proximal SNPs in a Region A locus in genomic DNA for females, males and combined results, respectively. Region A contains the rs214140 SNP. A position of each SNP in the chromosome is shown on the x-axis and the y-axis provides the negative logarithm of the p-value comparing the estimated allele allele frequency in the cases to that of the control group. Also shown in the figures are exons and introns of the genes in the approximate chromosomal positions.

Detailed Description

[0011] It has been discovered that polymorphic variants described in Table 1 are associated with occurrence of type II diabetes in subjects. Thus, detecting genetic determinants in and around these loci associated with an increased risk of type II diabetes occurrence can lead to early identification of a risk of type II diabetes and early application of preventative and treatment measures. Also, associating the polymorphic variants with type II diabetes has provided new targets for diagnosing type II diabetes, screening molecules useful in diabetes treatments and diabetes preventatives.

Table 1 includes information pertaining to the incident polymorphic variant associated with type II diabetes identified herein. Public information pertaining to the polymorphism and the genomic sequence that includes the polymorphism are indicated. The genomic sequences identified in Table 1 may be accessed at the http address www.ncbi.nih.gov/entrez/query.fcgi, for example, by using the publicly available SNP reference number {e.g., rs903910). The chromosome position refers to the position of the SNP within NCBI's Genome Build 34, which may be accessed at the following http address: www.ncbi.nhn.nih.gov/mapview/map_search.cgi?chr=hum_chr.inf&query=. The "Contig Position" provided in Table 1 corresponds to a nucleotide position set forth in the contig sequence, and designates the polymorphic site corresponding to the SNP reference number. The sequence containing the polymorphisms also may be referenced by the "Sequence Identification" set forth in Table 1. The "Sequence Identification" corresponds to cDNA sequence that encodes associated target polypeptides (e.g., SKI) of the invention. The "locus" and "locus ID" provide identifiers (e.g. , locus link name and locus link number) for the associated gene. The position of the SNP relative to the gene is provided in the "Sequence Position" column. Also, the allelic variation at the polymorphic site is specified in Table 1. All nucleotide sequences referenced and accessed by the parameters set forth in Table 1 are incorporated herein by reference.

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HI Contiq Accession Number which can be found in the NCBl Database: http address: www.ncbi.nih.gov/entrez/query.fcgi '

T21 Sequence Identification or Nucleotide Accession Number which can be found in the NCBI Database: http address: www.ncbi.nih.gov/enfrez/query.fcgi

Type II Diabetes and Sample Selection

[0012] The term "type II diabetes" as used herein refers to non-insulin-dependent diabetes. Type II diabetes refers to an insulin-related disorder in which there is a relative disparity between endogenous insulin production and insulin requirements, leading to elevated hepatic glucose production, elevated blood glucose levels, inappropriate insulin secretion, and peripheral insulin resistance. Type II diabetes has been regarded as a relatively distinct disease entity, but type II diabetes is often a manifestation of a much broader underlying disorder (Zimmet et al (2001) Nature 414: 782-787), which may include metabolic syndrome (syndrome X), diabetes {e.g., type I diabetes, type II diabetes, gestational diabetes, autoimmune diabetes), hyperinsulinemia, hyperglycemia, impaired glucose tolerance (IGT), hypoglycemia, B-cell failure, insulin resistance, dyslipidemias, atheroma, insulinoma, hypertension, hypercoagulability, microalbuminuria, and obesity and obesity-related disorders such as visceral obesity, central fat, obesity-related type II diabetes, obesity-related atherosclerosis, heart disease, obesity-related insulin resistance, obesity- related hypertension, microangiopathic lesions resulting from obesity-related type II diabetes, ocular lesions caused by microangiopathy in obese individuals with obesity-related type II diabetes, and renal lesions caused by microangiopathy in obese individuals with obesity-related type II diabetes.

[0013] Some of the more common adult onset diabetes symptoms include fatigue, excessive thirst, frequent urination, blurred vision, a high rate of infections, wounds that heal slowly, mood changes and sexual problems. Despite these known symptoms, the onset of type II diabetes is often not discovered by health care professionals until the disease is well developed. Once identified, type II diabetes can be recognized in a patient by measuring fasting plasma glucose levels and/or casual plasma glucose levels, measuring fasting plasma insulin levels and/or casual plasma insulin levels, or administering oral glucose tolerance tests or hyperinsulinemic euglycemic clamp tests.

[0014] Based in part upon selection criteria set forth above, individuals having type II diabetes can be selected for genetic studies. Also, individuals having no history of metabolic disorders, particularly type II diabetes, often are selected for genetic studies as controls. The individuals selected for each pool of case and controls, were chosen following strict selection criteria in order to make the pools as homogenous as possible. Selection criteria for the study described herein included patient age, ethnicity, BMI, GAD (Glutamic Acid Decarboxylase) antibody concentration, and HbAIc (glycosylated hemoglobin AIc) concentration. GAD antibody is present in association with islet cell destruction, and therefore can be utilized to differentiate insulin dependent diabetes (type I diabetes) from non-insulin dependent diabetes (type II diabetes). HbAIc levels will reveal the average blood glucose over a period of 2-3 months or more specifically, over the life span of a red blood cell, by recording the number of glucose molecules attached to hemoglobin. Polymorphic Variants Associated with Type II Diabetes

[0015] A genetic analysis provided herein linked type II diabetes with polymorphic variant nucleic acid sequences in the human genome. As used herein, the term "polymorphic site" refers to a region in a nucleic acid at which two or more alternative nucleotide sequences are observed in a significant number of nucleic acid samples from a population of individuals. A polymorphic site may be a nucleotide sequence of two or more nucleotides, an inserted nucleotide or nucleotide sequence, a deleted nucleotide or nucleotide sequence, or a microsatellite, for example. A polymorphic site that is two or more nucleotides in length may be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more, 20 or more, 30 or more, 50 or more, 75 or more, 100 or more, 500 or more, or about 1000 nucleotides in length, where all or some of the nucleotide sequences differ within the region. A polymorphic site is often one nucleotide in length, which is referred to herein as a "single nucleotide polymorphism" or a "SNP."

[0016] Where there are two, three, or four alternative nucleotide sequences at a polymorphic site, each nucleotide sequence is referred to as a "polymorphic variant" or "nucleic acid variant." Where two polymorphic variants exist, for example, the polymorphic variant represented in a minority of samples from a population is sometimes referred to as a "minor allele" and the polymorphic variant that is more prevalently represented is sometimes referred to as a "major allele." Many organisms possess a copy of each chromosome (e.g., humans), and those individuals who possess two major alleles or two minor alleles are often referred to as being "homozygous" with respect to the polymorphism, and those individuals who possess one major allele and one minor allele are normally referred to as being "heterozygous" with respect to the polymorphism. Individuals who are homozygous with respect to one allele are sometimes predisposed to a different phenotype as compared to individuals who are heterozygous or homozygous with respect to another allele.

[0017] Ih genetic analysis that associate polymorphic variants with type II diabetes, samples from individuals having type II diabetes and individuals not having type II diabetes often are allelotyped and/or genotyped. The term "allelotype" as used herein refers to a process for determining the allele frequency for a polymorphic variant in pooled DNA samples from cases and controls. By pooling DNA from each group, an allele frequency for each SNP in each group is calculated. These allele frequencies are then compared to one another. The term "genotyped" as used herein refers to a process for determining a genotype of one or more individuals, where a "genotype" is a representation of one or more polymorphic variants in a population.

[0018] A genotype or polymorphic variant may be expressed in terms of a "haplotype," which as used herein refers to two or more polymorphic variants occurring within genomic DNA in a group of individuals within a population. For example, two SNPs may exist within a gene where each SNP position includes a cytosine variation and an adenine variation. Certain individuals in a population may carry one allele (heterozygous) or two alleles (homozygous) having the gene with a cytosine at each SNP position. As the two cytosines corresponding to each SNP in the gene travel together on one or both alleles in these individuals, the individuals can be characterized as having a cytosine/cytosine haplotype with respect to the two SNPs in the gene.

[0019] As used herein, the term "phenotype" refers to a trait which can be compared between individuals, such as presence or absence of a condition, a visually observable difference in appearance between individuals, metabolic variations, physiological variations, variations in the function of biological molecules, and the like. An example of a phenotype is occurrence of type II diabetes.

[0020] Researchers sometimes report a polymorphic variant in a database without determining whether the variant is represented in a significant fraction of a population. Because a subset of these reported polymorphic variants are not represented in a statistically significant portion of the population, some of them are sequencing errors and/or not biologically relevant. Thus, it is often not known whether a reported polymorphic variant is statistically significant or biologically relevant until the presence of the variant is detected in a population of individuals and the frequency of the variant is determined. Methods for detecting a polymorphic variant in a population are described herein, specifically in Example 2. A polymorphic variant is statistically significant and often biologically relevant if it is represented in 5% or more of a population, sometimes 10% or more, 15% or more, or 20% or more of a population, and often 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more of a population.

[0021] A polymorphic variant may be detected on either or both strands of a double-stranded nucleic acid. Also, a polymorphic variant may be located within an intron or exon of a gene or within a portion of a regulatory region such as a promoter, a 5 ' untranslated region (UTR), a 3 ' UTR, and in DNA (e.g., genomic DNA (gDNA) and complementary DNA (cDNA)), RNA (e.g., mRNA, tRNA, and rRNA), or a polypeptide. Polymorphic variations may or may not result in detectable differences in gene expression, polypeptide structure, or polypeptide function.

[0022] In certain examples, it was determined that polymorphic variations associated with an increased risk of type II diabetes existed in LOC391238, EIF4G2 and Region A nucleotide sequences. Incident polymorphisms identified in each locus are reported in Table 1, and other polymorphisms associated with type II diabetes were identified in these regions. In the LOC391238 locus, polymorphic variants at positions selected from the group consisting of rs3835246, rs6106927, rs8117966, rs8123888, rs6114827, rs6114828, rs6083586, rsl883926, rs6083587, rs6114829, rs8121573, rs8114991, rsόl 14830, rs6114831, rs6138352, rs6036883, rs6049883, rs6036884, rs6106928, rs6076250, rsόl 14832, rsδl 14833, rs6106929, rsδl 14834, rs6049884, rsβl 14835, rsόl 14836, rsδl 14837, rs6106930, rs6049886, rs6049887, rsβl 14838, rs2424621, rs6049888, rsβl 14839, rs6036886, rsβl 14840, rs6049889, rs608358.8, rs6083589, rs6049890, rs6049891,rs6049892,rs6049893,rs6106932,rs2223829,rs6049895,rs6036887,rs6049896, rs6049897,rs6106933,rs6114841,rsόl14842,rs7351911,rs6036888,rs6076251,rs6083591, rs7345410,rs7363529,rs6515520,rs6515521,rs6049901,rs6515522,rs7344627,rs7345403, rs8183524,rs7353085,rs6083595,rs7343729,rs6049905,rs6076252,rsόl14844,rs2424624, rsβl14845,rsόl14846,rsόl14847,rsβl14848,rs6076253,rs2064435,rs6083596,rs6106935, rs6049906,rs6106936,rs6106937,rs6076254,rs6049907,rs6076255,rs6106938,rs6049908, rs6049909,rs8117631,rs6036892,rs6114850,rs926708,rs8124149,rs2424625,rs6049910, rs6132758,rs6036893,rs2424626,rs7343706,rs6049912,rs6049913,rs7352378,rs7348240, rs7345192,rs2143822,rs7265774,rs8118433,rs7345343,rs2179799,rs2424627,rs6049917, rs6049918,rs6076258,rs6083598,rs2424628,rs6076259,rs6049920,rs6049921,rs926709, rs6138355,rs4815302,rsόl14852,rs6049922,rs6049923,rs6049924,rs6049925,rs6036896, rsόl14853,rs714689,rs2424629,rs910236,rsόl14854,rs2245957,rs6076261,rs910237, rs910238,rs6049926,rs910239,rs910240,rs6049927,rs6049928,rs6049929,rs2424630, rs2424631,rs4239747,rs4239748,rs4239749,rs7273541,rs2424632,rs2424633,rs8125275, rs2424634,rs8125200,rs7273856,rs2424635,rs2424636,rs2424637,rs8120600,rs6132759, rs6049930,rs8114121,rs7260865,rs2424638,rs2424639,rs2424640,rs2424641,rs8114459, rsόl14855,rs2424642,rs2424643,rsόl14856,rsόl14857,rs6049931,rs8116150,rs6049932, rs926710,rs926711,rs2424644,rs2424645,rsόl14858,rs974647,rs4815303,rs6106939, rs6049933,rs4813530,rsόl14859,rs2424646,rs8120183,rs971956,rs971957,rs6036897, rs6049934,rs6049935,rs6049936,rs6049937,rsl883922,rs6049938,rs6049939,rs7360533, rs4815304,rs2424647,rs2424648,rs6138357,rs6076264,rs6076265,rs6076266,rs2424651, rs6036898,rs4813531,rs4813532,rs4815305,rs4815306,rs6049940,rs6049941,rs6049942, rs6083602,rs2424652,rs2424653,rs2424654,rs6049943,rs4239750,rs2424655,rs6132761, rs4546069,rs6083603,rs4398330,rs6049944,rs6049945,rs2424656,rs2424657,rs2424658, rs6036899,rs6083604,rs6083605,rs6049946,rsl569756,rsl007136,rsl474776,rs6076269, rs6049947,rs6036900,rs6049948,rs5841039,rsl007135,rs6106942,rs6138360,rs6049949, rs6049950,rs7271933,rs6114862,rs2424660,rs6049952,rs2424661,rs2424662,rs2253628, rs2424663,rs2424664,rs2424665,rs2424666,rs2424667,rs6138361,rs6049954,rs4815307, rs2424668,rs3085897,rs6138362,rs6138363,rs6138364,rs2424669,rs6083608,rs7345304, rs6049956,rs4813535,rs8118505,rs2424670,rs6076272,rs2424671,rs7345970,rs6138365, rs8184060,rs8184072,rs2424673,rs2424674,rs6049962,rs2424675,rs6106943,rs2424676, rs7265148,rsόl14863,rs7354663,rs2424677,rs5841040,rs6114864,rs2424678,rs6036903, rs6106944,rs910241,rs8123123,rs910242,rsl535065,rsl535066,rs2424679,rs2424680, rs6049963,rs2892219,rs732829,rs6049964,rs6049965,rs6515532,rs2244284,rs2424681, rs2424682,rs6083610,rs2424683,rsόl14865,rs6049966,rsόl14866,rs6076274,rs2424684, rs6083612,rs4815308,rs2424685,rs6138369,rs2424686,rs6049967,rs6138370,rs6132762, rs7264110, rs6076275, rs6132763, rs6138371, rs6138372, rs4815309, rs6132764, rs6083615, rs6083616, rs6049968, rs6036904, rs4813536, rs6138373, «7274381, rs6076276, rs6076277, rs6049969, rs6036905, rs8120681, rs6083617, rs6114867, rs6049970, rs6083618, rs6083619, rsl998153, rsl998154, rs6106945, rsl998155, rsl000044, rsl000043, rsl000042, rs6083620, rs6049971, rs6106946, rs6132765, rs4815311, rs4813537, rs6083621, rs6036906, rs6036907, rs6036908, rs6036909, rsδl 14868, rs7272507, rs7274081, rs6036910, rs4813538, rs4813539, rs226664, rs226665, rs8123361, rs8116690, rs226666, rs6083622, rs6114869, rs73329, rs7270151, rs7272053, rs6138374, rs6114870, rs226667, rs226668, rs6114871, rs226669, rs226670, rs226671, rs6049972, rs6049973, rs226672, rs911173, rs6049974, rs6049975, rs6114872, rs226674, rs4815312, rs3055823, rs226675, rs4588255, rs226676, rs226677, rs226678, rs226679, rs6049976, rs226680, rs2424688 and rs2424689 were tested for association with type II diabetes. Polymorphic variants at the following positions in particular were associated with an increased risk of type II diabetes: rs2223829, rs6515520, rs6515521, rs6076253, rs2064435, rs6049907, rs8117631, rs6049925, rs910237, rs910238, rs2424630, rs2424631, rs2424634, rs8114459, rs974647, rs4813530, rs2424646, rs971957, rsl883922, rs6049941, rs6049944, rs6049945, rsl569756, rs6049948, rs7271933, rs2424661, rs2253628, rs4815307, rs2424669, rs2424670, rs2424671, rs2424675, rs2424678, rs910242, rs2244284, rs6049967, rs6076275, rs6076276, rs6049971, rs6036906, rs4813538, rs4813539, rs226664, rs226665, rs226666, rs226670, rs226672, rs226674, rs226675 and rs4588255. At these positions, a cytosine at position 15272, a thymine at position 18661, a thymine at position 18728, an adenine at position 27493, an adenine at position 27930, a thymine at position 29343, a thymine at position 29808, a guanine at position 40623, an adenine at position 42344, an adenine at position 42388, a cytosine at position 43014, an adenine at position 43088, a guanine at position 43676, a guanine at position 44772, a guanine at position 47592, a thymine at position 48249, a guanine at position 48691, a guanine at position 49454, an adenine at position 50222, a thymine at position 53237, a thymine at position 54675, a thymine at position 54685, an adenine at position 55970, an adenine at position 57748, a guanine at position 59816, a cytosine at position 60783, a thymine at position 60826, an adenine at position 62466, a cytosine at position 63806, a guanine at position 64954, a thymine at position 65110, a guanine at position 68904, a thymine at position 71727, a thymine at position 72328, an adenine at position 75232, a cytosine at position 77073, an adenine at position 77632, a guanine at position 82564, a guanine at position 85770, a thymine at position 86936, a guanine at position 90441, a cytosine at position 90520, an adenine at position 90667, a thymine at position 90983, an adenine at position 91555, a guanine at position 97031, a thymine at position 97358, a thymine at position 97767, a thymine at position 98003, and a cytosine at position 98014 were associated with risk of type II diabetes.

[0023] Ih the EIF4G2 locus, polymorphic variants at positions selected from the group consisting of rs2029892, rs7103192, rs2403370, rs7106206, rs7130566, rs7111238, rs2132518, rs2132519, rs7118054, rs4528318, rs7115107, rs7103582, rs903834, rs4255529, rs7944101, rs7128310, rs3215082, rs7117587, rs4909953, rs3736327, rs4910190, rs7103202, rs3816958, rs2270620, rs2242361, rs2242360, rs7932171, rsl546164, rs7952450, rs7927566, rs3840763, rs7123900, rs7951151, rs2029890, rs2173004, rs2403333, rs4910192, rs7948465, rs7948713, rs6484495, rs7928753, rs7109030, rs7936245, rs7103352, rs7115367, rs7937695, rs963372, rs4910193, rs4910194, rs4910195, rs7106243, rs4910196, rs4910197, rs4910198, rs2132522, «2132521, rsl603397, rs6416069, rs2403335, rs4367939, rs2403336, rs7119484, rs903836, rs903835, rs7120720, rs7931361, rsl908705, rs6484497, rs4910199, rs7117811, rs7114654, rs7125589, rs7125751, rs2687486, rs7947838, rs2644720, rs7933687, rs2088279, rs2687487, rs771379, rs771378, rs811295, rs811294, rs7950234, rs7939447, rs7950378, rs771374, rs771375, rsl016180, rs771376, rs771377, rsll20852, rsl580744, rs7935433, rs2687489, rs2644721, rs903831, rs903832, rs903833, rs755910, rs2644718, rs2644719, rs7931839, rs7925687, rs771371, rs2232929, rs2232928, rs2232927, rs2232926, rs2232925, rs2232924, rs2232923, rs2232922, rs2232921, rs2232920, rs2232919, rs2232918, rs2232917, rs2232916, rsl4229, rsl5752, rs2232915, rs2232914, rs2232913, rs4477433, rs2232912, rs771372, rs771373, rs4397842, rsl980286, rsl980287, rs7106192, rs7109947, rs7126003, rs7950031, rs2403432, rs2091001, rs7125450, rslO47110, rs2403429 and rs2403431 were tested for association with type II diabetes. Polymorphic variants at the following positions in particular were associated with an increased risk of type π diabetes: rs2403370, rs7103582, rs3215082, rs7117587, rs4910190, rs2270620, rs2242361, rs2242360, rs3840763, rs2173004, rs7109030, rs2132521, rs4367939, rs903835, rsl908705, rs4910199, rs2687486, rs2088279, rs771374, rs771375, rsl016180, rs771376, rs903832 and rs2644718. At these positions, a thymine at position 2531, a guanine at position 10272, GA at positions 15106^15107, a cytosine at position 16523, a cytosine at position 18861, a guanine at position 21390, a guanine at position 22915, a thymine at position 23000, TCCT at positions 28358, a cytosine at position 34289, a cytosine at position 38669, a thymine at position 47181, a thymine at position 48578, a thymine at position 49559, an adenine at position 51381, a cytosine at position 53036, a guanine at position 55917, an adenine at position 57307, a cytosine at position 62398, a cytosine at position 63189, a thymine at position 64450, a cytosine at position 64487, a guanine at position 67424, and a guanine at position 68207 were associated with risk of type II diabetes. [0024] In the Region A locus, polymorphic variants at positions selected from the group consisting of rs2223795, rs2206993, rs2344472, rs2880867, rs2344471, rs2143790, rs2143791, rs2880866, rs2344470, rs2344469, rs2344468, rs2344466, rs2344465, rs2344464, rs7757684, rs7740570, rs7763133, rs2206994, rs2223797, rs7769108, rs7746260, rs4710287, rs2344462, rs2344461, rs2880864, rs7451281, rsl591554, rs448006, rsl075170, rsl577639, rsl591553, rsl 832210, rsl 115388, rs2344460, rs450321, rs2206995, rs2206996, rs410069, rs405339, rsl574970, rs432463, rsl932678, rsl932676, rsl77282, rs7452381, rsl855929, rsl77283, rsl577640, rs7740122, rs7769425, rsl336341, rs6927479, rs6927714, rs214140, rs6919904, is214141, rsl932674, rsl932673, rs2223801, rsl855927, rsl855928, rs214143, rs214146, rs2210875, rs7746503, rs2210874, rsl932672, rsl414816, rsl414815, rsl414814, rsl336354, rs958834, rs4598053, rs4472334, rs4472335, rsl932671, rs6910633, rs4710346, rs7769976, rsl414813, rsl414812, rslO41718, rs6902053, rsl336353, rsl953630, rsl953629, rs3904731, rsl932670, rsl932669, rsl577645, rsl577644, rs6926794, rs6903599, rs6908227, rsl953628, rs7746839, rs7758848, rsl577643, rsl591556, rs4407695, rsl932668, rsl577642, rs7770087, rsl336352, rsl336351, rsl336350, rsl336349, rs4569947, rs7764580, rs7744442, rsl932667, rs6913091, rs6913467, rs6455373, rs7381824, rs6455374, rs7383515, rsl414811, rs4710349, rs4710350, rs4710687, rsl414809, rs4710688, rs4710689, rsl414808, rs4710691, rs6908596, rsl360946, rs7751781, rsl932666, rsl932665, rsl932664, rs3056688, rs6912856, rs6936876, rs6937230, rs6937260, rs6913748, rsl577651, rsl577650, rs7747680, rs6453545, rsl577649, rs6903830, rs6917092, rsl855940, rsl855939, rsl855938, rsl855937, rsl855935, rsl855934, rsl855933, rsl577648, rs6940162, rsl577647, rs4443495, rs2344449, rs3056645, rs3056644, rs6928630, rs6915000, rs6915206, rs6929218, rsl932662, rs7454074, rs4524585, rsl932661, rsl336364, rsl336363, rsl336362, rsl537871, rsl537870, rs7776018, rs7776147, rs6921345 and rs6453584 were tested for association with type II diabetes. Polymorphic variants at the following positions in particular were associated with an increased risk of type II diabetes: rs4710287, rs7451281, rsl577639, rs432463, rsl77282, rs214140, rsl336353, rsl591556, rs4407695, rsl336351, rsl932665, rs6929218 and rsl932661. At these positions, an adenine at position 21348, a thymine at position 24092, a cytosine at position 26030, a guanine at position 34364, a cytosine at position 37500, an adenine at position 47872, an adenine at position 68541, an adenine at position 74326, a thymine at position 74353, a cytosine at position 76877, a thymine at position 85675, a thymine at position 93848 and a cytosine at position 95483 were associated with risk of type II diabetes.

[0025] Based in part upon analyses summarized in Figures IA-C, 2A-C and 3A-C, regions with significant association have been identified in loci associated with type II diabetes. Any polymorphic variants associated with type II diabetes in a region of significant association can be utilized for embodiments described herein. The following reports such regions, where "begin" and "end" designate the boundaries of the region according to chromosome positions within NCBFs Genome build 34. The locus, the chromosome on which the locus resides and an incident polymorphism in the locus also are noted.

Additional Polymorphic Variants Associated with Type II Diabetes

[0026] Also provided is a method for identifying polymorphic variants proximal to an incident, founder polymorphic variant associated with type II diabetes. Thus, featured herein are methods for identifying a polymorphic variation associated with type II diabetes that is proximal to an incident polymorphic variation associated with type II diabetes, which comprises identifying a polymorphic variant proximal to the incident polymorphic variant associated with type II diabetes, where the incident polymorphic variant is in a nucleotide sequence set forth in Table 1 or SEQ ID NO: 1-6. The nucleotide sequence often comprises a polynucleotide sequence selected from the group consisting of (a) a polynucleotide sequence set forth in Table 1 or SEQ ID NO: 1-6; (b) a polynucleotide sequence that encodes a polypeptide having an amino acid sequence encoded by a nucleotide sequence set forth in Table 1 or SEQ ID NO: 1-6; and (c) a polynucleotide sequence that encodes a polypeptide having an amino acid sequence that is 90% or more identical to an amino acid sequence encoded by a nucleotide sequence set forth in Table 1 or SEQ ID NO: 1-6 or a polynucleotide sequence 90% or more identical to the polynucleotide sequence set forth in Table 1 or SEQ ID NO: 1-6. The presence or absence of an association of the proximal polymorphic variant with type II diabetes then is determined using a known association method, such as a method described in the Examples hereafter. In an embodiment, the incident polymorphic variant is described in Table 1 or SEQ ID NO: 1-6. In another embodiment, the proximal polymorphic variant identified sometimes is a publicly disclosed polymorphic variant, which for example, sometimes is published in a publicly available database. In other embodiments, the polymorphic variant identified is not publicly disclosed and is discovered using a known method, including, but not limited to, sequencing a region surrounding the incident polymorphic variant in a group of nucleic samples. Thus, multiple polymorphic variants proximal to an incident polymorphic variant are associated with type II diabetes using this method.

[0027] The proximal polymorphic variant often is identified in a region surrounding the incident polymorphic variant. In certain embodiments, this surrounding region is about 50 kb flanking the first polymorphic variant (e.g. about 50 kb 5' of the first polymorphic variant and about 50 kb 3' of the first polymorphic variant), and the region sometimes is composed of shorter flanking sequences, such as flanking sequences of about 40 kb, about 30 kb, about 25 kb, about 20 kb, about 15 kb, about 10 kb, about 7 kb, about 5 kb, or about 2 kb 5' and 3' of the incident polymorphic variant. In other embodiments, the region is composed of longer flanking sequences, such as flanking sequences of about 55 kb, about 60 kb, about 65 kb, about 70 kb, about 75 kb, about 80 kb, about 85 kb, about 90 kb, about 95 kb, or about 100 kb 5' and 3' of the incident polymorphic variant.

[0028] In certain embodiments, polymorphic variants associated with type II diabetes are identified iteratively. For example, a first proximal polymorphic variant is associated with type II diabetes using the methods described above and then another polymorphic variant proximal to the first proximal polymorphic variant is identified (e.g., publicly disclosed or discovered) and the presence or absence of an association of one or more other polymorphic variants proximal to the first proximal polymorphic variant with type II diabetes is determined.

[0029] The methods described herein are useful for identifying or discovering additional polymorphic variants that may be used to further characterize a gene, region or loci associated with a condition, a disease (e.g., type II diabetes), or a disorder. For example, allelotyping or genotyping data from the additional polymorphic variants may be used to identify a functional mutation or a region of linkage disequilibrium. In certain embodiments, polymorphic variants identified or discovered within a region comprising the first polymorphic variant associated with type II diabetes are genotyped using the genetic methods and sample selection techniques described herein, and it can be determined whether those polymorphic variants are in linkage disequilibrium with the first polymorphic variant. The size of the region in linkage disequilibrium with the first polymorphic variant also can be assessed using these genotyping methods. Thus, provided herein are methods for determining whether a polymorphic variant is in linkage disequilibrium with a first polymorphic variant associated with type II diabetes, and such information can be used in prognosis methods described herein.

Isolated Nucleic Acids

[0030] Featured herein are isolated nucleic acid variants depicted in Table 1, and substantially identical nucleic acids thereof. For example, nucleic acids having nucleotide sequences in SEQ ID NO: 1-6 and substantially identical sequences thereof are featured. A nucleic acid variant may be represented on one or both strands in a double-stranded nucleic acid or on one chromosomal complement (heterozygous) or both chromosomal complements (homozygous)).

[0031] As used herein, the term "nucleic acid" includes DNA molecules (e.g. , a complementary DNA (cDNA) and genomic DNA (gDNA)) and RNA molecules (e.g., mRNA, rRNA, siRNA and tRNA) and analogs of DNA or RNA, for example, by use of nucleotide analogs. The nucleic acid molecule can be single-stranded and it is often double-stranded. The term "isolated or purified nucleic acid" refers to nucleic acids that are separated from other nucleic acids present in the natural source of the nucleic acid. For example, with regard to genomic DNA, the term "isolated" includes nucleic acids which are separated from the chromosome with which the genomic DNA is naturally associated. An "isolated" nucleic acid is often free of sequences which naturally flank the nucleic acid {i.e., sequences located at the 5' and/or 3' ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated nucleic acid molecule can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of 5" and/or 3' nucleotide sequences which flank the nucleic acid molecule in genomic DNA of the cell from which the nucleic acid is derived. Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. As used herein, the term "gene" refers to a nucleotide sequence that encodes a polypeptide.

[0032] The nucleic acid often comprises a part of or all of a nucleotide sequence in SEQ ID NO: 1, 2, 3, 4, 5 and/or 6, or a substantially identical sequence thereof. Such a nucleotide sequence sometimes is a 5' and/or 3' sequence flanking a polymorphic variant described above that is 5-10000 nucleotides in length, or in some embodiments 5-5000, 5-1000, 5-500, 5-100, 5-75, 5-50, 5-45, 5- 40, 5-35, 5-30, 5-25 or 5-20 nucleotides in length.

[0033] Also included herein are nucleic acid fragments. These fragments often are a nucleotide sequence identical to a nucleotide sequence set forth in Table 1 or SEQ ID NO: 1-6, a nucleotide sequence substantially identical to a nucleotide sequence set forth in Table 1 or SEQ ID NO: 1-6, or a nucleotide sequence that is complementary to the foregoing. The nucleic acid fragment may be identical, substantially identical or homologous to a nucleotide sequence in an exon or an intron in a nucleotide sequence of Table 1 or SEQ ID NO: 1-6, and may encode a domain or part of a domain of a polypeptide. Sometimes, the fragment will comprises one or more of the polymorphic variations described herein as being associated with type II diabetes. The nucleic acid fragment is often 50, 100, or 200 or fewer base pairs in length, and is sometimes about 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 2000, 3000, 4000, 5000, 10000, 15000, or 20000 base pairs in length. A nucleic acid fragment that is complementary to a nucleotide sequence identical or substantially identical to a nucleotide sequence in Table 1 or SEQ ID NO: 1-6 and hybridizes to such a nucleotide sequence under stringent conditions is often referred to as a "probe." Nucleic acid fragments often include one or more polymorphic sites, or sometimes have an end that is adjacent to a polymorphic site as described hereafter.

[0034] An example of a nucleic acid fragment is an oligonucleotide. As used herein, the term "oligonucleotide" refers to a nucleic acid comprising about 8 to about 50 covalently linked nucleotides, often comprising from about 8 to about 35 nucleotides, and more often from about 10 to about 25 nucleotides. The backbone and nucleotides within an oligonucleotide may be the same as those of naturally occurring nucleic acids, or analogs or derivatives of naturally occurring nucleic acids, provided that oligonucleotides having such analogs or derivatives retain the ability to hybridize specifically to a nucleic acid comprising a targeted polymorphism. Oligonucleotides described herein may be used as hybridization probes or as components of prognostic or diagnostic assays, for example, as described herein.

[0035] Oligonucleotides are typically synthesized using standard methods and equipment, such as the ABF^M3900 High Throughput DNA Synthesizer and the EXPEDITE™ 8909 Nucleic Acid Synthesizer, both of which are available from Applied Biosystems (Foster City, CA). Analogs and derivatives are exemplified in U.S. Pat. Nos. 4,469,863; 5,536,821; 5,541,306; 5,637,683; 5,637,684; 5,700,922; 5,717,083; 5,719,262; 5,739,308; 5,773,601; 5,886,165; 5,929,226; 5,977,296; 6,140,482; WO 00/56746; WO 01/14398, and related publications. Methods for synthesizing oligonucleotides comprising such analogs or derivatives are disclosed, for example, in the patent publications cited above and in U.S. Pat. Nos. 5,614,622; 5,739,314; 5,955,599; 5,962,674; 6,117,992; in WO 00/75372; and in related publications.

[0036] Oligonucleotides may also be linked to a second moiety. The second moiety may be an additional nucleotide sequence such as a tail sequence (e.g., a polyadenosine tail), an adapter sequence (e.g., phage M13 universal tail sequence), and others. Alternatively, the second moiety may be a non-nucleotide moiety such as a moiety which facilitates linkage to a solid support or a label to facilitate detection of the oligonucleotide. Such labels include, without limitation, a radioactive label, a fluorescent label, a chemiluminescent label, a paramagnetic label, and the like. The second moiety may be attached to any position of the oligonucleotide, provided the oligonucleotide can hybridize to the nucleic acid comprising the polymorphism.

Uses for Nucleic Acid Sequence

[0037] Nucleic acid coding sequences depicted in Table 1 may be used for diagnostic purposes for detection and control of polypeptide expression (e.g., nucleotide sequences in SEQ E) NO: 4-6). Also, included herein are oligonucleotide sequences such as antisense RNA, small-interfering RNA (siRNA) and DNA molecules and ribozymes that function to inhibit translation of a polypeptide. Antisense techniques and RNA interference techniques are known in the art and are described herein.

[0038] Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. The mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage. For example, hammerhead motif ribozyme molecules may be engineered that specifically and efficiently catalyze endonucleolytic cleavage of RNA sequences corresponding to or complementary to the nucleotide sequences set forth in Table 1. Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites which include the following sequences, GUA, GUU and GUC. Once identified, short RNA sequences of between fifteen (15) and twenty (20) ribonucleotides corresponding to the region of the target gene containing the cleavage site may be evaluated for predicted structural features such as secondary structure that may render the oligonucleotide sequence unsuitable. The suitability of candidate targets may also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using ribonuclease protection assays.

[0039] Antisense RNA and DNA molecules, siRNA and ribozymes may be prepared by any method known in the art for the synthesis of RNA molecules. These include techniques for chemically synthesizing oligodeoxyribonucleotides well known in the art such as solid phase phosphoramidite chemical synthesis. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding the antisense RNA molecule. Such DNA sequences may be incorporated into a wide variety of vectors which incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters. Alternatively, antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be introduced stably into cell lines.

[0040] DNA encoding a polypeptide also may have a number of uses for the diagnosis of diseases, including type II diabetes, resulting from aberrant expression of a target gene described herein. For example, the nucleic acid sequence may be used in hybridization assays of biopsies or autopsies to diagnose abnormalities of expression or function (e.g., Southern or Northern blot analysis, in situ hybridization assays).

[0041] In addition, the expression of a polypeptide during embryonic development may also be determined using nucleic acid encoding the polypeptide. As addressed, infra, production of functionally impaired polypeptide is the cause of various disease states, such as type II diabetes. In situ hybridizations using polypeptide as a probe may be employed to predict problems related to type II diabetes. Further, as indicated, infra, administration of human active polypeptide, recombinantly produced as described herein, may be used to treat disease states related to functionally impaired polypeptide. Alternatively, gene therapy approaches may be employed to remedy deficiencies of functional polypeptide or to replace or compete with dysfunctional polypeptide.

Expression Vectors, Host Cells, and Genetically Engineered Cells [0042] Provided herein are nucleic acid vectors, often expression vectors, which contain a nucleotide sequence set forth in Table 1 or SEQ ID NO: 1-6 or a substantially identical sequence thereof. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked and can include a plasmid, cosmid, or viral vector. The vector can be capable of autonomous replication or it can integrate into a host DNA. Viral vectors may include replication defective retroviruses, adenoviruses and adeno-associated viruses for example.

[0043] A vector can include a nucleotide sequence from Table 1 or SEQ ID NO: 1-6 in a form suitable for expression of an encoded target polypeptide or target nucleic acid in a host cell. A "target polypeptide" is a polypeptide encoded by a nucleotide sequence from Table 1 or SEQ ID NO: 1-6 or a substantially identical nucleotide sequence thereof. The recombinant expression vector typically includes one or more regulatory sequences operatively linked to the nucleic acid sequence to be expressed. The term "regulatory sequence" includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence, as well as tissue-specific regulatory and/or inducible sequences. The design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of polypeptide desired, and the like. Expression vectors can be introduced into host cells to produce target polypeptides, including fusion polypeptides.

[0044] Recombinant expression vectors can be designed for expression of target polypeptides in prokaryotic or eukaryotic cells. For example, target polypeptides can be expressed in E. coli, insect cells (e.g., using baculovirus expression vectors), yeast cells, or mammalian cells. Suitable host cells are discussed further in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

[0045] Expression of polypeptides in prokaryotes is most often carried out in E. coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion polypeptides. Fusion vectors add a number of amino acids to a polypeptide encoded therein, usually to the amino terminus of the recombinant polypeptide. Such fusion vectors typically serve three purposes: 1) to increase expression of recombinant polypeptide; 2) to increase the solubility of the recombinant polypeptide; and 3) to aid in the purification of the recombinant polypeptide by acting as a ligand in affinity purification. Often, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant polypeptide to enable separation of the recombinant polypeptide from the fusion moiety subsequent to purification of the fusion polypeptide. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokiαase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith & Johnson, Gene 67: 31-40 (1988)), pMAL (New England Biolabs, Beverly, MA) and pRTT5 (Pharmacia, Piscataway, NJ) which fuse glutathione S-transferase (GST), maltose E binding polypeptide, or polypeptide A, respectively, to the target recombinant polypeptide.

[0046] Purified fusion polypeptides can be used in screening assays and to generate antibodies specific for target polypeptides. In a therapeutic embodiment, fusion polypeptide expressed in a retroviral expression vector is used to infect bone marrow cells that are subsequently transplanted into irradiated recipients. The pathology of the subject recipient is then examined after sufficient time has passed (e.g., six (6) weeks).

[0047] Expressing the polypeptide in host bacteria with an impaired capacity to proteolytically cleave the recombinant polypeptide is often used to maximize recombinant polypeptide expression (Gottesman, S., Gene Expression Technology: Methods in Enzymology, Academic Press, San Diego, California 185: 119-128 (1990)). Another strategy is to alter the nucleotide sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (Wada et ah, Nucleic Acids Res. 20: 2111-2118 (1992)). Such alteration of nucleotide sequences can be carried out by standard DNA synthesis techniques.

[0048] When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, Adenovirus 2, cytomegalovirus and Simian Virus 40. Recombinant mammalian expression vectors are often capable of directing expression of the nucleic acid in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Non-limiting examples of suitable tissue-specific promoters include an albumin promoter (liver-specific; Pinkert et al, Genes Dev. 1: 268-277 (1987)), lymphoid-specific promoters (Calame & Eaton, Adv. Immunol. 43: 235-275 (1988)), promoters of T cell receptors (Winoto & Baltimore, EMBOJ. 8: 729-733 (1989)) promoters of immunoglobulins (Banerji et al, Cell 33: 729-740 (1983); Queen & Baltimore, Cell 33: 741-748 (1983)), neuron-specific promoters (e.g., the neurofilament promoter; Byrne & Ruddle, Proc. Natl. Acad. Sci. USA 86: 5473-5477 (1989)), pancreas-specific promoters (Edlund et al, Science 230: 912-916 (1985)), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Patent No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are sometimes utilized, for example, the murine hox promoters (Kessel & Grass, Science 249: 374-379 (1990)) and the α-fetopolypeptide promoter (Campes & Tilghman, Genes Dev. 3: 537-546 (1989)).

[0049] A nucleic acid from Table 1 or SEQ E) NO: 1-6 may also be cloned into an expression vector in an antisense orientation. Regulatory sequences (e.g., viral promoters and/or enhancers) operatively linked to a nucleic acid of Table 1 or SEQ ID NO: 1-6 cloned in the antisense orientation can be chosen for directing constitutive, tissue specific or cell type specific expression of antisense RNA in a variety of cell types. Antisense expression vectors can be in the form of a recombinant plasmid, phagemid or attenuated virus. For a discussion of the regulation of gene expression using antisense genes see, e.g., Weintraub et ah, Antisense RNA as a molecular tool for genetic analysis, Reviews - Trends in Genetics, Vol. 1(1) (1986).

[0050] Also provided herein are host cells that include a nucleotide sequence from Table 1 or SEQ ID NO: 1-6 within a recombinant expression vector or a fragment of a nucleotide sequence from Table 1 or SEQ ID NO: 1-6 which facilitate homologous recombination into a specific site of the host cell genome. The terms "host cell" and "recombinant host cell" are used interchangeably herein. Such terms refer not only to the particular subject cell but rather also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. A host cell can be any prokaryotic or eukaryotic cell. For example, a target polypeptide can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art.

[0051] Vectors can be introduced into host cells via conventional transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid {e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, transduction/infection, DEAE-dextran-mediated transfection, lipofection, or electroporation.

[0052] A host cell provided herein can be used to produce {i.e., express) a target polypeptide or a substantially identical polypeptide thereof. Accordingly, further provided are methods for producing a target polypeptide using host cells described herein. In one embodiment, the method includes culturing host cells into which a recombinant expression vector encoding a target polypeptide has been introduced in a suitable medium such that a target polypeptide is produced. Ih another embodiment, the method further includes isolating a target polypeptide from the medium or the host cell.

[0053] Also provided are cells or purified preparations of cells which include a transgene from Table 1 or SEQ ID NO: 1-6, or which otherwise misexpress target polypeptide. Cell preparations can consist of human or non-human cells, e.g., rodent cells, e.g., mouse or rat cells, rabbit cells, or pig cells. In preferred embodiments, the cell or cells include a transgene from Table 1 or SEQ ID NO: 1-6 (e.g., a heterologous form of a gene in Table 1 or SEQ ID NO: 1-6, such as a human gene expressed in non-human cells). The transgene can be misexpressed, e.g., overexpressed or underexpressed. In other preferred embodiments, the cell or cells include a gene which misexpress an endogenous target polypeptide (e.g., expression of a gene is disrupted, also known as a knockout). Such cells can serve as a model for studying disorders which are related to mutated or mis-expressed alleles or for use in drug screening. Also provided are human cells (e.g., a hematopoietic stem cells) transformed with a nucleic acid from Table 1 or SEQ ID NO: 1-6.

[0054] Also provided are cells or a purified preparation thereof (e.g. , human cells) in which an endogenous nucleic acid from Table 1 or SEQ ID NO: 1-6 is under the control of a regulatory sequence that does not normally control the expression of the endogenous gene corresponding to the sequence from Table 1 or SEQ ID NO: 1-6. The expression characteristics of an endogenous gene within a cell (e.g., a cell line or microorganism) can be modified by inserting a heterologous DNA regulatory element into the genome of the cell such that the inserted regulatory element is operably linked to the corresponding endogenous gene. For example, an endogenous corresponding gene (e.g., a gene which is "transcriptionally silent," not normally expressed, or expressed only at very low levels) may be activated by inserting a regulatory element which is capable of promoting the expression of a normally expressed gene product in that cell. Techniques such as targeted homologous recombinations, can be used to insert the heterologous DNA as described in, e.g., Chappel, US 5,272,071; WO 91/06667, published on May 16, 1991.

Transgenic Animals

[0055] Non-human transgenic animals that express a heterologous target polypeptide (e.g., expressed from a nucleic acid from Table 1 or SEQ ID NO: 1-6 or substantially identical sequence thereof) can be generated. Such animals are useful for studying the function and/or activity of a target polypeptide and for identifying and/or evaluating modulators of the activity of nucleic acids from Table 1 or SEQ ID NO: 1-6 and encoded polypeptides. As used herein, a "transgenic animal" is a non-human animal such as a mammal (e.g., a non-human primate such as chimpanzee, baboon, or macaque; an ungulate such as an equine, bovine, or caprine; or a rodent such as a rat, a mouse, or an Israeli sand rat), a bird (e.g., a chicken or a turkey), an amphibian (e.g., a frog, salamander, or newt), or an insect (e.g., Drosophila melanogaster), in which one or more of the cells of the animal includes a transgene. A transgene is exogenous DNA or a rearrangement (e.g., a deletion of endogenous chromosomal DNA) that is often integrated into or occurs in the genome of cells in a transgenic animal. A transgene can direct expression of an encoded gene product in one or more cell types or tissues of the transgenic animal, and other transgenes can reduce expression (e.g., a knockout). Thus, a transgenic animal can be one in which an endogenous nucleic acid homologous to a nucleic acid from Table 1 or SEQ ID NO: 1-6 has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal (e.g., an embryonic cell of the animal) prior to development of the animal.

[0056] Intronic sequences and polyadenylation signals can also be included in the transgene to increase expression efficiency of the transgene. One or more tissue-specific regulatory sequences can be operably linked to a nucleotide sequence of Table 1 or SEQ ID NO: 1-6 to direct expression of an encoded polypeptide to particular cells. A transgenic founder animal can be identified based upon the presence of a nucleotide sequence from Table 1 or SEQ ID NO: 1-6 in its genome and/or expression of encoded mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a nucleotide sequence from Table 1 or SEQ ID NO: 1-6 can further be bred to other transgenic animals carrying other transgenes.

[0057] Target polypeptides can be expressed in transgenic animals or plants by introducing, for example, a nucleic acid from Table 1 or SEQ ID NO: 1-6 into the genome of an animal that encodes the target polypeptide. In preferred embodiments the nucleic acid is placed under the control of a tissue specific promoter, e.g., a milk or egg specific promoter, and recovered from the milk or eggs produced by the animal. Also included is a population of cells from a transgenic animal.

Target Polypeptides

[0058] Also featured herein are isolated target polypeptides, which are encoded by a nucleotide sequence from Table 1 or SEQ ID NO: 1-6 or a substantially identical nucleotide sequence thereof. Examples of target polypeptide amino acid sequences are shown in SEQ ID NO: 7-9. The term "polypeptide" as used herein includes proteins and peptides. An "isolated" or "purified" polypeptide or protein is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. In one embodiment, the language "substantially free" means preparation of a target polypeptide having less than about 30%, 20%, 10% and more preferably 5% (by dry weight), of non-target polypeptide (also referred to herein as a "contaminating protein"), or of chemical precursors or non-target chemicals. When the target polypeptide or a biologically active portion thereof is recombinantly produced, it is also preferably substantially free of culture medium, specifically, where culture medium represents less than about 20%, sometimes less than about 10%, and often less than about 5% of the volume of the polypeptide preparation. Isolated or purified target polypeptide preparations are sometimes 0.01 milligrams or more or 0.1 milligrams or more, and often 1.0 milligrams or more and 10 milligrams or more in dry weight.

[0059] Further included herein are target polypeptide fragments. The polypeptide fragment may be a domain or part of a domain of a target polypeptide. The polypeptide fragment may have increased, decreased or unexpected biological activity. The polypeptide fragment is often 50 or fewer, 100 or fewer, or 200 or fewer amino acids in length, and is sometimes 300, 400, 500, 600, 700, or 900 or fewer amino acids in length. [0060] Substantially identical target polypeptides may depart from the amino acid sequences of target polypeptides in different manners. For example, conservative amino acid modifications may be introduced at one or more positions in the amino acid sequences of target polypeptides. A "conservative amino acid substitution" is one in which the amino acid is replaced by another amino acid having a similar structure and/or chemical function. Families of amino acid residues having similar structures and functions are well known. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Also, essential and non-essential amino acids may be replaced. A "non-essential" amino acid is one that can be altered without abolishing or substantially altering the biological function of a target polypeptide, whereas altering an "essential" amino acid abolishes or substantially alters the biological function of a target polypeptide. Amino acids that are conserved among target polypeptides are typically essential amino acids.

[0061] Also, target polypeptides may exist as chimeric or fusion polypeptides. As used herein, a target "chimeric polypeptide" or target "fusion polypeptide" includes a target polypeptide linked to a non-target polypeptide. A "non-target polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a polypeptide which is not substantially identical to the target polypeptide, which includes, for example, a polypeptide that is different from the target polypeptide and derived from the same or a different organism. The target polypeptide in the fusion polypeptide can correspond to an entire or nearly entire target polypeptide or a fragment thereof. The non-target polypeptide can be fused to the N-terminus or C-terminus of the target polypeptide.

[0062] Fusion polypeptides can include a moiety having high affinity for a ligand. For example, the fusion polypeptide can be a GST-target fusion polypeptide in which the target sequences are fused to the C-terminus of the GST sequences, or a polyhistidine-target fusion polypeptide in which the target polypeptide is fused at the N- or C-terminus to a string of histidine residues. Such fusion polypeptides can facilitate purification of recombinant target polypeptide. Expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide), and a nucleotide sequence from Table 1 or SEQ TD NO: 1-6, or a substantially identical nucleotide sequence thereof, can be cloned into an expression vector such that the fusion moiety is linked in-frame to the target polypeptide. Further, the fusion polypeptide can be a target polypeptide containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression, secretion, cellular internalization, and cellular localization of a target polypeptide can be increased through use of a heterologous signal sequence. Fusion polypeptides can also include all or a part of a serum polypeptide (e.g., an IgG constant region or human serum albumin).

[0063] Target polypeptides can be incorporated into pharmaceutical compositions and administered to a subject in vivo. Administration of these target polypeptides can be used to affect the bioavailability of a substrate of the target polypeptide and may effectively increase target polypeptide biological activity in a cell. Target fusion polypeptides may be useful therapeutically for the treatment of disorders caused by, for example, (i) aberrant modification or mutation of a gene encoding a target polypeptide; (ii) mis-regulation of the gene encoding the target polypeptide; and (iii) aberrant post-translational modification of a target polypeptide. Also, target polypeptides can be used as immunogens to produce anti-target antibodies in a subject, to purify target polypeptide ligands or binding partners, and in screening assays to identify molecules which inhibit or enhance the interaction of a target polypeptide with a substrate.

[0064] In addition, polypeptides can be chemically synthesized using techniques known in the art (See, e.g., Creighton, 1983 Proteins. New York, N. Y.: W. H. Freeman and Company; and Hunkapiller et at, (1984) Nature July 12 -18;310(5973):105-l 1). For example, a relative short fragment can be synthesized by use of a peptide synthesizer. Furthermore, if desired, nonclassical amino acids or chemical amino acid analogs can be introduced as a substitution or addition into the fragment sequence. Non-classical amino acids include, but are not limited to, to the D-isomers of the common amino acids, 2,4-diaminobutyric acid, a-amino isobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, g-Abu, e-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3- amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, b- alanine, fluoroamino acids, designer amino acids such as b-methyl amino acids, Ca-methyl amino acids, Na-methyl amino acids, and amino acid analogs in general. Furthermore, the amino acid can be D (dextrorotary) or L (levorotary).

[0065] Polypeptides and polypeptide fragments sometimes are differentially modified during or after translation, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any of numerous chemical modifications may be carried out by known techniques, including but not limited, to specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH4; acetylation, formylation, oxidation, reduction; metabolic synthesis in the presence of tunicamycin; and the like. Additional post-translational modifications include, for example, N-linked or 0-linked carbohydrate chains, processing of N- terminal or C-terminal ends), attachment of chemical moieties to the amino acid backbone, chemical modifications of N-linked or O-linked carbohydrate chains, and addition or deletion of an N-terminal methionine residue as a result of prokaryotic host cell expression. The polypeptide fragments may also be modified with a detectable label, such as an enzymatic, fluorescent, isotopic or affinity label to allow for detection and isolation of the polypeptide.

[0066] Also provided are chemically modified derivatives of polypeptides that can provide additional advantages such as increased solubility, stability and circulating time of the polypeptide, or decreased immunogenicity (see e.g., U.S. Pat. No: 4,179,337). The chemical moieties for derivitization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like. The polypeptides may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three or more attached chemical moieties.

[0067] The polymer may be of any molecular weight, and may be branched or unbranched. For polyethylene glycol, the preferred molecular weight is between about 1 kDa and about 100 kDa (the term "about" indicating that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight) for ease in handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (e.g. , the duration of sustained release desired, the effects, if any on biological activity, the ease in handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a therapeutic protein or analog).

[0068] The polymers should be attached to the polypeptide with consideration of effects on . functional or antigenic domains of the polypeptide. There are a number of attachment methods available to those skilled in the art (e.g., EP 0 401 384 (coupling PEG to G-CSF) and Malik et al. (1992) Exp Hematol. September;20(8): 1028-35 (pegylation of GM-CSF using tresyl chloride)). For example, polyethylene glycol may be covalently bound through amino acid residues via a reactive group, such as a free amino or carboxyl group. Reactive groups are those to which an activated polyethylene glycol molecule may be bound. The amino acid residues having a free amino group may include lysine residues and the N-terminal amino acid residues; those having a free carboxyl group may include aspartic acid residues, glutamic acid residues and the C-terminal amino acid residue. Sulfhydryl groups may also be used as a reactive group for attaching the polyethylene glycol molecules. For therapeutic purposes, the attachment sometimes is at an amino group, such as attachment at the N-terminus or lysine group.

[0069] Proteins can be chemically modified at the N-terminus. Using polyethylene glycol as an illustration of such a composition, one may select from a variety of polyethylene glycol molecules (by molecular weight, branching, and the like), the proportion of polyethylene glycol molecules to protein (polypeptide) molecules in the reaction mix, the type of pegylation reaction to be performed, and the method of obtaining the selected N-terminally pegylated protein. The method of obtaining the N-terminally pegylated preparation (i.e., separating this moiety from other monopegylated moieties if necessary) may be by purification of the N-terminally pegylated material from a population of pegylated protein molecules. Selective proteins chemically modified at the N- terminus may be accomplished by reductive alkylation, which exploits differential reactivity of different types of primary amino groups (lysine versus the N-teπninal) available for derivatization in a particular protein. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved.

Substantially Identical Nucleic Acids and Polypeptides

[0070] Nucleotide sequences and polypeptide sequences that are substantially identical to the nucleotide sequences in Table 1 or SEQ ID NO: 1-6 and the target polypeptide sequences encoded by those nucleotide sequences, respectively, are included herein. The term "substantially identical" as used herein refers to two or more nucleic acids or polypeptides sharing one or more identical nucleotide sequences or polypeptide sequences, respectively. Included are nucleotide sequences or polypeptide sequences that are 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more (each often within a 1%, 2%, 3% or 4% variability) identical to the nucleotide sequences in Table 1 or SEQ ID NO: 1-6 or the encoded target polypeptide amino acid sequences. One test for determining whether two nucleic acids are substantially identical is to determine the percent of identical nucleotide sequences or polypeptide sequences shared between the nucleic acids or polypeptides. -

[0071] Calculations of sequence identity are often performed as follows. Sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). The length of a reference sequence aligned for comparison purposes is sometimes 30% or more, 40% or more, 50% or more, often 60% or more, and more often 70% or more, 80% or more, 90% or more, or 100% of the length of the reference sequence. The nucleotides or amino acids at corresponding nucleotide or polypeptide positions, respectively, are then compared among the two sequences. When a position in the first sequence is occupied by the same nucleotide or amino acid as the corresponding position in the second sequence, the nucleotides or amino acids are deemed to be identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, introduced for optimal alignment of the two sequences.

[0072] Comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. Percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of Meyers & Miller, CABIOS 4: 11-17 (1989), which has been incorporated into the ALIGN program (version 2.0), using a PAMl 20 weight residue table, a gap length penalty of 12 and a gap penalty of 4. Also, percent identity between two amino acid sequences can be determined using the Needleman & Wunsch, J. MoI. Biol. 48: 444-453 (1970) algorithm which has been incorporated into the GAP program in the GCG software package (available at the http address www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. Percent identity between two nucleotide sequences can be determined using the GAP program in the GCG software package (available at http address www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A set of parameters often used is a Blossum 62 scoring matrix with a gap open penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

[0073] Another manner for determining if two nucleic acids are substantially identical is to assess whether a polynucleotide homologous to one nucleic acid will hybridize to the other nucleic acid under stringent conditions. As use herein, the term "stringent conditions" refers to conditions for hybridization and washing. Stringent conditions are known to those skilled in the art and can be found in Current Protocols in Molecular Biology ; John Wiley & Sons, N. Y. , 6.3.1-6.3.6 (1989). Aqueous and non-aqueous methods are described in that reference and either can be used. An example of stringent hybridization conditions is hybridization in 6X sodium chloride/sodium citrate (SSC) at about 45⁰C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 50⁰C. Another example of stringent hybridization conditions are hybridization in 6X sodium chloride/sodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 55°C. A further example of stringent hybridization conditions is hybridization in 6X sodium chloride/sodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 60⁰C. Often, stringent hybridization conditions are hybridization in 6X sodium chloride/sodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 65°C. More often, stringency conditions are 0.5M sodium phosphate, 7% SDS at 65°C, followed by one or more washes at 0.2X SSC, 1% SDS at 65°C.

[0074] An example of a substantially identical nucleotide sequence to a nucleotide sequence in Table 1 or SEQ ID NO: 1-6 is one that has a different nucleotide sequence but still encodes the same polypeptide sequence encoded by the nucleotide sequence in Table 1 or SEQ ID NO: 1-6. Another example is a nucleotide sequence that encodes a polypeptide having a polypeptide sequence that is more than 70% or more identical to, sometimes more than 75% or more, 80% or more, or 85% or more identical to, and often more than 90% or more and 95% or more identical to a polypeptide sequence encoded by a nucleotide sequence in Table 1 or SEQ ID NO: 1-6. As used herein, "SEQ ID NO: 1-6" typically refers to one, or more sequences in SEQ ID NO: 1, 2, 3, 4, 5 and/or 6. Many of the embodiments described herein are applicable to (a) a nucleotide sequence of SEQ ID NO: 1-6; (b) a nucleotide sequence which encodes a polypeptide consisting of an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO: 1-6; (c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO: 1-6, or a nucleotide sequence about 90% or more identical to a nucleotide sequence of SEQ ID NO: 1 -6; (d) a fragment of a nucleotide sequence of (a), (b), or (c); and/or a nucleotide sequence complementary to the nucleotide sequences of (a), (b), (c) and/or (d), where nucleotide sequences of (b) and (c), fragments of (b) and (c) and nucleotide sequences complementary to (b) and (c) are examples of substantially identical nucleotide sequences. Examples of substantially identical nucleotide sequences include nucleotide sequences from subjects that differ by naturally occurring genetic variance, which sometimes is referred to as background genetic variance (e.g., nucleotide sequences differing by natural genetic variance sometimes are 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one another).

[0075] Nucleotide sequences from Table 1 or SEQ ID NO: 1-6 and amino acid sequences of encoded polypeptides can be used as "query sequences" to perform a search against public databases to identify other family members or related sequences, for example. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul et ah, J. MoI. Biol. 215: 403-10 (1990). BLAST nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to nucleotide sequences from Table 1 or SEQ ID NO: 1-6. BLAST polypeptide searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to polypeptides encoded by the nucleotide sequences of Table 1 or SEQ ID NO: 1-6. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et ah, Nucleic Acids Res. 25(17): 3389-3402 (1997). When utilizing BLAST and Gapped BLAST programs, default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used (see the http address www.ncbi.nhn.nih.gov).

[0076] A nucleic acid that is substantially identical to a nucleotide sequence in Table 1 or SEQ ID NO: 1-6 may include polymorphic sites at positions equivalent to those described herein when the sequences are aligned. For example, using the alignment procedures described herein, SNPs in a sequence substantially identical to a sequence in Table 1 or SEQ ID NO: 1-6 can be identified at nucleotide positions that match with or correspond to (i.e., align with) nucleotides at SNP positions in each nucleotide sequence in Table 1 or SEQ DD NO: 1-6. Also, where a polymorphic variation results in an insertion or deletion, insertion or deletion of a nucleotide sequence from a reference sequence can change the relative positions of other polymorphic sites in the nucleotide sequence.

[0077] Substantially identical nucleotide and polypeptide sequences include those that are naturally occurring, such as allelic variants (same locus), splice variants, homologs (different locus), and orthologs (different organism) or can be non-naturally occurring. Non-naturally occurring variants can be generated by mutagenesis techniques, including those applied to polynucleotides, cells, or organisms. The variants can contain nucleotide substitutions, deletions, inversions and insertions. Variation can occur in either or both the coding and non-coding regions. The variations can produce both conservative and non-conservative amino acid substitutions (as compared in the encoded product). Orthologs, homologs, allelic variants, and splice variants can be identified using methods known in the art. These variants normally comprise a nucleotide sequence encoding a polypeptide that is 50% or more, about 55% or more, often about 70-75% or more or about 80-85% or more, and sometimes about 90-95% or more identical to the amino acid sequences of target polypeptides or a fragment thereof. Such nucleic acid molecules can readily be identified as being able to hybridize under stringent conditions to a nucleotide sequence in Table 1 or SEQ ID NO: 1-6 or a fragment of this sequence. Nucleic acid molecules corresponding to orthologs, homologs, and allelic variants of a nucleotide sequence in Table 1 or SEQ ID NO: 1-6 can further be identified by mapping the sequence to the same chromosome or locus as the nucleotide sequence in Table 1 or SEQ ID NO: 1-6.

[0078] Also, substantially identical nucleotide sequences may include codons that are altered with respect to the naturally occurring sequence for enhancing expression of a target polypeptide in a particular expression system. For example, the nucleic acid can be one in which one or more codons are altered, and often 10% or more or 20% or more of the codons are altered for optimized expression in bacteria {e.g., E. coli), yeast {e.g., S. cervesiae), human {e.g., 293 cells), insect, or rodent {e.g., hamster) cells.

Methods for Identifying Subjects at Risk of Diabetes and Risk of Diabetes in a Subject [0079] Methods for prognosing and diagnosing type II diabetes, its related disorders {e.g., metabolic disorders, syndrome X, obesity, insulin resistance, hyperglycemia) are included herein. These methods include detecting the presence or absence of one or more polymorphic variations in a nucleotide sequence associated with type II diabetes, such as variants in or around the loci set forth in Table 1 or SEQ ID NO: 1-6, or a substantially identical sequence thereof, in a sample from a subject, where the presence of a polymorphic variant described herein is indicative of a risk of type II diabetes or one or more type II diabetes related disorders {e.g., metabolic disorders, syndrome X, obesity, insulin resistance, hyperglycemia). Determining a risk of type II diabetes refers to determining whether an individual is at an increased risk of type II diabetes {e.g., intermediate risk or higher risk).

[0080] Thus, featured herein is a method for identifying a subject who is at risk of type II diabetes, which comprises detecting an type II diabetes-associated aberration in a nucleic acid sample from the subject. An embodiment is a method for detecting a predisposition to type II diabetes in a subject, which comprises detecting the presence or absence of a polymorphic variation associated with type II diabetes at a polymorphic site in a nucleotide sequence in a nucleic acid sample from a subject, where the nucleotide sequence comprises a polynucleotide sequence selected from the group consisting of: (a) a nucleotide sequence set forth in Table 1 or SEQ ED NO: 1-6; (V) a nucleotide sequence which encodes a polypeptide consisting of an amino acid sequence described in Table 1 or SEQ ID NO: 1-6; (c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to an amino acid sequence described in Table 1 or SEQ ID NO: 1-6, or a nucleotide sequence about 90% or more identical to the nucleotide sequence set forth, in Table 1 or SEQ ID NO: 1-6; and (d) a fragment of a nucleotide sequence of (a), (b), or (c) comprising the polymorphic site; whereby the presence of the polymorphic variation is indicative of a predisposition to type II diabetes in the subject. In certain embodiments, polymorphic variants at the positions described in Table 1 or SEQ ID NO: 1-6 are detected for determining a risk of type II diabetes, and polymorphic variants at positions in linkage disequilibrium with these positions are detected for determining a risk of type II diabetes.

[0081] Results from prognostic tests may be combined with other test results to diagnose type II diabetes related disorders, including metabolic disorders, syndrome X, obesity, insulin resistance, hyperglycemia. For example, prognostic results may be gathered, a patient sample may be ordered based on a determined predisposition to type II diabetes, the patient sample is analyzed, and the results of the analysis may be utilized to diagnose the type II diabetes related condition (e.g., metabolic disorders, syndrome X, obesity, insulin resistance, hyperglycemia). Also type II diabetes diagnostic methods can be developed from studies used to generate prognostic methods in which populations are stratified into subpopulations having different progressions of a type II diabetes related disorder or condition. In another embodiment, prognostic results may be gathered, a patient's risk factors for developing type II diabetes (e.g., age, weight, race, diet) analyzed, and a patient sample may be ordered based on a determined predisposition to type II diabetes.

[0082] Risk of type II diabetes sometimes is expressed as a probability, such as an odds ratio, percentage, or risk factor. The predisposition is based upon the presence or absence of one or more polymorphic variants described herein, and also may be based in part upon phenotypic traits of the individual being tested. Methods for calculating predispositions based upon patient data are well known (see, e.g., Agresti, Categorical Data Analysis, 2nd Ed. 2002. Wiley). Allelotyping and genotyping analyses may be carried out in populations other than those exemplified herein to enhance the predictive power of the prognostic method. These further analyses are executed in view of the exemplified procedures described herein, and may be based upon the same polymorphic variations or additional polymorphic variations. In one embodiment, type II diabetes risk determinations are used by clinicians to direct appropriate detection, preventative and treatment procedures to subjects who most require these. In another embodiment, type II diabetes risk determinations are used by health insurers for preparing actuarial tables and for calculating insurance premiums.

[0083] The nucleic acid sample typically is isolated from a biological sample obtained from a subject. For example, nucleic acid can be isolated from blood, saliva, sputum, urine, cell scrapings, and biopsy tissue. The nucleic acid sample can be isolated from a biological sample using standard techniques, such as the technique described in Example 2. As used herein, the term "subject" refers primarily to humans but also refers to other mammals such as dogs, cats, and ungulates (e.g., cattle, sheep, and swine). Subjects also include avians (e.g., chickens and turkeys), reptiles, and fish (e.g., salmon), as embodiments described herein can be adapted to nucleic acid samples isolated from any of these organisms. The nucleic acid sample may be isolated from the subject and then directly utilized in a method for determining the presence of a polymorphic variant, or alternatively, the sample may be isolated and then stored (e.g., frozen) for a period of time before being subjected to analysis.

[0084] The presence or absence of a polymorphic variant is determined using one or both chromosomal complements represented in the nucleic acid sample. Determining the presence or absence of a polymorphic variant in both chromosomal complements represented in a nucleic,- acid sample from a subject having a copy of each chromosome is useful for determining the zygosity of an individual for the polymorphic variant (i.e., whether the individual is homozygous or heterozygous for the polymorphic variant). Any oligonucleotide-based diagnostic may be utilized to determine whether a sample includes the presence or absence of a polymorphic variant in a sample. For example, primer extension methods, ligase sequence determination methods (e.g., U.S. Pat. Nos. 5,679,524 and 5,952,174, and WO 01/27326), mismatch, sequence determination methods (e.g., U.S. Pat. Nos. 5,851,770; 5,958,692; 6,110,684; and 6,183,958), microarray sequence determination methods, restriction fragment length polymorphism (RFLP), single strand conformation polymorphism detection (SSCP) (e.g., U.S. Pat. Nos. 5,891,625 and 6,013,499), PCR- based assays (e.g., TAQMAN^® PCR System (Applied Biosystems)), and nucleotide sequencing methods may be used.

[0085] Oligonucleotide extension methods typically involve providing a pair of oligonucleotide primers in a polymerase chain reaction (PCR) or in other nucleic acid amplification methods for the purpose of amplifying a region from the nucleic acid sample that comprises the polymorphic variation. One oligonucleotide primer is complementary to a region 3' of the polymorphism and the other is complementary to a region 5' of the polymorphism. A PCR primer pair may be used in methods disclosed in U.S. Pat. Nos. 4,683,195; 4,683,202, 4,965,188; 5,656,493; 5,998,143; 6,140,054; WO 01/27327; and WO 01/27329 for example. PCR primer pairs may also be used in any commercially available machines that perform PCR, such as any of the GENEAMP^® Systems available from Applied Biosystems. Also, those of ordinary skill in the art will be able to design oligonucleotide primers based upon a nucleotide sequence set forth in Table 1 or SEQ ID NO: 1-6 using knowledge available in the art.

[0086] Also provided is an extension oligonucleotide that hybridizes to the amplified fragment adjacent to the polymorphic variation. As used herein, the term "adjacent" refers to the 3' end of the extension oligonucleotide being often 1 nucleotide from the 5' end of the polymorphic site, and sometimes 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the 5' end of the polymorphic site, in the nucleic acid when the extension oligonucleotide is hybridized to the nucleic acid. The extension oligonucleotide then is extended by one or more nucleotides, and the number and/or type of nucleotides that are added to the extension oligonucleotide determine whether the polymorphic variant is present. Oligonucleotide extension methods are disclosed, for example, in U.S. Pat. Nos. 4,656,127; 4,851,331; 5,679,524; 5,834,189; 5,876,934; 5,908,755; 5,912,118; 5,976,802; 5,981,186; 6,004,744; 6,013,431; 6,017,702; 6,046,005; 6,087,095; 6,210,891; and WO 01/20039. Oligonucleotide extension methods using mass spectrometry are described, for example, in U.S. Pat. Nos. 5,547,835; 5,605,798; 5,691,141; 5,849,542; 5,869,242; 5,928,906; 6,043,031; and 6,194,144, and a method often utilized is described herein in Example 2.

[0087] A microarray can be utilized for determining whether a polymorphic variant is present or absent in a nucleic acid sample. A microarray may include any oligonucleotides described herein, and methods for making and using oligonucleotide microarrays suitable for diagnostic use are disclosed in U.S. Pat. Nos. 5,492,806; 5,525,464; 5,589,330; 5,695,940; 5,849,483; 6,018,041; 6,045,996; 6,136,541; 6,142,681; 6,156,501; 6,197,506; 6,223,127; 6,225,625; 6,229,911; 6,239,273; WO 00/52625; WO 01/25485; and WO 01/29259. The microarray typically comprises a solid support and the oligonucleotides may be linked to this solid support by covalent bonds or by non-covalent interactions. The oligonucleotides may also be linked to the solid support directly or by a spacer molecule. A microarray may comprise one or more oligonucleotides complementary to a polymorphic site set forth in Table 1 or SEQ ID NO: 1-6.

[0088] A kit also may be utilized for determining whether a polymorphic variant is present or absent in a nucleic acid sample. A kit often comprises one or more pairs of oligonucleotide primers useful for amplifying a fragment of a sequence set forth in Table 1 or SEQ ID NO: 1-6 or a substantially identical sequence thereof, where the fragment includes a polymorphic site. The kit sometimes comprises a polymerizing agent, for example, a thermostable nucleic acid polymerase such as one disclosed in U.S. Pat. Nos. 4,889,818 or 6,077,664. Also, the kit often comprises an elongation oligonucleotide that hybridizes to a nucleic acid set forth in Table 1 or SEQ ID NO: 1-6 in a nucleic acid sample adjacent to the polymorphic site. Where the kit includes an elongation oligonucleotide, it also often comprises chain elongating nucleotides, such as dATP, dTTP, dGTP, dCTP, and dITP, including analogs of dATP, dTTP, dGTP, dCTP and dITP, provided that such analogs are substrates for a thermostable nucleic acid polymerase and can be incorporated into a nucleic acid chain elongated from the extension oligonucleotide. Along with chain elongating nucleotides would be one or more chain terminating nucleotides such as ddATP, ddTTP, ddGTP, ddCTP, and the like. In an embodiment, the kit comprises one or more oligonucleotide primer pairs, a polymerizing agent, chain elongating nucleotides, at least one elongation oligonucleotide, and one or more chain terminating nucleotides. Kits optionally include buffers, vials, microtiter plates, and instructions for use.

[0089] An individual identified as being at risk of type II diabetes may be heterozygous or homozygous with respect to the allele associated with a higher risk of type II diabetes. A subject homozygous for an allele associated with an increased risk of type II diabetes is at a comparatively high risk of type II diabetes, a subject heterozygous for an allele associated with an increased risk of type π diabetes is at a comparatively intermediate risk of type II diabetes, and a subject homozygous for an allele associated with a decreased risk of type II diabetes is at a comparatively low risk of type II diabetes. A genotype may be assessed for a complementary strand, such that the complementary nucleotide at a particular position is detected.

[0090] Also featured are methods for determining risk of type II diabetes and/or identifying a subject at risk of type II diabetes by contacting a polypeptide or protein encoded by a nucleotide sequence in Table 1 or SEQ ID NO: 1-6 from a subject with an antibody that specifically binds to an epitope associated with increased risk of type II diabetes in the polypeptide. In certain embodiments, the antibody specifically binds to an epitope that comprises an alanine or valine at position 580 in a PIGR polypeptide, a valine or isoleucine at position 264 in a LOC166350/DNAJB11 polypeptide, a threonine or alanine at position 247 in a KIAA0141 polypeptide, a glutamic acid or glutamine at position 652 in a Fl 3Al polypeptide, an aspartic acid or tyrosine at position 905 in a PPP1R3A polypeptide, an alanine or threonine at position 435 in a C 14orfl 31 polypeptide, or an isoleucine or threonine at position 117 in a COPE polypeptide.

Applications of Prognostic and Diagnostic Results to Pharmacogenomic Methods [0091] Pharmacogenomics is a discipline that involves tailoring a treatment for a subject according to the subject's genotype as a particular treatment regimen may exert a differential effect depending upon the subject's genotype. For example, based upon the outcome of a prognostic test described herein, a clinician or physician may target pertinent information and preventative or therapeutic treatments to a subject who would be benefited by the information or treatment and avoid directing such information and treatments to a subject who would not be benefited {e.g., the treatment has no therapeutic effect and/or the subject experiences adverse side effects).

[0092] The following is an example of a pharmacogenomic embodiment. A particular treatment regimen can exert a differential effect depending upon the subject's genotype. Where a candidate therapeutic exhibits a significant interaction with a major allele and a comparatively weak interaction with a minor allele (e.g., an order of magnitude or greater difference in the interaction), such a therapeutic typically would not be administered to a subject genotyped as being homozygous for the minor allele, and sometimes not administered to a subject genotyped as being heterozygous for the minor allele. In another example, where a candidate therapeutic is not significantly toxic when administered to subjects who are homozygous for a major allele but is comparatively toxic when administered to subjects heterozygous or homozygous for a minor allele, the candidate therapeutic is not typically administered to subjects who are genotyped as being heterozygous or homozygous with respect to the minor allele.

[0093] The methods described herein are applicable to pharmacogenomic methods for preventing, alleviating or treating type II diabetes conditions such as metabolic disorders, syndrome X, obesity, insulin resistance, hyperglycemia, or hypertension. For example, a nucleic acid sample from an individual may be subjected to a prognostic test described herein. Where one or more polymorphic variations associated with increased risk of type II diabetes are identified in a subject, information for preventing or treating type II diabetes and/or one or more type II diabetes treatment regimens then may be prescribed to that subject.

[0094] In certain embodiments, a treatment or preventative regimen is specifically prescribed and/or administered to individuals who will most benefit from it based upon their risk of developing type II diabetes assessed by the prognostic methods described herein. Thus, provided are methods for identifying a subject predisposed to type II diabetes and then prescribing a therapeutic or preventative regimen to individuals identified as having a predisposition. Thus, certain embodiments are directed to a method for reducing type II diabetes in a subject, which comprises: detecting the presence or absence of a polymorphic variant associated with type II diabetes in a nucleotide sequence set forth herein in a nucleic acid sample from a subject, where the nucleotide sequence comprises a polynucleotide sequence selected from the group consisting of: (a) a nucleotide sequence set forth in Table 1 or SEQ ID NO: 1-6; (b) a nucleotide sequence which encodes a polypeptide consisting of an amino acid sequence described in Table 1 or SEQ ID NO: 1- 6; (c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to an amino acid sequence described in Table 1 or SEQ ID NO: 1-6, or a nucleotide sequence about 90% or more identical to the nucleotide sequence set forth in Table 1 or SEQ ID NO: 1-6; and (d) a fragment of a polynucleotide sequence of (a), (b), or (c); and prescribing or administering a treatment regimen to a subject from whom the sample originated where the presence of a polymorphic variation associated with type II diabetes is detected in the nucleotide sequence. In these methods, predisposition results may be utilized in combination with other test results to diagnose type II diabetes associated conditions, such as metabolic disorders, syndrome X, obesity, insulin resistance, hyperglycemia or hypertension. [0095] Certain preventative treatments often are prescribed to subjects having a predisposition to type II diabetes and where the subject is diagnosed with type II diabetes or is diagnosed as having symptoms indicative of early stage type II diabetes, (e.g. , impaired glucose tolerance, or IGT). For example, recent studies have highlighted the potential for intervention in IGT subjects to reduce progression to type II diabetes. One such study showed that over three years lifestyle intervention (targeting diet and exercise) reduced the risk of progressing from IGT to diabetes by 58% (The Diabetes Prevention Program. (1999) Diabetes Care 22:623-634). In a similar Finnish study, the cumulative incidence of diabetes after four years was 11% in the intervention group and 23% in the control group. During the trial, the risk of diabetes was reduced by 58% in the intervention group (Tuomilehto et al. (2001) N. Eng. J Med. 344:1343-1350). Clearly there is great benefit in the early diagnosis and subsequent preventative treatment of type II diabetes.

[0096] The treatment sometimes is preventative (e.g., is prescribed or administered to reduce the probability that a type II diabetes associated condition arises or progresses), sometimes is therapeutic, and sometimes delays, alleviates or halts the progression of a type II diabetes associated condition. Any known preventative or therapeutic treatment for alleviating or preventing the occurrence of a type II diabetes associated disorder is prescribed and/or administered. For example, the treatment sometimes includes changes in diet, increased exercise, and the administration of therapeutics such as sulphonylureas (and related insulin secretagogues), which increase insulin release from pancreatic islets; metformin, which acts to reduce hepatic glucose production; peroxisome proliferator-activated receptor-gamma (PPAR) agonists (thiazolidinediones), which enhance insulin action; alpha-glucosidase inhibitors, which interfere with gut glucose absorption; and insulin itself, which suppresses glucose production and augments glucose utilization (MollerNαtore 414, 821-827 (2001)).

[0097] As therapeutic approaches for type II diabetes continue to evolve and improve, the goal of treatments for type II diabetes related disorders is to intervene even before clinical signs (e.g., impaired glucose tolerance, or IGT) first manifest. Thus, genetic markers associated with susceptibility to type II diabetes prove useful for early diagnosis, prevention and treatment of type II diabetes.

[0098] As type II diabetes preventative and treatment information can be specifically targeted to subjects in need thereof (e.g., those at risk of developing type II diabetes or those that have early stages of type II diabetes), provided herein is a method for preventing or reducing the risk of developing type II diabetes in a subject, which comprises: (a) detecting the presence or absence of a polymorphic variation associated with type II diabetes at a polymorphic site in a nucleotide sequence in a nucleic acid sample from a subject; (b) identifying a subject with a predisposition to type II diabetes, whereby the presence of the polymorphic variation is indicative of a predisposition to type II diabetes in the subject; and (c) if such a predisposition is identified, providing the subject with information about methods or products to prevent or reduce type II diabetes or to delay the onset of type II diabetes. Also provided is a method of targeting information or advertising to a subpopulation of a human population based on the subpopulation being genetically predisposed to a disease or condition, which comprises: (a) detecting the presence or absence of a polymorphic variation associated with type II diabetes at a polymorphic site in a nucleotide sequence in a nucleic acid sample from a subject; (b) identifying the subpopulation of subjects in which the polymorphic variation is associated with type II diabetes; and (c) providing information only to the subpopulation of subjects about a particular product which may be obtained and consumed or applied by the subject to help prevent or delay onset of the disease or condition.

[0099] Pharmacogenomics methods also may be used to analyze and predict a response to a type II diabetes treatment or a drug. For example, if pharmacogenomics analysis indicates a likelihood that an individual will respond positively to a type II diabetes treatment with a particular drug, the drug may be administered to the individual. Conversely, if the analysis indicates that an individual is likely to respond negatively to treatment with a particular drug, an alternative course of treatment may be prescribed. A negative response may be defined as either the absence of an efficacious response or the presence of toxic side effects. The response to a therapeutic treatment can be predicted in a background study in which subjects in any of the following populations are genotyped: a population that responds favorably to a treatment regimen, a population that does not respond significantly to a treatment^" regimen, arid ^"a pδpulation that respόrϊds^~aciversely to a treatment regiment (e.g., exhibits one or more side effects). These populations are provided as examples and other populations and subpopulations may be analyzed. Based upon the results of these analyses, a subject is genotyped to predict whether he or she will respond favorably to a ^{• "} treatment regimen, not respond significantly to a treatment regimen, or respond adversely to a treatment regimen.

[0100] The prognostic tests described herein also are applicable to clinical drug trials. One or more polymorphic variants indicative of response to an agent for treating type II diabetes or to side effects to an agent for treating type II diabetes may be identified using the methods described herein. Thereafter, potential participants in clinical trials of such an agent may be screened to identify those individuals most likely to respond favorably to the drug and exclude those likely to experience side effects. In that way, the effectiveness of drug treatment may be measured in individuals who respond positively to the drug, without lowering the measurement as a result of the inclusion of individuals who are unlikely to respond positively in the study and without risking undesirable safety problems. i

[0101] Thus, another embodiment is a method of selecting an individual for inclusion in a clinical trial of a treatment or drug comprising the steps of: (a) obtaining a nucleic acid sample from an individual; (b) determining the identity of a polymorphic variation which is associated with a positive response to the treatment or the drug, or at least one polymorphic variation which is associated with a negative response to the treatment or the drug in the nucleic acid sample, and (c) including the individual in the clinical trial if the nucleic acid sample contains said polymorphic variation associated with a positive response to the treatment or the drug or if the nucleic acid sample lacks said polymorphic variation associated with a negative response to the treatment or the drug. In addition, the methods described herein for selecting an individual for inclusion in a clinical trial of a treatment or drug encompass methods with any further limitation described in this disclosure, or those following, specified alone or in any combination. The polymorphic variation may be in a sequence selected individually or in any combination from the group consisting of (i) a polynucleotide sequence set forth in Table 1 or SEQ ID NO: 1-6; (ii) a polynucleotide sequence that is 90% or more identical to a nucleotide sequence set forth in Table 1 or SEQ ID NO: 1-6; (iii) a polynucleotide sequence that encodes a polypeptide having an amino acid sequence identical to or 90% or more identical to an amino acid sequence encoded by a nucleotide sequence set forth in Table 1 or SEQ ID NO: 1-6; and (iv) a fragment of a polynucleotide sequence of (i), (ii), or (iii) comprising the polymorphic site. The including step (c) optionally comprises administering the drug or the treatment to the individual if the nucleic acid sample contains the polymorphic variation associated with a positive response to the treatment or the drug and the nucleic acid sample lacks said biallelic marker associated with a negative response to the treatment or the drug.

[0102] Also provided herein is a method of partnering between a diagnostic/prognostic testing provider and a provider of a consumable product, which comprises: (a) the diagnostic/prognostic testing provider detects the presence or absence of a polymorphic variation associated with type II diabetes at a polymorphic site in a nucleotide sequence in a nucleic acid sample from a subject; (b) the diagnostic/prognostic testing provider identifies the subpopulation of subjects in which the polymorphic variation is associated with type II diabetes; (c) the diagnostic/prognostic testing provider forwards information to the subpopulation of subjects about a particular product which may be obtained and consumed or applied by the subject to help prevent or delay onset of the disease or condition; and (d) the provider of a consumable product forwards to the diagnostic test provider a fee every time the diagnostic/prognostic test provider forwards information to the subject as set forth in step (c) above.

Compositions Comprising Diabetes-Directed Molecules

[0103] Featured herein is a composition comprising a cell from a subject having type II diabetes or at risk of type II diabetes and one or more molecules specifically directed and targeted to a nucleic acid comprising a nucleotide sequence or amino acid sequence referenced in Table 1 or SEQ ID NO: 1-6. Such directed molecules include, but are not limited to, a compound that binds to a nucleotide sequence or amino acid sequence referenced in Table 1 or SEQ ID NO: 1-6; a nucleic acid having a nucleotide sequence complementary to a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6 and capable of hybridizing under conditions of high stringency; a RNAi or siRNA molecule having a strand complementary to a nucleotide sequence in Table 1 or SEQ ID NO: 1-6; an antisense nucleic acid complementary to an RNA encoded by a nucleotide sequence in Table 1 or SEQ ID NO: 1-6 sequence; a ribozyme that hybridizes to a nucleotide sequence in Table 1 or SEQ ID NO: 1-6; a nucleic acid aptamer that specifically binds a polypeptide encoded by nucleotide sequence in Table 1 or SEQ ID NO: 1-6; and an antibody that specifically binds to a polypeptide encoded by nucleotide sequence in Table 1 or SEQ ID NO: 1-6 or binds to a nucleic acid having such a nucleotide sequence. In certain embodiments, the antibody specifically binds to an epitope that comprises an aspartate at position 905 in a PPP1R3A polypeptide, a valine at position 264 in a LOC166350/DNAJB11 polypeptide, a threonine at position 117 in a COPE polypeptide, a threonine at position 247 in a KIAAO 141 polypeptide, or a glutamate at position 652 in a F13A1 polypeptide. In specific embodiments, the diabetes directed molecule interacts with a nucleic acid or polypeptide variant associated with diabetes, such as variants referenced in Table 1 or SEQ ID NO: 1-6. In other embodiments, the diabetes directed molecule interacts with a polypeptide involved in a signal pathway of a polypeptide encoded by a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6, or a nucleic acid comprising such a nucleotide sequence. [0104] Compositions sometimes include an adjuvant known to stimulate an immune response, and in certain embodiments, an adjuvant that stimulates a T-cell lymphocyte response. Adjuvants are known, including but not limited to an aluminum adjuvant (e.g., aluminum hydroxide); a cytokine adjuvant or adjuvant that stimulates a cytokine response (e.g., interleukin (EL)-12 and/or γ- interferon cytokines); a Freund-type mineral oil adjuvant emulsion (e.g., Freund's complete or incomplete adjuvant); a synthetic lipoid compound; a copolymer adjuvant (e.g., TitreMax); a saponin; Quil A; a liposome; an oil-in-water emulsion (e.g., an emulsion stabilized by Tween 80 and pluronic polyoxyethlene/polyoxypropylene block copolymer (Syntex Adjuvant Formulation); TitreMax; detoxified endotoxin (MPL) and mycobacterial cell wall components (TDW, CWS) in 2% squalene (Ribi Adjuvant System)); a muramyl dipeptide; an immune-stimulating complex (ISCOM₃ e.g., an Ag-modified saponin/cholesterol micelle that forms stable cage-like structure); an aqueous phase adjuvant that does not have a depot effect (e.g., Gerbu adjuvant); a carbohydrate polymer (e.g., AdjuPrime); L-tyrosine; a manide-oleate compound (e.g., Montanide); an ethylene- vinyl acetate copolymer (e.g., Elvax 40Wl, 2); or lipid A, for example. Such compositions are useful for generating an immune response against a diabetes directed molecule (e.g., an HLA- binding subsequence within a polypeptide encoded by a nucleotide sequence in Table 1 or in Figure 2). In such methods, a peptide having an amino acid subsequence of a polypeptide encoded by a nucleotide sequence in Table 1 or in Figure 2 is delivered to a subject, where the subsequence binds to an HLA molecule and induces a CTL lymphocyte response. The peptide sometimes is delivered to the subject as an isolated peptide or as a minigene in a plasmid that encodes the peptide. Methods for identifying HLA-binding subsequences in such polypeptides are known (see e.g., publication WO02/20616 and PCT application US98/01373 for methods of identifying such sequences).

[0105] The diabetes cell may be in a group of diabetes cells and/or other types of cells cultured in vitro or in a tissue having diabetes cells (e.g., a melanocytic lesion) maintained in vitro or present in an animal in vivo (e.g., a rat, mouse, ape or human). In certain embodiments, a composition comprises a component from a diabetes cell or from a subject having a diabetes cell instead of the diabetes cell or in addition to the diabetes cell, where the component sometimes is a nucleic acid molecule (e.g., genomic DNA), a protein mixture or isolated protein, for example. The aforementioned compositions have utility in diagnostic, prognostic and pharmacogenomic methods described previously and in diabetes therapeutics described hereafter. Certain diabetes molecules are described in greater detail below.

Compounds

[0106] Compounds can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; peptoid libraries (libraries of molecules having the functionalities of peptides, but with a novel, non-peptide backbone which are resistant to enzymatic degradation but which nevertheless remain bioactive (see, e.g., Zuckermann et al, J. Med. Chem.37: 2678-85 (1994)); spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; "one-bead one-compound" library methods; and synthetic library methods using affinity chromatography selection. Biological library and peptoid library approaches are typically limited to peptide libraries, while the other approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds (Lam, Anticancer Drug Des. 12: 145, (1997)). Examples of methods for synthesizing molecular libraries are described, for example, in DeWitt et al, Proc. Natl. Acad. ScL U.S.A. 90: 6909 (1993); Erb et al., Proc. Natl. Acad. ScL USA 91: 11422 (1994); Zuckermann et al, J. Med. Chem. 37: 2678 (1994); Cho et al, Science 261: 1303 (1993); Carrell et al, Angew. Chem. Int. Ed. Engl. 33: 2059 (1994); Carell et al, Angew. Chem. Int. Ed. Engl. 33: 2061 (1994); and in Gallop et al, J. Med. Chem. 37: 1233 (1994).

[0107] Libraries of compounds may be presented in solution (e.g., Houghten, Biotechniques 13: 412-421 (1992)), or on beads (Lam, Nature 354: 82-84 (1991)), chips (Fodor, Nature 364: 555- 556 (1993)), bacteria or spores (Ladner, United States Patent No. 5,223,409), plasmids (Cull et al, Proc. Natl. Acad. ScL USA 89: 1865-1869 (1992)) or on phage (Scott and Smith, Science 249: 386- 390 (1990); Devlin, Science 249: 404-406 (1990); Cwirla et al, Proc. Natl. Acad. ScL 87: 6378- 6382 (1990); Felici, J. MoI Biol. 222: 301-310 (1991); Ladner supra). [0108] A compound sometimes alters expression and sometimes alters activity of a polypeptide target and may be a small molecule. Small molecules include, but are not limited to, peptides, peptidomimetics (e.g., peptoids), amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, nucleotides, nucleotide analogs, organic or inorganic compounds (i.e., including heteroorganic and organometallic compounds) having a molecular weight less than about 10,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 5,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 1,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 500 grams per mole, and salts, esters, and other pharmaceutically acceptable forms of such compounds.

Antisense Nucleic Acid Molecules, Ribozymes, RNAi, siRNA and Modified Nucleic Acid Molecules

[0109] An "antisense" nucleic acid refers to a nucleotide sequence complementary to a "sense" nucleic acid encoding a polypeptide, e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence. The antisense nucleic acid can be complementary to an entire coding strand referenced in Table 1 or SEQ ID NO: 1-6, or to a portion thereof or a substantially identical sequence thereof. In another embodiment, the antisense nucleic acid molecule is antisense to a "noncodmg region" of the coding strand of a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6 (e.g., 5' and 3' untranslated regions).

[0110] An antisense nucleic acid can be designed such that it is complementary to the entire coding region of an mRNA encoded by a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6, and often the antisense nucleic acid is an oligonucleotide antisense to only a portion of a coding or noncoding region of the mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of the mRNA, e.g., between the - 10 and +10 regions of the target gene nucleotide sequence of interest. An antisense oligonucleotide can be, for example, about 7, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or more nucleotides in length. The antisense nucleic acids, which include the ribozymes described hereafter, can be designed to target a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6, often a variant associated with diabetes, or a substantially identical sequence thereof. Among the variants, minor alleles and major alleles can be targeted, and those associated with a higher risk of diabetes are often designed, tested, and administered to subjects.

[0111] An antisense nucleic acid can be constructed using chemical synthesis and enzymatic ligation reactions using standard procedures. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used. Antisense nucleic acid also can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation {i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).

[0112] When utilized as therapeutics, antisense nucleic acids typically are administered to a subject {e.g., by direct injection at a tissue site) or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a polypeptide and thereby inhibit expression of the polypeptide, for example, by inhibiting transcription and/or translation. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then are administered systemically. For systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface, for example, by linking antisense nucleic acid molecules to peptides or antibodies which bind to cell surface receptors or antigens. Antisense nucleic acid molecules can. also be delivered to cells using the vectors described herein. Sufficient intracellular concentrations of antisense molecules are achieved by incorporating a strong promoter, such as a pol II or pol III promoter, in the vector construct.

[0113] Antisense nucleic acid molecules sometimes are alpha anomeric nucleic acid molecules. An alpha-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual beta-units, the strands run parallel to each other (Gaultier et al, Nucleic Acids. Res. 15: 6625-6641 (1987)). Antisense nucleic acid molecules can also comprise a 2'-o-methylribonucleotide (Inoue et al, Nucleic Acids Res. 15: 6131-6148 (1987)) or a chimeric RNA-DNA analogue (Inoue et al, FEBS, Lett. 215: 327-330 (1987)). Antisense nucleic acids sometimes are composed of DNA or PNA or any other nucleic acid derivatives described previously.

[0114] In another embodiment, an antisense nucleic acid is a ribozyme. A ribozyme having specificity for a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6 can include one or more sequences complementary to such a nucleotide sequence, and a sequence having a known catalytic region responsible for mRNA cleavage (see e.g., U.S. Pat. No. 5,093,246 or Haselhoff and Gerlach, Nature 334: 585-591 (1988)). For example, a derivative of a Tetrahymena L-19 IVS RNA is sometimes utilized in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a mRNA (see e.g., Cech et al. U.S. Patent No. 4,987,071; and Cech et al U.S. Patent No. 5,116,742). Also, target mRNA sequences can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules {see e.g., Bartel & Szostak, Science 261: 1411-1418 (1993)). [0115] Diabetes directed molecules include in certain embodiments nucleic acids that can form triple helix structures with a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6 or a substantially identical sequence thereof, especially one that includes a regulatory region that controls expression of a polypeptide. Gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of a nucleotide sequence referenced herein or a substantially identical sequence {e.g., promoter and/or enhancers) to form triple helical structures that prevent transcription of a gene in target cells {see e.g., Helene, Anticancer Drug Des. 6{6): 569- 84 (1991); Helene et al, Ann. NY. Acad. ScL 660: 27-36 (1992); andMaher, Bioassays 14(12): 807-15 (1992). Potential sequences that can be targeted for triple helix formation can be increased by creating a so-called "switchback" nucleic acid molecule. Switchback molecules are synthesized in an alternating 5 '-3 ', 3 '-5 ' manner, such that they base pair with first one strand of a duplex and then the other, eliminating the necessity for a sizeable stretch of either purines or pyrimidines to be present on one strand of a duplex.

[0116] Diabetes directed molecules include RNAi and siRNA nucleic acids. Gene expression may be inhibited by the introduction of double-stranded RNA (dsRNA), which induces potent and specific gene silencing, a phenomenon called RNA interference or RNAi. See, e.g., Fire et al, US Patent No. 6,506,559; Tuschl et al. PCT International Publication No. WO 01/75164; Kay et al. PCT International Publication No. WO 03/010180Al ; or Bosher JM, Labouesse, Nat Cell Biol 2000 Feb;2(2):E31-6. This process has been improved by decreasing the size of the double-stranded RNA to 20-24 base pairs (to create small-interfering RNAs or siRNAs) that "switched off genes in mammalian cells without initiating an acute phase response, i.e., a host defense mechanism that often results in cell death (see, e.g., Caplen et al. Proc Natl Acad Sci USA. 2001 Aug 14;98(17):9742-7 and Elbashir et al. Methods 2002 Feb;26(2):199-213). There is increasing evidence of post-transcriptional gene silencing by RNA interference (RNAi) for inhibiting targeted expression in mammalian cells at the mRNA level, in human cells. There is additional evidence of effective methods for inhibiting the proliferation and migration of tumor cells in human patients, and for inhibiting metastatic cancer development {see, e.g., U.S. Patent Application No. US2001000993183; Caplen et al,. Proc Natl Acad Sci USA; and Abderrahmani et al, MoI Cell Biol 2001 Nov21(21):7256-67).

[0117] An "siRNA" or "RNAi" refers to a nucleic acid that forms a double stranded RNA and has the ability to reduce or inhibit expression of a gene or target gene when the siRNA is delivered to or expressed in the same cell as the gene or target gene. "siRNA" refers to short double-stranded RNA formed by the complementary strands. Complementary portions of the siRNA that hybridize to form the double stranded molecule often have substantial or complete identity to the target molecule sequence. In one embodiment, an siRNA refers to a nucleic acid that has substantial or complete identity to a target gene and forms a double stranded siRNA. [0118] When designing the siRNA molecules, the targeted region often is selected from a given DNA sequence beginning 50 to 100 nucleotides downstream of the start codon. See, e.g., Elbashir et al,. Methods 26:199-213 (2002). Initially, 5' or 3' UTRs and regions nearby the start codon were avoided assuming that UTR-binding proteins and/or translation initiation complexes may interfere with binding of the siRNP or RISC endonuclease complex. Sometimes regions of the target 23 nucleotides in length conforming to the sequence motif AA(Nl 9)TT (N, an nucleotide), and regions with approximately 30% to 70% G/C-content (often about 50% G/C-content) often are selected. If no suitable sequences are found, the search often is extended using the motif NA(N21). The sequence of the sense siRNA sometimes corresponds to (Nl 9) TT or N21 (position 3 to 23 of the 23 -nt motif), respectively. In the latter case, the 3' end of the sense siRNA often is converted to TT. The rationale for this sequence conversion is to generate a symmetric duplex with respect to the sequence composition of the sense and antisense 3' overhangs. The antisense siRNA is synthesized as the complement to position 1 to 21 of the 23-nt motif. Because position 1 of the 23- nt motif is not recognized sequence-specifϊcally by the antisense siRNA, the 3 '-most nucleotide residue of the antisense siRNA can be chosen deliberately. However, the penultimate nucleotide of the antisense siRNA (complementary to position 2 of the 23-nt motif) often is complementary to the targeted sequence. For simplifying chemical synthesis, TT often is utilized. siRNAs corresponding to the target motif NAR(NlV)YNN, where R is purine (A,G) and Y is pyrimidine (C,U), often are selected. Respective 21 nucleotide sense and antisense siRNAs often begin with a purine nucleotide and can also be expressed from pol III expression vectors without a change in targeting site. Expression of RNAs from pol III promoters often is efficient when the first transcribed nucleotide is a purine.

[0119] The sequence of the siRNA can correspond to the full length target gene, or a subsequence thereof. Often, the siRNA is about 15 to about 50 nucleotides in length {e.g., each complementary sequence of the double stranded siRNA is 15-50 nucleotides in length, and the double stranded siRNA is about 15-50 base pairs in length, sometimes about 20-30 nucleotides in length or about 20-25 nucleotides in length, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. The siRNA sometimes is about 21 nucleotides in length. Methods of using siRNA are well known in the art, and specific siRNA molecules may be purchased from a number of companies including Dharmacon Research, Inc. An siRNA molecule sometimes is composed of a different chemical composition as compared to native RNA that imparts increased stability in cells {e.g., decreased susceptibility to degradation), and sometimes includes one or more modifications in siSTABLE RNA described at the http address www.dharmacon.com.

[0120] Antisense, ribozyme, RNAi and siRNA nucleic acids can be altered to form modified nucleic acid molecules. The nucleic acids can be altered at base moieties, sugar moieties or phosphate backbone moieties to improve stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of nucleic acid molecules can be modified to generate peptide nucleic acids (see Hyrup et al, Bioorganic & Medicinal Chemistry 4 (1): 5-23 (1996)). As used herein, the terms "peptide nucleic acid" or "PNA" refers to a nucleic acid mimic such as a DNA mimic, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of a PNA can allow for specific hybridization to DNA and RNA under conditions of low ionic strength. Synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described, for example, in Hyrup et al, (1996) supra and Perry-O'Keefe et al, Proc. Natl. Acad. Sd. 93: 14670-675 (1996).

[0121] PNA nucleic acids can be used in prognostic, diagnostic, and therapeutic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, for example, inducing transcription or translation arrest or inhibiting replication. PNA nucleic acid molecules can also be used in the analysis of single base pair mutations in a gene, {e.g., by PNA-directed PCR clamping); as "artificial restriction enzymes" when used in combination with other enzymes, {e.g., Sl nucleases (Hyrup (1996) supra)); or as probes or primers for DNA sequencing or hybridization (Hyrup et al., (1996) supra; Perry-O'Keefe supra).

[0122] In other embodiments, oligonucleotides may include other appended groups such as peptides {e.g., for targeting host cell receptors in vivo), or agents facilitating transport across cell membranes (see e.g., Letsinger et al., Proc. Natl. Acad. Sd. USA 86: 6553-6556 (1989); Lemaitre et al, Proc. Natl. Acad. Sd. USA 84: 648-652 (1987); PCT Publication No. W088/09810) or the blood-brain barrier {see, e.g., PCT Publication No. W089/10134). In addition, oligonucleotides can be modified with hybridization-triggered cleavage agents {See, e.g., Krol et al, Bio-Techniques 6: 958-976 (1988)) or intercalating agents. {See, e.g., Zon, Pharm. Res. 5: 539-549 (1988) ). To this end, the oligonucleotide may be conjugated to another molecule, {e.g., a peptide, hybridization triggered cross-linking agent, transport agent, or hybridization-triggered cleavage agent).

[0123] Also included herein are molecular beacon oligonucleotide primer and probe molecules having one or more regions complementary to a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6 or a substantially identical sequence thereof, two complementary regions one having a fluorophore and one a quencher such that the molecular beacon is useful for quantifying the presence of the nucleic acid in a sample. Molecular beacon nucleic acids are described, for example, in Lizardi et al, U.S. Patent No. 5,854,033; Nazarenko et al, U.S. Patent No. 5,866,336, and Livak et al, U.S. Patent No. 5,876,930. Antibodies

[0124] The term "antibody" as used herein refers to an immunoglobulin molecule or immunologically active portion thereof, i.e., an antigen-binding portion. Examples of immunologically active portions of immunoglobulin molecules include F(ab) and F(ab')₂ fragments which can be generated by treating the antibody with an enzyme such as pepsin. An antibody sometimes is a polyclonal, monoclonal, recombinant {e.g., a chimeric or humanized), fully human, non-human {e.g., murine), or a single chain antibody. An antibody may have effector function and can fix complement, and is sometimes coupled to a toxin or imaging agent.

[0125] A full-length polypeptide or antigenic peptide fragment encoded by a nucleotide sequence referenced herein can be used as an immunogen or can be used to identify antibodies made with other immunogens, e.g., cells, membrane preparations, and the like. An antigenic peptide often includes at least 8 amino acid residues of the amino acid sequences encoded by a nucleotide sequence referenced herein, or substantially identical sequence thereof, and encompasses an epitope. Antigenic peptides sometimes include 10 or more amino acids, 15 or more amino acids, 20 or more amino acids, or 30 or more amino acids. Hydrophilic and hydrophobic fragments of polypeptides sometimes are used as immunogens.

[0126] Epitopes encompassed by the antigenic peptide are regions located on the surface of the polypeptide {e.g., hydrophilic regions) as well as regions with high antigenicity. For example, an Emini surface probability analysis of the human polypeptide sequence can be used to indicate the regions that have a particularly high probability of being localized to the surface of the polypeptide and are thus likely to constitute surface residues useful for targeting antibody production. The antibody may bind an epitope on any domain or region on polypeptides described herein.

[0127] Also, chimeric, humanized, and completely human antibodies are useful for applications which include repeated administration to subjects. Chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, can be made using standard recombinant DNA techniques. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in Robinson et al International Application No. PCT/US86/02269; Akira, et at, European Patent Application 184,187; Taniguchi, M., European Patent Application 171,496; Morrison et al European Patent Application 173,494; Neuberger et at, PCT International Publication No. WO 86/01533; Cabilly et at, U.S. Patent No. 4,816,567; Cabilly et at, European Patent Application 125,023; Better et at, Science 240: 1041-1043 (1988); Liu et at, Proc. Natl. Acad. ScL USA 84: 3439.3443 (1987); Liu et at, J. Immunol. 139: 3521-3526 (1987); Sun et at, Proc. Natl. Acad. ScL USA 84: 214-218 (1987); Nishimura et at, Cane. Res. 47: 999-1005 (1987); Wood et at, Nature 314: 446-449 (1985); and Shaw et at, J. Natl. Cancer Inst. 80: 1553-1559 (1988); Morrison, S. L., Science 229: 1202-1207 (1985); Oi et at, BioTechniques 4: 214 (1986); Winter U.S. Patent 5,225,539; Jones et al, Nature 321: 552-525 (1986); Verhoeyan et al, Science 239: 1534; and Beidler et al, J. Immunol. 141: 4053-4060 (1988).

[0128] Completely human antibodies are particularly desirable for therapeutic treatment of human patients. Such antibodies can be produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes. See, for example, Lonberg and Huszar, Int. Rev. Immunol. 13: 65-93 (1995); and U.S. Patent Nos. 5,625,126; 5,633,425; 5,569,825; 5,661,016; and 5,545,806. hi addition, companies such as Abgenix, Inc. (Fremont, CA) and Medarex, Inc. (Princeton, NJ), can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above. Completely human antibodies that recognize a selected epitope also can be generated using a technique referred to as "guided selection." In this approach a selected non- human monoclonal antibody {e.g., a murine antibody) is used to guide the selection of a completely human antibody recognizing the same epitope. This technology is described for example by Jespers et al, Bio/Technology 12: 899-903 (1994).

[0129] An antibody can be a single chain antibody. A single chain antibody (scFV) can be engineered (see, e.g., Colcher et al, Ann. NY Acad. ScL 880: 263-80 (1999); andReiter, Clin. Cancer Res. 2: 245-52 (1996)). Single chain antibodies can be dimerized or multirnerized to generate multivalent antibodies having specificities for different epitopes of the same target polypeptide.

[0130] Antibodies also may be selected or modified so that they exhibit reduced or no ability to bind an Fc receptor. For example, an antibody may be an isotype or subtype, fragment or other mutant, which does not support binding to an Fc receptor {e.g., it has a mutagenized or deleted Fc receptor binding region).

[0131] Also, an antibody (or fragment thereof) may be conjugated to a therapeutic moiety such as a cytotoxin, a therapeutic agent or a radioactive metal ion. A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1 dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites {e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents {e.g., mechlorethamine, thiotepa chlorambucil, melphalan, carmustine (BCNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomanήitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines {e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (foπnerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti¬ mitotic agents (e.g., vincristine and vinblastine).

[0132] Antibody conjugates can be used for modifying a given biological response. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a polypeptide such as tumor necrosis factor, γ-interferon, α-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin-1 ("IL-I"), interleukin-2 ("IL-2"), interleukin-6 ("EL-6"), granulocyte macrophage colony stimulating factor ("GM-CSF"), granulocyte colony stimulating factor ("G-CSF"), or other growth factors. Also, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Patent No. 4,676,980, for example.

[0133] An antibody (e.g., monoclonal antibody) can be used to isolate target polypeptides by standard techniques, such as affinity chromatography or immunoprecipitation. Moreover, an antibody can be used to detect a target polypeptide (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the polypeptide. Antibodies can be used diagnostically to monitor polypeptide levels in tissue as part of a clinical testing procedure, e.g., to determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance (i.e., antibody labeling). Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ¹²⁵1, ¹³¹1, ³⁵S or ³H. Also, an antibody can be utilized as a test molecule for determining whether it can treat diabetes, and as a therapeutic for administration to a subject for treating diabetes.

[0134] An antibody can be made by immunizing with a purified antigen, or a fragment thereof, e.g., a fragment described herein, a membrane associated antigen, tissues, e.g., crude tissue preparations, whole cells, preferably living cells, lysed cells, or cell fractions.

[0135] Included herein are antibodies which bind only a native polypeptide, only denatured or otherwise non-native polypeptide, or which bind both, as well as those having linear or conformational epitopes. Conformational epitopes sometimes can be identified by selecting antibodies that bind to native but not denatured polypeptide. Also featured are antibodies that specifically bind to a polypeptide variant associated with diabetes.

Methods for Identifying Candidate Therapeutics for Treating Type II Diabetes [0136] Current therapies for the treatment of type II diabetes have limited efficacy, limited tolerability and significant mechanism-based side effects, including weight gain and hypoglycemia. Few of the available therapies adequately address underlying defects such as obesity and insulin resistance (Moller D., Nature. 414:821-827 (2001)). Current therapeutic approaches were largely developed in the absence of defined molecular targets or even a solid understanding of disease pathogenesis. Therefore, provided are methods of identifying candidate therapeutics that target biochemical pathways related to the development of diabetes.

[0137] Thus, featured herein are methods for identifying a candidate therapeutic for treating type π diabetes. The methods comprise contacting a test molecule with a target molecule in a system. A "target molecule" as used herein refers to a nucleic acid of Table 1 or SEQ ID NO: 1-6, a substantially identical nucleic acid thereof, or a fragment thereof, and an encoded polypeptide of the foregoing. The methods also comprise determining the presence or absence of an interaction between the test molecule and the target molecule, where the presence of an interaction between the test molecule and the nucleic acid or polypeptide identifies the test molecule as a candidate type II diabetes therapeutic. The interaction between the test molecule-and the target molecule may be- quantified.

[0138] Test molecules and candidate therapeutics include, but are not limited to, compounds, antisense nucleic acids, siRNA molecules, ribozymes, polypeptides or proteins encoded by a nucleotide sequence in Table 1 or SEQ ID NO: 1-6, or a substantially identical sequence or fragment thereof, and immunotherapeutics {e.g., antibodies and HLA-presented polypeptide fragments). A test molecule or candidate therapeutic may act as a modulator of target molecule concentration or target molecule function in a system. A "modulator" may agonize {i.e., up- regulates) or antagonize {i.e., down-regulates) a target molecule concentration partially or completely in a system by affecting such cellular functions as DNA replication and/or DNA processing {e.g., DNA methylation or DNA repair), RNA transcription and/or RNA processing {e.g., removal of intronic sequences and/or translocation of spliced mRNA from the nucleus), polypeptide production {e.g. , translation of the polypeptide from mRNA), and/or polypeptide post- translational modification {e.g., glycosylation, phosphorylation, and proteolysis of pro- polypeptides). A modulator may also agonize or antagonize a biological function of a target molecule partially or completely, where the function may include adopting a certain structural conformation, interacting with one or more binding partners, ligand binding, catalysis {e.g., phosphorylation, dephosphorylation, hydrolysis, methylation, and isomerization), and an effect upon a cellular event (e.g., effecting progression of type II diabetes). In certain embodiments, a candidate therapeutic increases glucose uptake in cells of a subject (e.g., in certain cells of the pancreas).

[0139] As used herein, the term "system" refers to a cell free in vitro environment and a cell- based environment such as a collection of cells, a tissue, an organ, or an organism. A system is "contacted" with a test molecule in a variety of manners, including adding molecules in solution and allowing them to interact with one another by diffusion, cell injection, and any administration routes in an animal. As used herein, the term "interaction" refers to an effect of a test molecule on test molecule, where the effect sometimes is binding between the test molecule and the target molecule, and sometimes is an observable change in cells, tissue, or organism.

[0140] There are many standard methods for detecting the presence or absence of interaction between a test molecule and a target molecule. For example, titrametric, acidimetric, radiometric, NMR, monolayer, polarographic, spectrophotometric, fluorescent, and ESR assays probative of a target molecule interaction may be utilized.

[0141] Test molecule/target molecule interactions can be detected and/or quantified using assays known in the art. For example, an interaction can be determined by labeling the test molecule and/or the target molecule, where the label is covalently or non-covalently attached to the test molecule or target molecule. The label is sometimes a radioactive molecule such as ¹²⁵1, ¹³¹I, ³⁵S or ³H, which can be detected by direct counting of radioemission or by scintillation counting. Also, enzymatic labels such as horseradish peroxidase, alkaline phosphatase, or luciferase may be utilized where the enzymatic label can be detected by determining conversion of an appropriate substrate to product. In addition, presence or absence of an interaction can be determined without labeling. For example, a microphysiometer (e.g., Cytosensor) is an analytical instrument that measures the rate at which a cell acidifies its environment using a light-addressable potentiometric sensor (LAPS). Changes in this acidification rate can be used as an indication of an interaction between a test molecule and target molecule (McConnell, H. M. et ah, Science 257: 1906-1912 (1992)).

[0142] In cell-based systems, cells typically include a nucleic acid from Table 1 or SEQ ID NO: 1-6, an encoded polypeptide, or substantially identical nucleic acid or polypeptide thereof, and are often of mammalian origin, although the cell can be of any origin. Whole cells, cell homogenates, and cell fractions (e.g., cell membrane fractions) can be subjected to analysis. Where interactions between a test molecule with a target polypeptide are monitored, soluble and/or membrane bound forms of the polypeptide may be utilized. Where membrane-bound forms of the polypeptide are used, it may be desirable to utilize a solubilizing agent. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n- dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton® X-100, Triton® X-114, Thesit®, Isotridecypoly(etliylene glycol ether)_n, 3-[(3- ckolaπύdopropyl)dimethylamminio]-l -propane sulfonate (CHAPS), 3-[(3- cholamidopropyl)drmethylamminio]-2-hydroxy-l -propane sulfonate (CHAPSO), or N-dodecyl- N,N-dimethyl-3 -ammonio- 1 -propane sulfonate.

[0143] An interaction between a test molecule and target molecule also can be detected by monitoring fluorescence energy transfer (FET) {see, e.g., Lakowicz et al, U.S. Patent No. 5,631,169; Stavrianopoulos et al. U.S. Patent No. 4,868,103). A fiuorophore label on a first, "donor" molecule is selected such that its emitted fluorescent energy will be absorbed by a fluorescent label on a second, "acceptor" molecule, which in turn is able to fluoresce due to the absorbed energy. Alternately, the "donor" polypeptide molecule may simply utilize the natural fluorescent energy of tryptophan residues. Labels are chosen that emit different wavelengths of light, such that the "acceptor" molecule label may be differentiated from that of the "donor". Since the efficiency of energy transfer between the labels is related to the distance separating the molecules, the spatial relationship between the molecules can be assessed. In a situation in which binding occurs between the molecules, the fluorescent emission of the "acceptor" molecule label in the assay should be maximal. An FET binding event can be conveniently measured through standard fluorometric detection means well known in the art (e.g., using a fluorimeter).

[0144] In another embodiment, determining the presence or absence of an interaction between a test molecule and a target molecule can be effected by monitoring surface plasmon resonance (see, e.g., Sjolander & Urbaniczk, Anal. Chem. 63: 2338-2345 (1991) and Szabo et al, Curr. Opin. Struct. Biol.5,: 699-705 (1995)). "Surface plasmon resonance" or "biomolecular interaction analysis (BIA)" can be utilized to detect biospecifϊc interactions in real time, without labeling any of the interactants (e.g., BIAcore). Changes in the mass at the binding surface (indicative of a binding event) result in alterations of the refractive index of light near the surface (the optical phenomenon of surface plasmon resonance (SPR)), resulting in a detectable signal which can be used as an indication of real-time reactions between biological molecules.

[0145] In another embodiment, the target molecule or test molecules are anchored to a solid phase, facilitating the detection of target molecule/test molecule complexes and separation of the complexes from free, uncomplexed molecules. The target molecule or test molecule is immobilized to the solid support. In an embodiment, the target molecule is anchored to a solid surface, and the test molecule, which is not anchored, can be labeled, either directly or indirectly, with detectable labels discussed herein.

[0146] It may be desirable to immobilize a target molecule, an anti-target molecule antibody, and/or test molecules to facilitate separation of target molecule/test molecule complexes from uncomplexed forms, as well as to accommodate automation of the assay. The attachment between a test molecule and/or target molecule and the solid support may be covalent or non-covalent (see, e.g., U.S. Patent No. 6,022,688 for non-covalent attachments). The solid support may be one or more surfaces of the system, such as one or more surfaces in each well of a microtiter plate, a surface of a silicon wafer, a surface of a bead (see, e.g., Lam, Nature 354: 82-84 (1991)) that is optionally linked to another solid support, or a channel in a microfluidic device, for example. Types of solid supports, linker molecules for covalent and non-covalent attachments to solid supports, and methods for immobilizing nucleic acids and other molecules to solid supports are well known (see, e.g., U.S. Patent Nos. 6,261,776; 5,900,481; 6,133,436; and 6,022,688; and WIPO publication WO 01/18234).

[0147] In an embodiment, target molecule may be immobilized to surfaces via biotin and streptavidin. For example, biotinylated target polypeptide can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques known in the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, IL), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). In another embodiment, a target polypeptide can be prepared as a fusion polypeptide. For example, glutathione-S-transferase/target polypeptide fusion can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione derivitized microtiter plates, which are then combined with a test molecule under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, or the matrix is immobilized in the case of beads, and complex formation is determined directly or indirectly as described above. Alternatively, the complexes can be dissociated from the matrix, and the level of target molecule binding or activity is determined using standard techniques.

[0148] In an embodiment, the non-immobilized component is added to the coated surface containing the anchored component. After the reaction is complete, unreacted components are removed (e.g., by washing) under conditions such that a significant percentage of complexes formed will remain immobilized to the solid surface. The detection of complexes anchored on the solid surface can be accomplished in a number of manners. Where the previously non-immobilized component is pre-labeled, the detection of label immobilized on the surface indicates that complexes were formed. Where the previously non-immobilized component is not pre-labeled, an indirect label can be used to detect complexes anchored on the surface, e.g., by adding a labeled antibody specific for the immobilized component, where the antibody, in turn, can be directly labeled or indirectly labeled with, e.g., a labeled anti-Ig antibody.

[0149] In another embodiment, an assay is performed utilizing antibodies that specifically bind target molecule or test molecule but do not interfere with binding of the target molecule to the test molecule. Such antibodies can be derivitized to a solid support, and unbound target molecule may be immobilized by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the target molecule, as well as enzyme-linked assays which rely on detecting an enzymatic activity associated with the target molecule.

[0150] Cell free assays also can be conducted in a liquid phase. In such an assay, reaction products are separated from unreacted components, by any of a number of standard techniques, including but not limited to: differential centrifugation {see, e.g., Rivas, G., and Minton, Trends Biochem SciAug;18(8): 284-7 (1993)); chromatography (gel filtration chromatography, ion- exchange chromatography); electrophoresis (see, e.g., Ausubel et al., eds. Current Protocols in Molecular Biology , J. Wiley: New York (1999)); and immunoprecipitation (see, e.g., Ausubel et al, eds., supra). Media and chromatographic techniques are known to one skilled in the art (see, e.g., Heegaard, JMoI. Recognit. Winter; 11(1-6): 141-8 (1998); Hage & Tweed, J. Chromatogr. B Biomed. ScL Appl. Oct 10; 699 (1-2): 499-525 (1997)). Further, fluorescence energy transfer may also be conveniently utilized, as described herein, to detect binding without further purification of the complex from solution.

[0151] In another embodiment, modulators of target molecule expression are identified. For example, a cell or cell free mixture is contacted with a candidate compound and the expression of target mRNA or target polypeptide is evaluated relative to the level of expression of target mRNA or target polypeptide in the absence of the candidate compound. When expression of target mRNA or target polypeptide is greater in the presence of the candidate compound than in its absence, the candidate compound is identified as an agonist of target mRNA or target polypeptide expression. Alternatively, when expression of target mRNA or target polypeptide is less (e.g., less with statistical significance) in the presence of the candidate compound than in its absence, the candidate compound is identified as an antagonist or inhibitor of target mRNA or target polypeptide expression. The level of target mRNA or target polypeptide expression can be determined by methods described herein.

[0152] In another embodiment, binding partners that interact with a target molecule are detected. The target molecules can interact with one or more cellular or extracellular macromolecules, such as polypeptides in vivo, and these interacting molecules are referred to herein as "binding partners." Binding partners can agonize or antagonize target molecule biological activity. Also, test molecules that agonize or antagonize interactions between target molecules and binding partners can be useful as therapeutic molecules as they can up-regulate or down-regulated target molecule activity in vivo and thereby treat type II diabetes.

[0153] Binding partners of target molecules can be identified by methods known in the art. For example, binding partners may be identified by lysing cells and analyzing cell lysates by electrophoretic techniques. Alternatively, a two-hybrid assay or three-hybrid assay can be utilized (see, e.g., U.S. Patent No. 5,283,317; Zervos et al, Cell 72:223-232 (1993); Madura et al, J. Biol. Chem. 268: 12046-12054 (1993); Bartel et al, Biotechniques 14: 920-924 (1993); Iwabuchi et al, Oncogene 8: 1693-1696 (1993); and Brent WO94/10300). A two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. The assay often utilizes two different DNA constructs. In one construct, a nucleic acid from Table 1 or SEQ ID NO: 1-6 (sometimes referred to as the "bait") is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In another construct, a DNA sequence from a library of DNA sequences that encodes a potential binding partner (sometimes referred to as the "prey") is fused to a gene that encodes an activation domain of the known transcription factor. Sometimes, a nucleic acid from Table 1 or SEQ ID NO: 1-6 can be fused to the activation domain. If the "bait" and the "prey" molecules interact in vivo, the DNA- binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) which is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to identify the potential binding partner.

[0154] In an embodiment for identifying test molecules that antagonize or agonize complex formation between target molecules and binding partners, a reaction mixture containing the target molecule and the binding partner is prepared, under conditions and for a time sufficient to allow complex formation. The reaction mixture often is provided in the presence or absence of the test molecule. The test molecule can be included initially in the reaction mixture, or can be added at a time subsequent to the addition of the target molecule and its binding partner. Control reaction mixtures are incubated without the test molecule or with a placebo. Formation of any complexes between the target molecule and the binding partner then is detected. Decreased formation of a complex in the reaction mixture containing test molecule as compared to in a control reaction mixture indicates that the molecule antagonizes target molecule/binding partner complex formation. Alternatively, increased formation of a complex in the reaction mixture containing test molecule as compared to in a control reaction mixture indicates that the molecule agonizes target molecule/binding partner complex formation. In another embodiment, complex formation of target molecule/binding partner can be compared to complex formation of mutant target molecule/binding partner (e.g., amino acid modifications in a target polypeptide). Such a comparison can be important in those cases where it is desirable to identify test molecules that modulate interactions of mutant but not non-mutated target gene products.

[0155] The assays can be conducted in a heterogeneous or homogeneous format. Ih heterogeneous assays, target molecule and/or the binding partner are immobilized to a solid phase, and complexes are detected on the solid phase at the end of the reaction. In homogeneous assays, the entire reaction is carried out in a liquid phase. In either approach, the order of addition of reactants can be varied to obtain different information about the molecules being tested. For example, test compounds that agonize target molecule/binding partner interactions can be identified by conducting the reaction in the presence of the test molecule in a competition format. Alternatively, test molecules that agonize preformed complexes, e.g., molecules with higher binding constants that displace one of the components from the complex, can be tested by adding the test compound to the reaction mixture after complexes have been formed.

[0156] In a heterogeneous assay embodiment, the target molecule or the binding partner is anchored onto a solid surface {e.g., a microtiter plate), while the non-anchored species is labeled, either directly or indirectly. The anchored molecule can be immobilized by non-covalent or covalent attachments. Alternatively, an immobilized antibody specific for the molecule to be anchored can be used to anchor the molecule to the solid surface. The partner of the immobilized species is exposed to the coated surface with or without the test molecule. After the reaction is complete, unreacted components are removed {e.g., by washing) such that a significant portion of any complexes formed will remain immobilized on the solid surface. Where the non-immobilized species is pre-labeled, the detection of label immobilized on the surface is indicative of complex. Where the non-immobilized species is not pre-labeled, an indirect label can be used to detect complexes anchored to the surface; e.g., by using a labeled antibody specific for the initially non- immobilized species. Depending upon the order of addition of reaction components, test compounds that inhibit complex formation or that disrupt preformed complexes can be detected.

[0157] In another embodiment, the reaction can be conducted in a liquid phase in the presence or absence of test molecule, where the reaction products are separated from unreacted components, and the complexes are detected {e.g., using an immobilized antibody specific for one of the binding components to anchor any complexes formed in solution, and a labeled antibody specific for the other partner to detect anchored complexes). Again, depending upon the order of addition of reactants to the liquid phase, test compounds that inhibit complex or that disrupt preformed complexes can be identified.

[0158] In an alternate embodiment, a homogeneous assay can be utilized. For example, a preformed complex of the target gene product and the interactive cellular or extracellular binding partner product is prepared. One or both of the target molecule or binding partner is labeled, and the signal generated by the label(s) is quenched upon complex formation {e.g., U.S. Patent No. 4,109,496 that utilizes this approach for immunoassays). Addition of a test molecule that competes with and displaces one of the species from the preformed complex will result in the generation of a signal above background. In this way, test substances that disrupt target molecule/binding partner complexes can be identified.

[0159] Candidate therapeutics for treating type II diabetes are identified from a group of test molecules that interact with a target molecule. Test molecules are normally ranked according to the degree with which they modulate {e.g., agonize or antagonize) a function associated with the target molecule (e.g. , DNA replication and/or processing, RNA transcription and/or processing, polypeptide production and/or processing, and/or biological function/activity), and then top ranking modulators are selected. Also, pharmacogenomic information described herein can determine the rank of a modulator. The top 10% of ranked test molecules often are selected for further testing as candidate therapeutics, and sometimes the top 15%, 20%, or 25% of ranked test molecules are selected for further testing as candidate therapeutics. Candidate therapeutics typically are formulated for administration to a subject.

Therapeutic Formulations

[0160] Formulations and pharmaceutical compositions typically include in combination with a pharmaceutically acceptable carrier one or more target molecule modulators. The modulator often is a test molecule identified as having an interaction with a target molecule by a screening method described above. The modulator may be a compound, an antisense nucleic acid, a ribozyme, an antibody, or a binding partner. Also, formulations may comprise a target polypeptide or fragment thereof in combination with a pharmaceutically acceptable carrier.

[0161] As used herein, the term "pharmaceutically acceptable carrier" includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds can also be incorporated into the compositions. Pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0162] A pharmaceutical composition typically is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral {e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0163] Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0164] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0165] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0166] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. [0167] Systemic administration can also be by transniucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. Molecules can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0168] In one embodiment, active molecules are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0169] It is advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0170] Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀ Molecules which exhibit high therapeutic indices are preferred. While molecules that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

[0171] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such molecules lies preferably within a range of circulating concentrations that include the ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any molecules used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC₅₀ (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.

[0172] As defined herein, a therapeutically effective amount of protein or polypeptide (i.e., an effective dosage) ranges from about 0.001 to 30 mg/kg body weight, sometimes about 0.01 to 25 mg/kg body weight, often about 0.1 to 20 mg/kg body weight, and more often about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight. The protein or polypeptide can be administered one time per week for between about 1 to 10 weeks, sometimes between 2 to 8 weeks, often between about 3 to 7 weeks, and more often for about 4, 5, or 6 weeks. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a protein, polypeptide, or antibody can include a single treatment or, preferably, can include a series of treatments.

[0173] With regard to polypeptide formulations, featured herein is a method for treating type II diabetes in a subject, which comprises contacting one or more cells in the subject with a first polypeptide, where the subject comprises a second polypeptide having one or more polymorphic variations associated with cancer, and where the first polypeptide comprises fewer polymorphic variations associated with cancer than the second polypeptide. The first and second polypeptides are encoded by a nucleic acid which comprises a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6; a nucleotide sequence which encodes a polypeptide consisting of an amino acid sequence encoded by a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6; a nucleotide sequence which encodes a polypeptide that is 90% or more identical to an amino acid sequence encoded by a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6 and a nucleotide sequence 90% or more identical to a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6. The subject often is a human.

[0174] For antibodies, a dosage of 0.1 mg/kg of body weight (generally 10 mg/kg to 20 mg/kg) is often utilized. If the antibody is to act in the brain, a dosage of 50 mg/kg to 100 mg/kg is often appropriate. Generally, partially human antibodies and fully human antibodies have a longer half- life within the human body than other antibodies. Accordingly, lower dosages and less frequent administration is often possible. Modifications such as lipidation can be used to stabilize antibodies and to enhance uptake and tissue penetration (e.g. , into the brain). A method for lipidation of antibodies is described by Cruikshank et ah, J. Acquired Immune Deficiency Syndromes and Human Retrovirology 14:193 (1997).

[0175] Antibody conjugates can be used for modifying a given biological response, the drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drag moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a polypeptide such as tumor necrosis factor, .alpha.-interferon, .beta. -interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin-1 ("IL-I"), interleukin-2 ("IL-2"), interleukin-6 ("IL-6"), granulocyte macrophage colony stimulating factor ("GM-CSF"), granulocyte colony stimulating factor ("G-CSF"), or other growth factors. Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Patent No. 4,676,980.

[0176] For compounds, exemplary doses include milligram or microgram amounts of the compound per kilogram of subject or sample weight, for example, about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram. It is understood that appropriate doses of a small molecule depend upon the potency of the small molecule with respect to the expression or activity to be modulated. When one or more of these small molecules is to be administered to an animal (e.g. , a human) in order to modulate expression or activity of a polypeptide or nucleic acid described herein, a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained. In addition, it is understood that the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.

[0177] With regard to nucleic acid formulations, gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Patent No. 5,328,470) or by stereotactic injection (see e.g., Chen et al, (1994) Proc. Natl. Acad. Sci. USA Pi:3054-3057). Pharmaceutical preparations of gene therapy vectors can include a gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells (e.g., retroviral vectors) the pharmaceutical preparation can include one or more cells which produce the gene delivery system. Examples of gene delivery vectors are described herein. Therapeutic Methods

[0178] A therapeutic formulation described above can be administered to a subject in need of a therapeutic for inducing a desired biological response.. Therapeutic formulations can be administered by any of the paths described herein. With regard to both prophylactic and therapeutic methods of treatment, such treatments may be specifically tailored or modified, based on knowledge obtained from pharmacogenomic analyses described herein.

[0179] As used herein, the term "treatment" is defined as the application or administration of a therapeutic formulation to a subject, or application or administration of a therapeutic agent to an isolated tissue or cell line from a subject with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect type II diabetes, symptoms of type II diabetes or a predisposition towards type II diabetes. A therapeutic formulation includes, but is not limited to, small molecules, peptides, antibodies, ribozymes and antisense oligonucleotides. Administration of a therapeutic formulation can occur prior to the manifestation of symptoms characteristic of type II diabetes, such that type II diabetes is prevented or delayed in its progression. The appropriate therapeutic composition can be determined based on screening assays described herein.

[0180] In related aspects, embodiments include methods of causing or inducing a desired biological response in an individual comprising the steps of: providing or administering to an individual a composition comprising a polypeptide described herein, or a fragment thereof, or a therapeutic formulation described herein, wherein said biological response is selected from the group consisting of: (a) modulating circulating (either blood, serum or plasma) levels (concentration) of glucose, wherein said modulating is preferably lowering; (b) increasing cell or tissue sensitivity to insulin, particularly muscle, adipose, liver or brain; (c) inhibiting the progression from impaired glucose tolerance to insulin resistance; (d) increasing glucose uptake in skeletal muscle cells; (e) increasing glucose uptake in adipose cells; (f) increasing glucose uptake in neuronal cells; (g) increasing glucose uptake in red blood cells; (h) increasing glucose uptake in the brain; and (i) significantly reducing the postprandial increase in plasma glucose following a meal, particularly a high carbohydrate meal.

[0181] In other embodiments, a pharmaceutical or physiologically acceptable composition can be utilized as an insulin sensitizer, or can be used in: a method to improve insulin sensitivity in some persons with type II diabetes in combination with insulin therapy; a method to improve insulin sensitivity in some persons with type II diabetes without insulin therapy; or a method of treating individuals with gestational diabetes. Gestational diabetes refers to the development of diabetes in an individual during pregnancy, usually during the second or third trimester of pregnancy. In further embodiments, the pharmaceutical or physiologically acceptable composition can be used in a method of treating individuals with impaired fasting glucose (EFG). Impaired fasting glucose (JFG) is a condition in which fasting plasma glucose levels in an individual are elevated but not diagnostic of overt diabetes (i.e. plasma glucose levels of less than 126 mg/dl and greater than or equal to 110 mg/dl).

[0182] In other embodiments, the pharmaceutical or physiologically acceptable composition can be used in a method of treating and preventing impaired glucose tolerance (IGT) in an individual. By providing therapeutics and methods for reducing or preventing IGT (i.e., for normalizing insulin resistance) the progression to type II diabetes can be delayed or prevented. Furthermore, by providing therapeutics and methods for reducing or preventing insulin resistance, provided are methods for reducing and/or preventing the appearance of Insulin-Resistance Syndrome (IRS). In further embodiments, the pharmaceutical or physiologically acceptable composition can be used in a method of treating a subject having polycystic ovary syndrome (PCOS). PCOS is among the most common disorders of premenopausal women, affecting 5-10% of this population. Insulin-sensitizing agents (e.g., troglitazone) have been shown to be effective in PCOS and that, in particular, the defects in insulin action, insulin secretion, ovarian steroidogenesis and fibrinolysis are improved (Ehrman et al. (1997) J Clin Invest 100:1230), such as in insulin- resistant humans. Accordingly, provided are methods for reducing insulin resistance, normalizing blood glucose thus treating and/or preventing PCOS.

[0183] In certain embodiments, the pharmaceutical or physiologically acceptable composition can be used in a method of treating a subject having insulin resistance, where a subject having insulin resistance is treated to reduce or cure the insulin resistance, As insulin resistance is^" also often associated with infections and cancer, preventing or reducing insulin resistance may prevent or reduce infections and cancer.

[0184] In other embodiments, the pharmaceutical compositions and methods described herein^' are useful for: preventing the development of insulin resistance in a subject, e.g., those known to have an increased risk of developing insulin resistance; controlling blood glucose in some persons with type II diabetes in combination with insulin therapy; increasing cell or tissue sensitivity to insulin, particularly muscle, adipose, liver or brain; inhibiting or preventing the progression from impaired glucose tolerance to insulin resistance; improving glucose control of type II diabetes patients alone, without an insulin secretagogue or an insulin sensitizing agent; and administering a complementary therapy to type II diabetes patients to improve their glucose control in combination with an insulin secretagogue (preferably oral form) or an insulin sensitizing (preferably oral form) agent. In the latter embodiment, the oral insulin secretagogue sometimes is l,l-dimethyl-2-(2- morpholino phenyl)guanidine fumarate (BTS67582) or a sulphonylurea selected from tolbutamide, tolazamide, chlorpropamide, glibenclamide, glimepiride, glipizide and glidazide. The insulin sensitizing agent sometimes is selected from metformin, ciglitazone, troglitazone and pioglitazone.

[0185] Further embodiments include methods of administering a pharmaceutical or physiologically acceptable composition concomitantly or concurrently, with an insulin secretagogue or insulin sensitizing agent, for example, in the form of separate dosage units to be used simultaneously, separately or sequentially {e.g., before or after the secretagogue or before or after the sensitizing agent). Accordingly, provided is a pharmaceutical or physiologically acceptable composition and an insulin secretagogue or insulin sensitizing agent as a combined preparation for simultaneous, separate or sequential use for the improvement of glucose control in type II diabetes patients.

[0186] Thus, any test known in the art or a method described herein can be used to determine that a subject is insulin resistant, and an insulin resistant patient can then be treated according to the methods described herein to reduce or cure the insulin resistance. Alternatively, the methods described herein also can be used to prevent the development of insulin resistance in a subject, e.g., those known to have an increased risk of developing insulin-resistance.

[0187] As discussed, successful treatment of type II diabetes can be brought about by techniques that serve to agonize target molecule expression or function, or alternatively, antagonize target molecule expression or function. These techniques include administration of modulators that include, but are not limited to, small organic or inorganic molecules; antibodies (including, for example, polyclonal, monoclonal, humanized, anti-idiotypic, chimeric or single chain antibodies, and Fab, F(ab')₂ and Fab expression library fragments, scFV molecules, and epitope-binding fragments thereof); and peptides, phosphopeptides, or polypeptides.

[0188] Further, antisense and ribozyme molecules that inhibit expression of the target gene can also be used to reduce the level of target gene expression, thus effectively reducing the level of target gene activity. Still further, triple helix molecules can be utilized in reducing the level of target gene activity. Antisense, ribozyme and triple helix molecules are discussed above. It is possible that the use of antisense, ribozyme, and/or triple helix molecules to reduce or inhibit mutant gene expression can also reduce or inhibit the transcription (triple helix) and/or translation (antisense, ribozyme) of mRNA produced by normal target gene alleles, such that the concentration of normal target gene product present can be lower than is necessary for a normal phenotype. In such cases, nucleic acid molecules that encode and express target gene polypeptides exhibiting normal target gene activity can be introduced into cells via gene therapy method. Alternatively, in instances in that the target gene encodes an extracellular polypeptide, it can be preferable to co¬ administer normal target gene polypeptide into the cell or tissue in order to maintain the requisite level of cellular or tissue target gene activity.

[0189] Another method by which nucleic acid molecules may be utilized in treating or preventing type II diabetes is use of aptamer molecules specific for target molecules. Aptamers are nucleic acid molecules having a tertiary structure which permits them to specifically bind to ligands {see, e.g., Osborne, et at, Curr. Opin. Chem. Biol.l(l): 5-9 (1997); and Patel, D. J., Curr. Opin. Chem. Biol. Jun;l(l): 32-46 (1997)). [0190] Yet another method of utilizing nucleic acid molecules for type II diabetes treatment-is gene therapy, which can also be referred to as allele therapy. Provided herein is a gene therapy method for treating type II diabetes in a subject, which comprises contacting one or more cells in the subject or from the subject with a nucleic acid having a first nucleotide sequence. Genomic DNA in the subject comprises a second nucleotide sequence having one or more polymorphic variations associated with type II diabetes (e.g., the second nucleic acid is selected from Table 1 or SEQ ID NO: 1-6). The first and second nucleotide sequences typically are substantially identical to one another, and the first nucleotide sequence comprises fewer polymorphic variations associated with type II diabetes than the second nucleotide sequence. The first nucleotide sequence may comprise a gene sequence that encodes a full-length polypeptide or a fragment thereof. The subject is often a human. Allele therapy methods often are utilized in conjunction with a method of first determining whether a subject has genomic DNA that includes polymorphic variants associated with type II diabetes.

[0191] In another allele therapy embodiment, provided herein is a method which comprises contacting one or more cells in the subject or from the subject with a polypeptide encoded by a nucleic acid having a first nucleotide sequence. Genomic DNA in the subject comprises a second nucleotide sequence having one or more polymorphic variations associated with type II diabetes (e.g., the second nucleic acid is selected from Table 1 or SEQ ID NO: 1-6). The first and second nucleotide sequences typically are substantially identical to one another, and the first nucleotide sequence comprises fewer polymorphic variations associated with type II diabetes than the second nucleotide sequence. The first nucleotide sequence may comprise a gene sequence that encodes a full-length polypeptide or a fragment thereof. The subject is often a human.

[0192] For antibody-based therapies, antibodies can be generated that are both specific for target molecules and that reduce target molecule activity. Such antibodies may be administered in instances where antagonizing a target molecule function is appropriate for the treatment of type II diabetes.

[0193] In circumstances where stimulating antibody production in an animal or a human subject by injection with a target molecule is harmful to the subject, it is possible to generate an immune response against the target molecule by use of anti-idiotypic antibodies (see, e.g., Herlyn, Ann. Med.; 31(1): 66-78 (1999); and Bhattacharya-Chatterjee & Foon, Cancer Treat. Res.; 94: 51- 68 (1998)). Introducing an anti-idiotypic antibody to a mammal or human subject often stimulates production of anti-anti-idiotypic antibodies, which typically are specific to the target molecule. Vaccines directed to type II diabetes also may be generated in this fashion.

[0194] In instances where the target molecule is intracellular and whole antibodies are used, internalizing antibodies may be preferred. Lipofectin or liposomes can be used to deliver the antibody or a fragment of the Fab region that binds to the target antigen into cells. Where fragments of the antibody are used, the smallest inhibitory fragment that binds to the target antigen is preferred. For example, peptides having an amino acid sequence corresponding to the Fv region of the antibody can be used. Alternatively, single chain neutralizing antibodies that bind to intracellular target antigens can also be administered. Such single chain antibodies can be administered, for example, by expressing nucleotide sequences encoding single-chain antibodies within the target cell population (see, e.g., Marasco et ah, Proc. Natl. Acad. ScL USA 90: 7889- 7893 (1993)).

[0195] Modulators can be administered to a patient at therapeutically effective doses to treat type II diabetes. A therapeutically effective dose refers to an amount of the modulator sufficient to result in amelioration of symptoms of type II diabetes. Toxicity and therapeutic efficacy of modulators can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD₅₀ZED₅₀. Modulators that exhibit large therapeutic indices are preferred. While modulators that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such molecules to the site of affected tissue in order to minimize potential damage to uninfected cells, thereby reducing side effects.

[0196] Data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED₅₀ with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC₅₀ (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography.

[0197] Another example of effective dose determination for an individual is the ability to directly assay levels of "free" and "bound" compound in the serum of the test subject. Such assays may utilize antibody mimics and/or "biosensors" that have been created through molecular imprinting techniques. Molecules that modulate target molecule activity are used as a template, or "imprinting molecule", to spatially organize polymerizable monomers prior to their polymerization with catalytic reagents. The subsequent removal of the imprinted molecule leaves a polymer matrix which contains a repeated "negative image" of the compound and is able to selectively rebind the molecule under biological assay conditions. A detailed review of this technique can be seen in Ansell et al., Current Opinion in Biotechnology 7: 89-94 (1996) and in Shea, Trends in Polymer Science 2: 166-173 (1994). Such "imprinted" affinity matrixes are amenable to ligand-binding assays, whereby the immobilized monoclonal antibody component is replaced by an appropriately imprinted matrix. An example of the use of such matrixes in this way can be seen in Vlatakis, et al, Nature 361: 645-647 (1993). Through the use of isotope-labeling, the "free" concentration of compound which modulates target molecule expression or activity readily can be monitored and used in calculations of IC₅₀. Such "imprinted" affinity matrixes can also be designed to include fluorescent groups whose photon-emitting properties measurably change upon local and selective binding of target compound. These changes readily can be assayed in real time using appropriate fiberoptic devices, in turn allowing the dose in a test subject to be quickly optimized based on its individual IC₅₀. An example of such a "biosensor" is discussed in Kriz et al, Analytical Chemistry 67: 2142-2144 (1995).

[0198] The examples set forth below are intended to illustrate but not limit the invention.

Examples

[0199] In the following studies a group of subjects were selected according to specific parameters pertaining to type II diabetes. Nucleic acid samples obtained from individuals in the study group were subjected to genetic analyses that identified associations between type II diabetes and certain polymorphic variants in human genomic DNA. In some instances, SNPs proximal to incident SNPs identified in Table 1 also were identified and analyzed in cases and controls (see Examples 5-8). Methods are described for producing target polypeptides encoded by the nucleic acids of Table 1 or SEQ ID NO: 1-6 in vitro or in vivo, which can be utilized in methods that screen ■ test molecules for those that interact with target polypeptides. Test molecules identified as being interactors with target polypeptides can be screened further as type II diabetes therapeutics.

Example 1 Samples and Pooling Strategies

Sample Selection

[0200] Blood samples were collected from individuals diagnosed with type II diabetes, which were referred to case samples. Also, blood samples were collected from individuals not diagnosed with type II diabetes or a history of type II diabetes; these samples served as gender and age- matched controls. A database was created that listed all phenotypic trait information gathered from individuals for each case and control sample. Genomic DNA was extracted from each of the blood samples for genetic analyses. DNA Extraction from Blood Samples

. [0201] Six to ten milliliters of whole blood was transferred to a 50 ml tube containing 27 ml of red cell lysis solution (RCL). The tube was inverted until the contents were mixed. Each tube was incubated for 10 minutes at room temperature and inverted once during the incubation. The tubes were then centrifuged for 20 minutes at 3000 x g and the supernatant was carefully poured off. 100-200 μl of residual liquid was left in the tube and was pipetted repeatedly to resuspend the pellet in the residual supernatant. White cell lysis solution (WCL) was added to the tube and pipetted repeatedly until completely mixed. While no incubation was normally required, the solution was incubated at 37°C or room temperature if cell clumps were visible after mixing until the solution was homogeneous. 2 ml of protein precipitation was added to the cell lysate. The mixtures were vortexed vigorously at high speed for 20 sec to mix the protein precipitation solution uniformly with the cell lysate, and then centrifuged for 10 minutes at 3000 x g. The supernatant containing the DNA was then poured into a clean 15 ml tube, which contained 7 ml of 100% isopropanol. The samples were mixed by inverting the tubes gently until white threads of DNA were visible. Samples were centrifuged for 3 minutes at 2000 x g and the DNA was visible as a small white pellet. The supernatant was decanted and 5 ml of 70% ethanol was added to each tube. Each tube was inverted several times to wash the DNA pellet, and then centrifuged for 1 minute at 2000 x g. The ethanol was decanted and each tube was drained on clean absorbent paper. The DNA was dried in the tube by inversion for 10 minutes, and then 1000 μl of IX TE was added. The size of each sample was estimated, and less TE buffer was added during the following DNA hydration step if the sample was smaller. The DNA was allowed to rehydrate overnight at room temperature, and DNA samples were stored at 2-8°C.

[0202] DNA was quantified by placing samples on a hematology mixer for at least 1 hour. DNA was serially diluted (typically 1:80, 1:160, 1:320, and 1:640 dilutions) so that it would be within the measurable range of standards. 125 μl of diluted DNA was transferred to a clear U- bottom microtiter plate, and 125 μl of IX TE buffer was transferred into each well using a multichannel pipette. The DNA and IX TE were mixed by repeated pipetting at least 15 times, and then the plates were sealed. 50 μl of diluted DNA was added to wells A5-H12 of a black flat bottom microtiter plate. Standards were inverted six times to mix them, and then 50 μl of IX TE buffer was pipetted into well Al , 1000 ng/ml of standard was pipetted into well A2, 500 ng/ml of standard was pipetted into well A3, and 250 ng/ml of standard was pipetted into well A4. PicoGreen (Molecular Probes, Eugene, Oregon) was thawed and freshly diluted 1:200 according to the number of plates that were being measured. PicoGreen was vortexed and then 50μl was pipetted into all wells of the black plate with the diluted DNA. DNA and PicoGreen were mixed by pipetting repeatedly at least 10 times with the multichannel pipette. The plate was placed into a Fluoroskan Ascent Machine (microplate fluorometer produced by Labsystems) and the samples were allowed to incubate for 3 minutes before the machine was run using filter pairs 485 nm excitation and 538 nm emission wavelengths. Samples having measured DNA concentrations of greater than 450 ng/μl were re-measured for conformation. Samples having measured DNA concentrations of 20 ng/μl or less were re-measured for confirmation.

Pooling Strategies

[0203] Samples were placed into one of four groups based on disease status. The four groups were female case samples, female control samples, male case samples and male control samples. A select set of samples from each group were utilized to generate pools, and one pool was created for each group. Each individual sample in a pool was represented by an equal amount of genomic DNA. For example, where 25 ng of genomic DNA was utilized in each PCR reaction and there were 200 individuals in each pool, each individual would provide 125 pg of genomic DNA. Inclusion or exclusion of samples for a pool was based upon the following criteria and detailed in the tables below: patient ethnicity, diagnosis with type II diabetes, GAD antibody concentration, HbAIc concentration, body mass (BMI), patient age, date of primary diagnosis, and age of individual as of primary diagnosis. (See Table 2 below). Cases with elevated GAD antibody titers and low age of diagnosis were excluded to increase the homogeneity of the diabetes sample in terms of underlying pathogenesis. Controls with elevated HbAIc were excluded to remove any potentially undiagnosed diabetics. Control samples were derived from non-diabetic individuals with no family history of type II diabetes. Secondary phenotypes were also measured in the diabetic cases, including HDL levels, LDL levels, triglyceride levels, insulin levels, C-peptide levels, nephropathy status, and neuropathy status, to name a few. The phenotype data collected may be used to perform secondary analysis of the cases in order to elucidate the potential pathway of a disease gene.

TABLE 2

[0204] The selection process yielded the pools described in Table 3, which were used in the studies described herein.

TABLE 3

Example 2 Association of Polymorphic Variants with Type II Diabetes

[0205] A whole-genome screen was performed to identify particular SNPs associated with occurrence of type II diabetes. As described in Example 1, two sets of samples were utilized: female individuals having type II diabetes (female cases) and samples from female individuals not having type II diabetes or any history of type II diabetes (female controls), and male individuals having type II diabetes (male cases) and samples from male individuals not having type II diabetes or any history of type II diabetes (male controls). The initial screen of each pool was performed in an allelotyping study, in which certain samples in each group were pooled. By pooling DNA from each group, an allele frequency for each SNP in each group was calculated. These allele frequencies were then compared to one another. Particular SNPs were considered as being associated with type II diabetes when allele frequency differences calculated between case and control pools were statistically significant. SNP disease association results obtained from the allelotyping study were then validated by genotyping each associated SNP across all samples from each pool. The results of the genotyping were then analyzed, allele frequencies for each group were calculated from the individual genotyping results, and a p-value was calculated to determine whether the case and control groups had statistically significantly differences in allele frequencies for a particular SNP. When the genotypiαg results agreed with the original allelotyping results, the SNP disease association was considered validated at the genetic level.

SNP Panel Used for Genetic Analyses- First Pass

[0206] A whole-genome SNP screen began with an initial screen of approximately 25,000 SNPs over each set of disease and control samples using a pooling approach. The pools studied in the screen are described in Example 1. The SNPs analyzed in this study were part of a set of 25,488 SNPs confirmed as being statistically polymorphic as each is characterized as having a minor allele frequency of greater than 10%. The SNPs in the set reside in genes or in close proximity to genes, and many reside in gene exons. Specifically, SNPs in the set are located in exons, introns, and within 5,000 base-pairs upstream of a transcription start site of a gene, hi addition, SNPs were selected according to the following criteria: they are located in ESTs; they are located in Locuslink or Ensembl genes; and they are located in Genomatix promoter predictions. SNPs in the set were also selected on the basis of even spacing across the genome, as depicted in Table 4.

TABLE 4

General Statistics Spacing Statistics

Total # of SNPs 25,488 Median 37,058 bp

# of Exonic SNPs >4,335 (17%) Minimum* 1,000 bp

# SNPs with refSNP ID 20,776 (81%) Maximum* 3,000,000 bp

Gene Coverage >10,000 Mean 122,412 bp

Chromosome Coveraj IQ All Std Deviation 373,325 bp

^Excludes outliers

Genotyping Results

[0207] The genetic studies summarized above and described in more detail below identified allelic variants associated with type II diabetes. The allelic variants identified from the SNP panel described in Table 4 are summarized in Table 1.

Assay for Verifying, Allelotyping, and Genotvping SNPs

[0208] A MassARRAY® system (Sequenom, Inc.) was utilized to perform SNP genotyping in a high-throughput fashion. This genotypiαg platform was complemented by a homogeneous, single-tube assay method (hME™ or homogeneous MassEXTEND™ (Sequenom, Inc.)) in which two genotyping primers anneal to and amplify a genomic target surrounding a polymorphic site of interest. A third primer (the MassEXTEND™ primer), which is complementary to the amplified target up to but not including the polymorphism, was then enzymatically extended one or a few bases through the polymorphic site and then terminated.

[0209] For each polymorphism, SpectroDESIGNER™ software (Sequenom, Inc.) was used to generate a set of PCR primers and a MassEXTEND™ primer which where used to genotype the polymorphism. Other primer design software could be used or one of ordinary skill in the art could manually design primers based on his or her knowledge of the relevant factors and considerations in designing such primers. Table 5 shows PCR primers and Table 6 shows extension probes used for analyzing the polymorphisms set forth in Table 1. The initial PCR amplification reaction was performed in a 5 μl total volume containing IX PCR buffer with 1.5 mM MgCl₂ (Qiagen), 200 μM each of dATP, dGTP, dCTP, dTTP (Gibco-BRL), 2.5 ng of genomic DNA, 0.1 units of HotStar DNA polymerase (Qiagen), and 200 nM each of forward and reverse PCR primers specific for the polymorphic region of interest.

TABLE 5: PCR Primers

[0210] Samples were incubated at 95⁰C for 15 minutes, followed by 45 cycles of 95°C for 20 seconds, 56°C for 30 seconds, and 72°C for 1 minute, finishing with a 3 minute final extension at 72°C. Following amplification, shrimp alkaline phosphatase (SAP) (0.3 units in a 2 μl volume) (Amersham Pharmacia) was added to each reaction (total reaction volume was 7 μl) to remove any residual dNTPs that were not consumed in the PCR step. Samples were incubated for 20 minutes at 37°C, followed by 5 minutes at 85°C to denature the SAP. [0211] Once the SAP reaction was complete, a primer extension reaction was initiated by adding a polymorphism-specific MassEXTEND™ primer cocktail to each sample. Each MassEXTEND™ cocktail included a specific combination of dideoxynucleotides (ddNTPs) and deoxynucleotides (dNTPs) used to distinguish polymorphic alleles from one another. Methods for verifying, allelotyping and genotyping SNPs are disclosed, for example, in U.S. Pat. No. 6,258,538, the content of which is hereby incorporated by reference. In Table 6, ddNTPs are shown and the fourth nucleotide not shown is the dNTP.

TABLE 6: Extension Primers

[0212] The MassEXTEND™ reaction was performed in a total volume of 9 μl, with the addition of IX ThermoSequenase buffer, 0.576 units of ThermoSequenase (Amersham Pharmacia), 600 nM MassEXTEND™ primer, 2 mM of ddATP and/or ddCTP and/or ddGTP and/or ddTTP, and 2 mM of dATP or dCTP or dGTP or dTTP. The deoxy nucleotide (dNTP) used in the assay normally was complementary to the nucleotide at the polymorphic site in the amplicon. Samples were incubated at 94⁰C for 2 minutes, followed by 55 cycles of 5 seconds at 94⁰C, 5 seconds at 52°C, and 5 seconds at 72°C.

[0213] Following incubation, samples were desalted by adding 16 μl of water (total reaction volume was 25 μl), 3 mg of SpectroCLEAN™ sample cleaning beads (Sequenom, Inc.) and allowed to incubate for 3 minutes with rotation. Samples were then robotically dispensed using a piezoelectric dispensing device (SpectroJET™ (Sequenom, Inc.)) onto either 96-spot or 384-spot silicon chips containing a matrix that crystallized each sample (SpectroCHJP® (Sequenom, Inc.)). Subsequently, MALDI-TOF mass spectrometry (Biflex and Autoflex MALDI-TOF mass spectrometers (Bruker Daltonics) can be used) and SpectroTYPER RT™ software (Sequenom, Inc.) were used to analyze and interpret the SNP genotype for each sample.

Genetic Analysis [0214] Minor allelic frequencies for the polymorphisms set forth in Table 1 were verified as being 10% or greater using the extension assay described above in a group of samples isolated from 92 individuals originating from the state of Utah in the United States, Venezuela and France (Coriell cell repositories).

[0215] Genotyping results for the allelic variants set forth in Table 1 are shown for female pools in Table 7, for male pools in Table 8, and for combined female and male results in Table 9. In Table 7, "F case" and "F control" refer to female case and female control groups, and in Table 8, "M case" and "M control" refer to male case and male control groups.

TABLE 7: Female Genotyping Results

TABLE 8: Male Genotyping Results

TABLE 9: Combined Genotyping Results

[0216] All of the single marker alleles set forth in Table 1 were considered validated, since the genotyping data for the females, males or both pools were significantly associated with type II diabetes, and because the genotyping results agreed with the original allelotyping results. Particularly significant associations with type II diabetes are indicated by a calculated p-value of less than 0.05 for genotype results, which are set forth in bold text.

[0217] An odds ratio (OR) can be calculated for each polymorphic association. An odds ratio is an unbiased estimate of relative risk which can be obtained from most case-control studies. Relative risk (RR) is an estimate of the likelihood of disease in the exposed group (susceptibility allele or genotype carriers) compared to the unexposed group (not carriers). It can be calculated by the following equation:

RR = /A//a

/A is the incidence of disease in the A carriers and /a is the incidence of disease in the non- carriers.

RR > 1 indicates the A allele increases disease susceptibility.

RR < 1 indicates the a allele increases disease susceptibility.

For example, RR = 1.5 indicates that carriers of the A allele have 1.5 times the risk of disease than non-carriers, i.e., 50% more likely to get the disease.

[0218] Case-control studies do not allow the direct estimation of /A and /a, therefore relative risk cannot be directly estimated. However, the odds ratio (OR) can be calculated using the following equation:

OR = (nDAnda)/(ndAnDa) =/>DA(l - PdA)^dA(I - PDA), or [0219] An odds ratio can be interpreted in the same way a relative risk is interpreted and can be directly estimated using the data from case-control studies, i.e., case and control frequencies. The higher the odds ratio value, the larger the effect that a particular allele has on the development of prostate cancer. Thus, a subject possessing an allele associated with a relatively high odds ratio is expected to be at a relatively higher risk of developing prostate cancer as compared to other individuals in a population.

Example 3 Polymorphic Positions in LOC391238

[0220] SNP rs971957 is associated with type II diabetes and falls near LOC391238. Four hundred-fourteen additional allelic variants proximal to rs971957 were identified and subsequently allelotyped in diabetes case and control sample sets as described in Examples 1 and 2. The polymorphic variants are set forth in Table 10. The chromosome positions provided in column four of Table 10 are based on Genome "Build 34" of NCBFs GenBank.

TABLE 10

Assay for Verifying and Allelotyping SNPs

[0221] The methods used to verify and allelotype the 414 proximal SNPs of Table 10 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 11 and Table 12, respectively.

TABLE 11

dbSNP Forward Reverse rs# PCR primer PCR primer

226680 AGAAAGCTGGCTGTTTCCTC CATGGACTC GATCCAC

2424688 GGGAAAGTGAGAGAAGAAGC CCAGAAAACCACCTCTCTTC

2424689 GGGAAAGTGAGAGAAGAAGC CCAGAAAACCACCTCTCTTC

TABLE 12

Genetic Analysis

[0222] Allelotyping results are shown for female (F) and male (M) cases and controls in Table 13 and 14, and the combined allelotyping results are shown in Table 15. The allele frequency for the A2 allele is noted in the fifth and sixth columns for diabetes case pools and control pools, respectively, where "AF" is allele frequency. The allele frequency for the Al allele can be easily calculated by subtracting the A2 allele frequency from 1 (Al AF = 1-A2 AF). For example, the SNP rs8121573 has the following case and control allele frequencies: case Al (C) = 0.058; case A2 (T) = 0.942; control Al (C) = 0.066; and control A2 (T) = 0.934, where the nucleotide is provided in parenthesis. Some SNPs are labeled "untyped" because of failed assays.

TABLE 13

TABLE 14

TABLE 15

[0223] Allelotyping results were considered particularly significant with a calculated p-value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p- values were plotted in Figures IA-C for females, males and combined, respectively. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in Figures IA-C can be determined by consulting Tables 13-15. For example, the left-most X on the left graph is at position 24668429. By proceeding down the Table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.

[0224] To aid the interpretation, multiple lines have been added to the graph. The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01. The vertical broken lines are drawn every 20kb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The light gray line (or generally bottom-most curve) is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W. S. Cleveland, E. Grosse and W.M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J.M. Chambers and TJ. Hastie, Wadsworth & Brooks/Cole.). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a 10kb sliding window with lkb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01 , to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 10^"8 were truncated at that value.

[0225] Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is placed at the 3 ' end of each gene to show the direction of transcription.

Example 4 Polymorphic Positions in EIF4G2

[0226] SNP rs903835 is associated with type II diabetes and falls near EIF4G2. One hundred forty additional allelic variants proximal to rs903835 were identified and subsequently allelotyped in diabetes case and control sample sets as described in Examples 1 and 2. The polymorphic variants are set forth in Table 16. The chromosome positions provided in column four of Table 16 are based on Genome "Build 34" of NCBFs GenBank. TABLE 16

Assay for Verifying and Allelotyping SNPs

[0227] The methods used to verify and allelotype the 140 proximal SNPs of Table 16 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 17 and Table 18, respectively.

TABLE 17

TABLE 18

Genetic Analysis

[0228] Allelotyping results are shown for female (F) and male (M) cases and controls in Table 19 and 20, and the combined allelotyping results are shown in Table 21. The allele frequency for the A2 allele is noted in the fifth and sixth columns for diabetes case pools and control pools, respectively, where "AF" is allele frequency. The allele frequency for the Al allele can be easily calculated by subtracting the A2 allele frequency from 1 (Al AF = 1-A2 AF). For example, the SNP rs7103192 has the following case and control allele frequencies: case Al (T) = 0.709; case A2 (C) = 0.291; control Al (T) = 0.733; and control A2 (C) = 0.267, where the nucleotide is provided in parenthesis. Some SNPs are labeled "untyped" because of failed assays.

TABLE 19

TABLE 20

TABLE 21

[0229] Allelotyping results were considered particularly significant with a calculated p- value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p-values were plotted in Figures 2A-C for females, males and combined, respectively. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in Figures 2A-C can be determined by consulting Tables 19-21. For example, the left-most X on the left graph is at position 10767886. By proceeding down the Table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.

[0230] To aid the interpretation, multiple lines have been added to the graph. The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01. The vertical broken lines are drawn every 20kb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The light gray line (or generally bottom-most curve) is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W.S. Cleveland, E. Grosse and W.M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J.M. Chambers and TJ. Hastie, Wadsworth & Brooks/Cole.). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a 10kb sliding window with lkb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01 , to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 10^"8 were truncated at that value. [0231] Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is placed at the 3' end of each gene to show the direction of transcription.

Example 5 Polymorphic Positions in Proximal to SNP rs rs214140

[0232] SNP rs214140 is associated with type II diabetes. One hundred seventy-five additional allelic variants proximal to rs214140 were identified and subsequently allelotyped in diabetes case and control sample sets as described in Examples 1 and 2. The polymorphic variants are set forth in Table 22. The chromosome positions provided in column four of Table 22 are based on Genome "Build 34" ofNCBFs GenBank.

TABLE 22

Assay for Verifying and Allelotyping SNPs

[0233] The methods used to verify and allelotype the 175 proximal SNPs of Table 22 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 23 and Table 24, respectively.

TABLE 23

TABLE 24

Genetic Analysis

[0234] Allelotyping results are shown for female (F) and male (M) cases and controls in Table 25 and 26, and the combined allelotyping results are shown in Table 27. The allele frequency for the A2 allele is noted in the fifth and sixth columns for diabetes case pools and control pools, respectively, where "AF" is allele frequency. The allele frequency for the Al allele can be easily calculated by subtracting the A2 allele frequency from 1 (Al AF = 1-A2 AF). For example, the SNP rs2206993 has the following case and control allele frequencies: case Al (C) = 0.877; case A2 (T) = 0.123; control Al (C) = 0.890; and control A2 (T) = 0.110, where the nucleotide is provided in parenthesis. Some SNPs are labeled "untyped" because of failed assays. TABLE 25

TABLE 26

TABLE 27

[0235] Allelotyping results were considered particularly significant with a calculated p-value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p-values were plotted in Figures 3A-C for females, males and combined, respectively. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in Figures 3A-C can be determined by consulting Tables 25-27. For example, the left-most X on the left graph is at position 62187734. By proceeding down the Table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.

[0236] To aid the interpretation, multiple lines have been added to the graph. The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01. The vertical broken lines are drawn every 20kb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The light gray line (or generally bottom-most curve) is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W.S. Cleveland, E. Grosse and W.M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J.M. Chambers and TJ. Hastie, Wadsworth & Brooks/Cole.). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a 10kb sliding window with lkb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01, to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 10^"8 were truncated at that value.

[0237] Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is placed at the 3' end of each gene to show the direction of transcription.

Example 6 In Vitro Production of Target Polypeptides

[0238] Polypeptides encoded by polynucleotides provided in Table 1 may be produced by the methods described herein.

[0239] cDNA is cloned into a pIVEX 2.3-MCS vector (Roche Biochem) using a directional cloning method. A cDNA insert is prepared using PCR with forward and reverse primers having 5 ' restriction site tags (in frame) and 5-6 additional nucleotides in addition to 3' gene-specific portions, the latter of which is typically about twenty to about twenty-five base pairs in length. A Sal I restriction site is introduced by the forward primer and a Sma I restriction site is introduced by the reverse primer. The ends of PCR products are cut with the corresponding restriction enzymes (i.e., Sal I and Sma I) and the products are gel-purified. The pIVEX 2.3-MCS vector is linearized using the same restriction enzymes, and the fragment with the correct sized fragment is isolated by gel-purification. Purified PCR product is ligated into the linearized pIVEX 2.3-MCS vector and E. coli cells transformed for plasmid amplification. The newly constructed expression vector is verified by restriction mapping and used for protein production.

[0240] E. coli lysate is reconstituted with 0.25 ml of Reconstitution Buffer, the Reaction Mix is reconstituted with 0.8 ml of Reconstitution Buffer; the Feeding Mix is reconstituted with 10.5 ml of Reconstitution Buffer; and the Energy Mix is reconstituted with 0.6 ml of Reconstitution Buffer. 0.5 ml of the Energy Mix was added to the Feeding Mix to obtain the Feeding Solution. 0.75 ml of Reaction Mix, 50 μl of Energy Mix, and 10 μg of the template DNA is added to the E. coli lysate.

[0241] Using the reaction device (Roche Biochem), 1 ml of the Reaction Solution is loaded into the reaction compartment. The reaction device is turned upside-down and 10 ml of the Feeding Solution is loaded into the feeding compartment. All lids are closed and the reaction device is loaded into the RTS500 instrument. The instrument is run at 3O⁰C for 24 hours with a stir bar speed of 150 rpm. The pIVEX 2.3 MCS vector includes a nucleotide sequence that encodes six consecutive histidine amino acids on the C-terminal end of the target polypeptide for the purpose of protein purification. Target polypeptide is purified by contacting the contents of reaction device with resin modified with Ni²⁺ ions. Target polypeptide is eluted from the resin with a solution containing free Ni²⁺ ions.

Example 7 In Vitro Tests of Metabolic-Related Activity

[0242] In vitro assays described hereafter are useful for identifying therapeutics for treating human diabetes. As used in Examples hereafter directed to in vitro assays, rodent models and studies in humans, the term "test molecule" refers to a molecule that is added to a system, where an agonist effect, antagonist effect, or lack of an effect of the molecule on a Table 1 GENE function or a related physiological function in the system is assessed. "A Table 1 GENE" as used herein refers to any of the genes or gene products provided in Table 1, including nucleotides, polypeptides or fragments thereof. An example of a test molecule is a test compound, such as a test compound described in the section "Compositions Comprising Diabetes-Directed Molecules" above. Another example of a test molecule is a test peptide, which includes, for example, a Table 1 GENE-related test peptide such as a soluble, extracellular form of a Table 1 GENE, a biologically active fragment of a Table 1 GENE, a Table 1 GENE binding partner or ligand, or a functional fragment of the foregoing. A concentration range or amount of test molecule utilized in the assays and models is selected from a variety of available ranges and amounts. For example, a test molecule sometimes is introduced to an assay system in a concentration range between 1 nanomolar and 100 micromolar or a concentration range between 1 nanograms/mL and 100 micrograms/mL. An effect of a test molecule on a Table 1 GENE function or a related physiological function often is determined by comparing an effect in a system administered the test molecule against an effect in system not admininstered the test molecule. Described directly hereafter are examples of in vitro assays.

Glucose Uptake Assay

[0243] One of the many responses of adipocytes and muscle cells after exposure to insulin is the transport of glucose intracellularly. This transport is mediated by GLUT4, an insulin- regulatable glucose transporter. Insulin binding to insulin receptors on the cell surface results in autophosphorylation and activation of the intrinsic tyrosine kinase activity of the insulin receptor. Phosphorylated tyrosine residues on the insulin receptor and its endogenous targets activate several intracellular signaling pathways that eventually lead to the translocation of GLUT4 from intracellular stores to the extracellular membrane.

Methods

[0244] Cells are plated in 6-well dishes, and grown to confluency. Cells are then differentiated with DMEM plus 10% fetal calf serum (FCS), 10 ug/mL insulin, 390 ng/mL dexamethasone and 112 ug/mL isobutylmethylxanthine for 2 days. After 2 days of differentiation, media is changed to maintenance media DMEM plus 10% FCS and 5 ug/mL insulin. Media is changed every 2 days thereafter. Cells are assayed for insulin-mediated glucose uptake 10 days after differentiation. On the day of the assay, cells are washed once with PBS, and serum starved by adding 2 mL of DMEM plus 2mg/mL BSA for 3 hours. During serum starvation, recombinant rat Table 1 GENE/Fc chimeric ligand is preclustered. In a solution of PBS plus 2 mg/mL BSA, recombinant rat Table 1 GENE/Fc chimeria is added to a concentration of 1.75 ug/mL, and anti-human IgG, Fc γ fragment specific antibody to a final concentration of 17.5 ug/mL. After 3 hours of serum starvation, media is replaced with 2 mL of preclustered Table 1 GENE, and incubated for 10, 40 and 90 min at 37 deg. After 10 min, porcine insulin is added to a final concentration of 100 nM for 10 min at 37 deg. For every 2 mL of media, 100 uL of PBS-2-DOG label is added to give a final concentration of 2 uCi. Cells are immediately placed on ice, washed three times with ice cold PBS, and lysed with 0.7 mL of 0.2 N NaOH. Lysates are read in a Wallac 1450 Microbeta Liquid Scintillation and Luminescence Counter. Example 8 Triacylglycerol (TG) Assay

[0245] A direct metabolic consequence of glucose transport intracellularly is its incorporation into the fatty acid and glycerol moieties of triacylglycerol (TG). TGs are highly concentrated stores of metabolic energy, and are the major energy reservoir of cells. In mammals, the major site of accumulation of triacylglycerols is the cytoplasm of adipose cells. Adipocytes are specialized for the synthesis, and storage of TG, and for their mobilization into fuel molecules that are transported to other tissues through the bloodstream. It is likely that changes in the transport of glucose intracellularly can affect cytoplasmic stores of triacylglycerols.

Methods

[0246] Cells are plated in 6-well dishes, and grown to confiuency. When cells reached confluency, cells are differentiated with DMEM plus 10% fetal calf serum (FCS), 10 ug/mL insulin, 390 ng/niL dexamethasone and 112 ug/mL isobutylmethylxanthine for 2 days. After 2 days of differentiation, media is changed to maintenance media DMEM plus 10% FCS and 5 ug/mL insulin. On the day of the assay (day 9 post-differentiation), cells are washed once with PBS, and serum starved by adding 2 mL of DMEM plus 2 mg/mL BSA for 3 hours. During serum starvation, recombinant rat Table 1 GENE/Fc chimeric ligand is preclustered. In a solution of PBS plus 2 mg/mL BSA recombinant rat Table 1 GENE/Fc chimeria is added to a concentration of 1.75 ug/mL, and anti-human IgG, Fc γ fragment specific antibody to a final concentration of 17.5 ug/mL. After 3 hours of serum starvation, media is replaced with pre-clustered Table 1 GENE solution, and incubated for 10 minutes at 37 degrees. Cells are then treated with 100 nM porcine insulin for 2 hours at 37 degrees. Cells are immediately placed on ice, and washed twice with ice cold PBS. Cells are lysed with 1% SDS, 1.2 mM Tris, pH 7.0 and heat treated at 95 degrees for 5 minutes. Samples are assayed using INFINITY Tryglyceride reagent. In a 96-well, flat bottom, transparent microtiter plate, 3 uL of sample are added to 300 uL of INFINITY Triglyceride Reagent. Samples are incubated at room temperature for 10 minutes. The assay is read at 500-550 run.

Example 9 Quantitative Assessment of mResistin Levels

[0247] Resistin is a secreted factor specifically expressed in white adipocyte. It was initially discovered in a screen for genes downregulated in adipocytes by PPAR gamma, and expression was found to be attenuated by insulin. Elevated levels of resistin have been measured in genetically obese, and high fat fed obese mice. It is therefore thought that resistin contributes to peripheral tissue insulin unresponsiveness, one of the pathological hallmarks of diabetes. Methods

[0248] 3T3-L1 cells are differentiated for 3 days as previously described and maintained for three days prior to splitting. At day 5 post-differentiation, differentiated cells are plated in 10 cm dish at a cell density of 3X10⁶ cells. Cells are then serum starved on day 7 after initiation of differentiation. On day 8, cells are treated with pre-clustered recombinant rat Table 1 GENE/Fc chimera as described above for 10 min and treated with 10 nM insulin for 2 hours. Cells are harvested, mRNA extracted using magnetic DYNAL beads and reverse transcribed to cDNA using Superscript First-Strand Synthesis as described by the manufacturer. Appropriate primers are designed and used in 15 uL PCR reaction using 55 deg annealing temperature and 30 cycles of amplification.

Example 10 Effect on Muscle Differentiation

[0249] C2C12 cells (murine skeletal muscle cell line; ATCC CRL 1772, Rockville, MD) are seeded sparsely (about 15-20%) in complete DMEM (w/glutamine, pen/strep, etc) + 10% FCS. Two days later they become 80-90% confluent. At this time, the media is changed to DMEM+2% horse serum to allow differentiation. The media is changed daily. Abundant myotube formation occurs after 3-4 days of being in 2% horse serum, although the exact time course of C2C12 differentiation depends on how long they have been passaged and how they have been maintained, among other factors.

[0250] To test the effect of the presence of test molecules on muscle differentiation, test molecules (e.g., test peptides added in a range of 1 to 2.5 μg/mL) are added the day after seeding when the cells are still in DMEM with 10% FCS. Two days after plating the cells (one day after the test molecule was first added), at about 80-90% confluency, the media is changed to DMEM+2% horse serum plus the test molecule.

Effect on Muscle Cell Fatty Acid Oxidation'

[0251] C2C12 cells are differentiated in the presence or absence of 2 μg/mL test molecules for 4 days. On day 4, oleate oxidation rates are determined by measuring conversion of l-¹⁴C-oleate (0.2 mM) to ¹⁴CO₂ for 90 min. This experiment can be used to screen for active polypeptides and peptides as well as agonists and antagonists or activators and inhibitors of Table 1 GENE polypeptides or binding partners.

[0252] The effect of test molecules on the rate of oleate oxidation can be compared in differentiated C2C12 cells (murine skeletal muscle cells; ATCC, Manassas, VA CRL-1772) and in a hepatocyte cell line (Hepal-6; ATCC, Manassas, VA CRL-1830). Cultured cells are maintained according to manufacturer's instructions. The oleate oxidation assay is performed as previously described (Muoio et al (1999) Biochem J 338;783-791). Briefly, nearly confluent myocytes are kept in low serum differentiation media (DMEM, 2.5% Horse serum) for 4 days, at which time formation of myotubes becomes maximal. Hepatocytes are kept in the same DMEM medium supplemented with 10% FCS for 2 days. One hour prior to the experiment the media is removed and 1 mL of preincubation media (MEM, 2.5% Horse serum, 3 mM glucose, 4 mM Glutamine, 25 mM Hepes, 1% FFA free BSA, 0.25 mM Oleate, 5 μg/mL gentamycin) is added. At the start of the oxidation experiment ¹⁴C-Oleic acid (lμCi/mL, American Radiolabeled Chemical Inc., St. Louis, MO) is added and cells are incubated for 90 min at 37⁰C in the absence/presence of test molecule (e.g., 2.5 μg/mL of a Table 1 GENE-related test peptide). After the incubation period 0.75 mL of the media is removed and assayed for ¹⁴C-oxidation products as described below for the muscle FFA oxidation experiment.

Triglyceride and Protein Analysis following Oleate Oxidation in Cultured Cells [0253] Following transfer of media for oleate oxidation assay, cells are placed on ice. To determine triglyceride and protein content, cells are washed with 1 mL of Ix PBS to remove residual media. To each well 300 μL of cell dissociation solution (Sigma) is added and incubated at 37⁰C for 10 min. Plates are tapped to loosen cells, and 0.5 mL of Ix PBS is added. The cell suspension is transferred to an Eppendorf tube, each well is rinsed with an additional 0.5 mL of Ix PBS, and is transferred to the appropriate Eppendorf tube. Samples are centrifuged at 1000 rpm for 10 minutes at room temperature. Each supernatant is discarded and 750 μL of Ix PBS/2% CHAPS is added to cell pellet. The cell suspension is vortexed and placed on ice for 1 hour. Samples are then centrifuged at 13000 rpm for 20 min at 4⁰C. Each supernatant is transferred to a new tube and frozen at -2O⁰C until analyzed. Quantitative measure of triglyceride level in each sample is determined using Sigma Diagnostics GPO-TRINDER enzymatic kit. The procedure outlined in the manual is followed, with the following exceptions: the assay is performed in 48 well plate, 350 μL of sample volume is assayed, a control blank consists of 350 μL PBS/2% CHAPS, and a standard contains 10 μL standard provide in the kit with 690 μL PBS/2% CHAPS. Analysis of samples is carried out on a Packard Spectra Count at a wavelength of 550 nm. Protein analysis is carried out on 25 μL of each supernatant sample using the BCA protein assay (Pierce) following manufacturer's instructions. Analysis of samples is carried out on a Packard Spectra Count at a wavelength of 550 nm.

Stimulation of insulin secretion in HIT-Tl 5 cells

[0254] HIT-T15 (ATCC CRL#1777) is an immortalized hamster insulm-producing cell line. It is known that stimulation of cAMP in HIT-Tl 5 cells causes an increase in insulin secretion when the glucose concentration in the culture media is changed from 3mM to 15 mM. Thus, test molecules also are tested for their ability to stimulate glucose-dependent insulin secretion (GSIS) in HIT-Tl 5 cells. In this assay, 30,000 cells/well in a 12-well plate are incubated in culture media containing 3 mM glucose and no serum for 2 hours. The media is then changed, wells receive media containing either 3 mM or 15 mM glucose, and in both cases the media contains either vehicle (DMSO) or test molecule at a concentration of interest. Some wells receive media containing 1 micromolar forskolin as a positive control. All conditions are tested in triplicate. Cells are incubated for 30 minutes, and the amount of insulin secreted into the media is determined by ELISA, using a kit from either Peninsula Laboratories (Cat # ELIS-7536) or Crystal Chem Inc. (Cat # 90060).

Stimulation of insulin secretion in isolated rat islets

[0255] As with HIT-Tl 5 cells, it is known that stimulation of cAMP in isolated rat islets causes an increase in insulin secretion when the glucose concentration in the culture media is changed from 60 mg/dl to 300 mg/dl. Ligands are tested for their ability to stimulate GSIS in rat islet cultures. This assay is performed as follows:

1. Select 75-150 islet equivalents (IEQ) for each assay condition using a dissecting microscope. Incubate overnight in low-glucose culture medium. (Optional.)

2. Divide the islets evenly into triplicate samples of 25-40 islet equivalents per sample. Transfer to 40 μm mesh sterile cell strainers in wells of a 6-well plate with 5 ml of low (60 mg/dl) glucose Krebs-Ringers Buffer (KRB) assay medium.

3. Incubate 30 minutes (1 hour if overnight step skipped) at 37° C and 5% CO₂. Save the supernatants if a positive control for the RIA is desired.

4. Move strainers with islets to new wells with 5ml/well low glucose KRB. This is the second pre-incubation and serves to remove residual or carryover insulin from the culture medium. Incubate 30 minutes.

5. Move strainers to next wells (Low 1) with 4 or 5 ml low glucose KRB. Incubate at 37°C for 30 minutes. Collect supernatants into low-binding polypropylene tubes pre- labelled for identification and keep cold.

6. Move strainers to high glucose wells (300mg/dl, which is equivalent to 16.7mM). Incubate and collect supernatants as before. Rinse islets in their strainers in low- glucose to remove residual insulin. If the rinse if to be collected for analysis, use one rinse well for each condition (i.e. set of triplicates.)

7. Move strainers to final wells with low-glucose assay medium (Low 2). Incubate and collect supernatants as before. 8. Maintaining a cold temperature, centrifuge supernatants at 1800rpm for 5 minutes at 4- 8°C to remove small islets/islet pieces that escape the 40mm mesh. Remove all but lower 0.5 - 1 ml and distribute in duplicate to pre-labelled low-binding tubes. Freeze and store at <-20° C until insulin concentrations can be determined.

9. Insulin determinations are performed as above, or by Linco Labs as a custom service, using a rat insulin RIA (Cat. # RI-13K).

Example 11 Effect of a Table 1 GENE-Related Test Peptides on Mice Fed a High-Fat Diet

[0256] Following is a representative rodent model for identifying thereapeutics for treating human diabetes. Experiments are performed using approximately 6 week old C57B1/6 mice (8 per group). All mice are housed individually. The mice are maintained on a high fat diet throughout each experiment. The high fat diet (cafeteria diet; D12331 from Research Diets, Inc.) has the following composition: protein kcal% 16, sucrose kcal% 26, and fat kcal% 58. The fat is primarily composed of coconut oil, hydrogenated.

[0257] After the mice are fed a high fat diet for 6 days, micro-osmotic pumps are inserted using isoflurane anesthesia, and are used to provide test molecule, saline, and a control molecule (e.g., an irrelevant peptide) to the mice subcutaneously (s.c.) for 18 days. For example, Table 1 GENE-related test peptides are provided at doses of 100, 50, 25, and 2.5 μg/day and an irrelevant peptide is provided at 10 μg/day. Body weight is measured on the first, third and fifth day of the high fat diet, and then daily after the start of treatment. Final blood samples are taken by cardiac puncture and are used to determine triglyceride (TG), total cholesterol (TC), glucose, leptin, and insulin levels. The amount of food consumed per day is also determined for each group.

Example 12 In vivo Effects of Test Molecules on Glucose Homeostasis in Mice

[0258] Following are representative rodent models for identifying thereapeutics for treating human diabetes.

Oral Glucose tolerance test (oGTD

[0259] Male C57bl/6N mice at age of 8 weeks are fasted for 18 hours and randomly grouped (n=l 1) to receive a Table 1 GENE-related test peptide, a test molecule at indicated doses, or with control extendin-4 (ex-4, 1 mg/kg), a GLP-I peptide analog known to stimulate glucose-dependent insulin secretion. Thirty minutes after administration of Table 1 GENE-related test peptides, test compound and control ex-4, mice are administered orally with dextrose at 5 g/kg dose. Test molecule is delivered orally via a gavage needle (p.o. volume at 100 ml). Control Ex-4 is delivered intraperitoneally. Levels of blood glucose are determined at regular time points using Glucometer Elite XL (Bayer).

Acute response of db mice to test molecule

[0260] Male db mice (C57BL/KsOlahsd-Leprdb, diabetic, Harlan) at age of 10 weeks are randomly grouped (n=6) to receive vehicle (oral gavage), Table 1 GENE-related test peptides (at concentration of interest), test molecule (e.g., 60 mg/kg, or another concentration of interest, oral gavage), or Ex-4 (1 mg/kg, intraperitoneally). After peptide and/or compound administration, food is removed and blood glucose levels are determined at regular time intervals. Reduction in blood glucose at each time point may be expressed as percentage of original glucose levels, averaged from the number of animals for each group. Results show the effect Table 1 GENE-related test peptides and test molecules for improving glucose homeostasis in diabetic animals.

Example 13 Effect of Test Molecules on Plasma Free Fatty Acid in C57 BL/6 Mice

[0261] Following is a representative rodent model for identifying thereapeutics for treating" human diabetes. The effect of test molecules on postprandial lipemia (PPL) in normal C57BL6/J mice is tested.

[0262] The mice used in this experiment are fasted for 2 hours prior to the experiment after which a baseline blood sample is taken. All blood samples are taken from the tail using EDTA coated capillary tubes (50 μL each time point). At time 0 (8:30 AM), a standard high fat meal (6g butter, 6 g sunflower oil, 1O g nonfat dry milk, 1O g sucrose, 12 mL distilled water prepared fresh following Nb#6, JF, pg.l) is given by gavage (vol.=l% of body weight) to all animals.

[0263] Immediately following the high fat meal, a test molecule is injected i.p. in 100 μL saline (e.g., 25μg of test peptide). The same dose (25μg/mL in lOOμL) is again injected at 45 min and at 1 hr 45 min. Control animals are injected with saline (3xl00μL). Untreated and treated animals are handled in an alternating mode.

[0264] Blood samples are taken in hourly intervals, and are immediately put on ice. Plasma is prepared by centrifugation following each time point. Plasma is kept at -20⁰C and free fatty acids (FFA), triglycerides (TG) and glucose are determined within 24 hours using standard test kits (Sigma and Wako). Due to the limited amount of plasma available, glucose is determined in duplicate using pooled samples. For each time point, equal volumes of plasma from all 8 animals per treatment group are pooled. Example 14 Effect of Test Molecules on Plasma FFA. TG and Glucose in C57 BL/6 Mice

[0265] Following is a representative rodent model for identifying thereapeutics for treating human diabetes. The experimental procedure is similar to that described in Example 13. Briefly, 14 mice are fasted for 2 hours prior to the experiment after which a baseline blood sample is taken. All blood samples are taken from the tail using EDTA coated capillary tubes (50 μL each time point). At time 0 (9:00AM), a standard high fat meal (see Example 4) is given by gavage (vol.=l% of body weight) to all animals. Immediately following the high fat meal, 4 mice are injected with a test molecule i.p. in lOOμL saline (e.g., 25 μg of test peptide). The same dose is again injected at 45 min and at 1 hr 45 min. A second treatment group receives 3 times a higher amount of the test molecule (e.g., 50 μg of test peptide) at the same intervals. Control animals are injected with saline (e.g., 3xl00μL). Untreated and treated animals are handled in an alternating mode.

[0266] Blood samples are immediately put on ice. Plasma is prepared by centrifugation following each tune point. Plasma is kept at -20 ⁰C and free fatty acids (FFA), triglycerides (TG) and glucose are determined within 24 hours using standard test kits (Sigma and Wako).

Example 15 Effect of Test Molecules on FFA following Epinephrine Injection

[0267] Following is a representative rodent model for identifying thereapeutics for treating human diabetes. In mice, plasma free fatty acids increase after intragastric administration of a high fat/sucrose test meal. These free fatty acids are mostly produced by the activity of lipolytic enzymes i.e. lipoprotein lipase (LPL) and hepatic lipase (HL). In this species, these en2ymes are found in significant amounts both bound to endothelium and freely circulating in plasma. Another source of plasma free fatty acids is hormone sensitive lipase (HSL) that releases free fatty acids from adipose tissue after β-adrenergic stimulation. To test whether test molecules also regulate the metabolism of free fatty acid released by HSL, mice are injected with epinephrine.

[0268] Two groups of mice are given epinephrine (5μg) by intraperitoneal injection. A treated group is injected with a test molecule (e.g., 25μg of test peptide) one hour before and again together with epinephrine, while control animals receive saline. Plasma is isolated and free fatty acids and glucose are measured as described above.

Example 16 Effect of Test Molecules on Muscle FFA Oxidation

[0269] Following is a representative rodent model for identifying thereapeutics for treating human diabetes. To investigate the effect of test molecules on muscle free fatty acid oxidation, intact hind limb muscles from C57BL/6J mice are isolated and FFA oxidation is measured using oleate as substrate (Clee, S. M. et al. Plasma and vessel wall lipoprotein lipase have different roles in atherosclerosis. J Lipid Res 41, 521-531 (2000); Muoio, D. M., Dohm, G. L., Tapscott, E. B. & Coleman, R. A. Leptin opposes insulin's effects on fatty acid partitioning in muscles isolated from obese ob/ob mice. Am J Physiol 276, E913-921 (1999)) Oleate oxidation in isolated muscle is measured as previously described (Cuendet et al (1976) J Clin Invest 58:1078-1088; Le Marchand- Brustel, Y., Jeanrenaud, B. & Freychet, P. Insulin binding and effects in isolated soleus muscle of lean and obese mice. Am J Physiol 234, E348-E358 (1978). Briefly, mice are sacrificed by cervical dislocation and soleus and EDL muscles are rapidly isolated from the hind limbs. The distal tendon of each muscle is tied to a piece of suture to facilitate transfer among different media. All incubations are carried out at 30⁰C in 1.5 mL of Krebs-Henseleit bicarbonate buffer (118.6 mM NaCl, 4.76 mM KCl, 1.19 mM KH₂PO₄, 1.19 mM MgSO₄, 2.54 mM CaCl₂, 25mM NaHCO₃, 10 mM Hepes, pH 7.4) supplemented with 4% FFA free bovine serum albumin (fraction V, RIA grade, Sigma) and 5 mM glucose (Sigma). The total concentration of oleate (Sigma) throughout the experiment is 0.25 mM. All media are oxygenated (95% O₂; 5% CO₂) prior to incubation. The gas mixture is hydrated throughout the experiment by bubbling through a gas washer (Kontes Inc., Vineland, NJ).

[0270] Muscles are rinsed for 30 min in incubation media with oxygenation. The muscles are then transferred to fresh media (1.5 mL) and incubated at 3O⁰C in the presence of 1 μCi/mL [1 -¹⁴C] oleic acid (American Radiolabeled Chemicals). The incubation vials containing this media are sealed with a rubber septum from which a center well carrying a piece of Whatman paper (1.5 cm x 11.5 cm) is suspended.

[0271] After an initial incubation period of lOmin with constant oxygenation, gas circulation is removed to close the system to the outside environment and the muscles are incubated for 90 min at 30⁰C. At the end of this period, 0.45 mL of Solvable (Packard Instruments, Meriden, CT) is injected onto the Whatman paper in the center well and oleate oxidation by the muscle is stopped by transferring the vial onto ice.

[0272] After 5 min, the muscle is removed from the medium, and an aliquot of 0.5 mL medium is also removed. The vials are closed again and 1 mL of 35% perchloric acid is injected with a syringe into the media by piercing through the rubber septum. The CO₂ released from the acidified media is collected by a Solvable in the center well. After a 90 min collection period at 30⁰C, the Whatman paper is removed from the center well and placed in scintillation vials containing 15 mL of scintillation fluid (HionicFlour, Packard Instruments, Meriden, CT). The amount of ¹⁴C radioactivity is quantitated by liquid scintillation counting. The rate of oleate oxidation is expressed as nmol oleate produced in 90min/g muscle. [0273] To test the effect of test molecules on oleate oxidation, the each test molecule is added to the media (e.g., a final concentration of 2.5 μg/mL of test peptide) and maintained in the media throughout the procedure.

Example 17 Effect of Test Molecules on FFA following Intralipid Injection

[0274] Following is a representative rodent model for identifying thereapeutics for treating human diabetes. Two groups of mice are intravenously (tail vein) injected with 30 μL bolus of Intraliρid-20% (Clintec) to generate a sudden rise in plasma FFAs, thus by-passing intestinal absorption. (Intralipid is an intravenous fat emulsion used in nutritional therapy). A treated group (treated with test molecule) is injected with a test molecule (e.g., 25 μg of a test peptide) at 30 and 60 minutes before Intralipid is given, while control animals receive saline. Plasma is isolated and FFAs are measured as described previously. The effect of a test molecule on the decay in plasma FFAs following the peak induced by Intralipid injection is then monitored.

Example 18 In Vivo Tests for Metabolic-related Activity in Rodent Diabetes Models

[0275] Following are representative rodent models for identifying thereapeutics for treating human diabetes. As metabolic profiles differ among various animal models of obesity and diabetes, analysis of multiple models is undertaken to separate the effects of test molecules on hyperglycemia, hyperinsulinemia, hyperlipidemia and obesity. Mutations within colonies of laboratory animals and different sensitivities to dietary regimens have made the development of animal models with non-insulin dependent diabetes associated with obesity and insulin resistance possible. Genetic models such as db/db and ob/ob (See Diabetes, (1982) 31(1): 1-6) in mice and fa/fa in zucker rats have been developed by the various laboratories for understanding the pathophysiology of disease and testing the efficacy of new antidiabetic compounds (Diabetes, (1983) 32: 830-838; AnnuRep Sankyo Res Lab (1994) 46: 1-57). The homozygous animals, C57 BL/KsJ-db/db mice developed by Jackson Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J Clin Invest, (1990) 85: 962-967), whereas hetero2ygous animals are lean and normoglycemic. The db/db mice progressively develop insulinopenia with age, a feature commonly observed in late stages of human type II diabetes when blood sugar levels are insufficiently controlled. The state of the pancreas and its course vary according to the models. Since this is a model of type II diabetes mellitus, test molecules are tested for blood sugar and triglycerides lowering activities. Zucker (fa/fa) rats are severely obese, hyperinsulinemic, and insulin resistant (Coleman, Diabetes 31:1, 1982; E. Shafrir, in Diabetes Mellitus; H. Rifkin and D. Porte, Jr. Eds. (Elsevier Science Publishing Co., Inc., New York, ed. 4, 1990), pp. 299-340), and the fa/fa mutation may be the rat equivalent of the murine db mutation (Friedman et al., Cell 69:217- 220, 1992; Truett et al., Proc. Natl. Acad. Sci. USA 88:7806, 1991). Tubby (tub/tub) mice are characterized by obesity, moderate insulin resistance and hyperinsulinemia without significant hyperglycemia (Coleman et al., J. Heredity 81:424, 1990).

[0276] Previously, leptin is reported to reverse insulin resistance and diabetes mellitus in mice with congenital lipodystrophy (Shimomura et al. Nature 401 : 73-76 (1999). Leptin is found to be less effective in a different lipodystrophic rodent model of lipoatrophic diabetes (Gavrilova et al Nature 403: 850 (2000); hereby incorporated herein in its entirety including any drawings, figures, or tables).

[0277] The streptozotocin (STZ) model for chemically-induced diabetes is tested to examine the effects of hyperglycemia in the absence of obesity. STZ-treated animals are deficient in insulin and severely hyperglycemic (Coleman, Diabetes 31:1, 1982; E. Shafrir, in Diabetes Mellitus; H. Rifkin and D. Porte, Jr. Eds. (Elsevier Science Publishing Co., Inc., New York, ed. 4, 1990), pp. 299-340). The monosodium glutamate (MSG) model for chemically-induced obesity (Olney, Science 164:719, 1969; Cameron et al., Clin Exp Pharmacol Physiol 5:41, 1978), in which obesity is less severe than in the genetic models and develops without hyperphagia, hyperinsulinemia and insulin resistance, is also examined. Also, a non-chemical, non-genetic model for induction of obesity includes feeding rodents a high fat/high carbohydrate (cafeteria diet) diet ad libitum.

[0278] Test molecules are tested for reducing hyperglycemia in any or all of the above rodent diabetes models or in humans with type II diabetes or other metabolic diseases described previously or models based on other mammals. In some assays, the test molecule sometimes is combined with another compatible pharmacologically active antidiabetic agent such as insulin, leptin (US provisional application No 60/155,506), or troglitazone, either alone or in combination.

Tests described in Gavrilova et al. ((2000) Diabetes 49:1910-6; (2000) Nature 403:850) using A-ZπVF-1 mice sometimes are utilized, test molecules are administered intraperitoneally, subcutaneously, intramuscularly or intravenously. Glucose and insulin levels of the mice are tested, food intake and liver weight monitored, and other factors, such as leptin, FFA, and TG levels, often are measured in these tests.

In Vivo Assay for Anti-hvperglvcemic Activity of Test Molecules

[0279] Genetically altered obese diabetic mice (db/db) (male, 7-9 weeks old) are housed (7-9 mice/cage) under standard laboratory conditions at 22° C and 50% relative humidity, and maintained on a diet of Purina rodent chow and water ad libitum. Prior to treatment, blood is collected from the tail vein of each animal and blood glucose concentrations are determined using One Touch Basic Glucose Monitor System (Lifescan). Mice that have plasma glucose levels between 250 to 500 mg/dl are used. Each treatment group consists of seven mice that are distributed so that the mean glucose levels are equivalent in each group at the start of the study, db/db mice are dosed by micro-osmotic pumps, inserted using isoflurane anesthesia, to provide test molecules, saline, and an irrelevant peptide to the mice subcutaneously (s.c.)- Blood is sampled from the tail vein hourly for 4 hours and at 24, 30 h post-dosing and analyzed for blood glucose concentrations. Food is withdrawn from 0-4 h post dosing and reintroduced thereafter. Individual body weights and mean food consumption (each cage) are also measured after 24 h. Significant differences between groups (comparing test molecule treated to saline-treated) are evaluated using a Student t-test.

Example 19 Tests of Metabolic-Related Activity in Humans

[0280] Tests of the efficacy of test molecules in humans are performed in accordance with a physician's recommendations and with established guidelines. The parameters tested in mice are also tested in humans {e.g. food intake, weight, TG, TC, glucose, insulin, leptin, FFA). It is expected that the physiological factors are modified over the short term. Changes in weight gain sometimes require a longer period of time. In addition, diet often is carefully monitored. Test molecules often are administered in daily doses (e.g., about 6 mg test peptide per 70 kg person or about 10 mg per day). Other doses are tested, for instance 1 mg or 5 mg per day up to 20 mg, 50 mg, or 100 mg per day.

Example 20 Cellular Production of Target Polypeptides

[0281] Nucleic acids are cloned into DNA plasmids having phage recombination cites and target polypeptides are expressed therefrom in a variety of host cells. Alpha phage genomic DNA contains short sequences known as attP sites, and E. coli genomic DNA contains unique, short sequences known as attB sites. These regions share homology, allowing for integration of phage DNA into E. coli via directional, site-specific recombination using the phage protein Int and the E. coli protein IHF. Integration produces two new att sites, L and R, which flank the inserted prophage DNA. Phage excision from E. coli genomic DNA can also be accomplished using these two proteins with the addition of a second phage protein, Xis. DNA vectors have been produced where the integration/excision process is modified to allow for the directional integration or excision of a target DNA fragment into a backbone vector in a rapid in vitro reaction (Gateway™

Technology (Invitrogen, Inc.)).

[0282] A first step is to transfer the nucleic acid insert into a shuttle vector that contains attL sites surrounding the negative selection gene, ccdB {e.g. pENTER vector, Invitrogen, Inc.). This transfer process is accomplished by digesting the nucleic acid from a DNA vector used for sequencing, and to ligate it into the multicloniαg site of the shuttle vector, which will place it between the two attL sites while removing the negative selection gene ccdB. A second method is to amplify the nucleic acid by the polymerase chain reaction (PCR) with primers containing attB sites. The amplified fragment then is integrated into the shuttle vector using Int and IHF. A third method is to utilize a topoisomerase-mediated process, in which the nucleic acid is amplified via PCR using gene-specific primers with the 5' upstream primer containing an additional CACC sequence {e.g.,

TOPO^® expression kit (Invitrogen, Inc.)). In conjunction with Topoisomerase I, the PCR amplified fragment can be cloned into the shuttle vector via the attL sites in the correct orientation.

[0283] Once the nucleic acid is transferred into the shuttle vector, it can be cloned into an expression vector having attR sites. Several vectors containing attR sites for expression of target polypeptide as a native polypeptide, N-fusion polypeptide, and C-fusion polypeptides are commercially available (e.g., pDEST (Invitrogen, Inc.)), and any vector can be converted into an expression vector for receiving a nucleic acid from the shuttle vector by introducing an insert having an attR site flanked by an antibiotic resistant gene for selection using the standard methods described above. Transfer of the nucleic acid from the shuttle vector is accomplished by directional recombination using Int, IHF, and Xis (LR clonase). Then the desired sequence can be transferred to an expression vector by carrying out a one hour incubation at room temperature with Int, IHF, and Xis, a ten minute incubation at 37°C with proteinase K, transforming bacteria and allowing expression for one hour, and then plating on selective media. Generally, 90% cloning efficiency is achieved by this method. Examples of expression vectors are pDEST 14 bacterial expression vector with att7 promoter, pDEST 15 bacterial expression vector with a T7 promoter and a N-terminal GST tag, pDEST 17 bacterial vector with a T7 promoter and a N-terminal polyhistidine affinity tag, and pDEST 12.2 mammalian expression vector with a CMV promoter and neo resistance gene. These expression vectors or others like them are transformed or transfected into cells for expression of the target polypeptide or polypeptide variants. These expression ivectors are often transfected, for example, into murine-transfoπned cell lines {e.g., adipocyte cell line 3T3-L1, (ATCC), human embryonic kidney cell line 293, and rat cardiomyocyte cell line H9C2). [0284] Following is a genomic nucleotide sequence for a LOC391238 region. The genomic nucleotide sequence is set forth in SEQ ID NO: 1. The following nucleotide representations are used throughout: "A" or "a" is adenosine, adenine, or adenylic acid; "C" or "c" is cytidine, cytosine, or cytidylic acid; "G" or "g" is guanosine, guanine, or guanylic acid; "T" or "t" is thymidine, thymine, or thymidylic acid; and "I" or "i" is inosine, hypoxanthine, or inosinic acid. Exons are indicated in italicized lower case type, introns are depicted in normal text lower case type, and polymorphic sites are depicted in bold upper case type. SNPs are designated by the following convention: "R" represents A or G, "M" represents A or C; "W" represents A or T; "Y" represents C or T; "S" represents C or G; "K" represents G or T; "V" represents A, C or G; "H" represents A, C, or T; "D" represents A, G, or T; "B" represents C, G, or T; and "N" represents A, G, C, or T.

>20:24668201-24767700

1 gaatgcagga ctgcagggtg aaaagagggc atggtgcggg gccagccagg gctgaggaag

61 cggccagtga tgcagagctc catgtcggca gggccccatc gacttgctct ggcagcctgc

121 tggggcctgg gtacaggttc agatcacaag tgcaggctca gagaagcagg gaaggatggt

181 gttcctcgat ggcagtaact ccatgctgtg tagttcactg tggagacaNc acagagccca

241 ccaggtccag cgttgcaggt gcgttggcYt gagaotgcaa caccactgac cgcttactct

301 cgaagactga gctactgctg tggYcYccgt ccctcacMtc atggctggag ggtgcaaagc

361 ggagccaggg tcagagcttc atgtgggact ggtgacagtg ccgtgactgg caggccccaa

421 gtccccagca cttcctctaa ttaagggaac ttggcatgtc cctgggcctc tctgagcttt

481 aacttcatct ttaaatKgtg acttgtaaat ggatcaagct tctcaaactc tagtgagcct

541 gagaacaacc cagggtgctt gtttaaaata taattcttgg gtctctggac tggattctgg

601 aacagaaaaa gaatgctaat ggaaaaacaa gtgaaatctg atgaaatcta gagttaatta

661 attgtaatga gccaatgttg ctttcttatt ttttactaat gaaccttgat actgtaagat

721 actattagag gaagcaaatt gggtgagggg catatgggaa cattcacatt atctttgcat

781 attttttgtg actctaaaac tattgcagaa taaaatgtgt attttttaaa aagcttgttc

841 cttaccccga ccacagccat tctgaattca gtaggtttgg gggtgggtcc ccacgggctg

901 tgatgggagt gatcagcaga ccgggttgga aaacactgaa ctttgttccc atggtgctag

961 ctggaaccac tcctgggtcc agattctctg aggtggcttt ccacccaagc aacaggggca

1021 cagccagaaa gcaggccaca gatgccagag agtcagaacc aggcctggag tctggaaggg

1081 ccagagagag ctgaggacac aggagatgag aagtccagat gtcagcaaag agggacgtga

1141 ggggacagag ctggggactc gcctccctca ctgccccatg cacctgccat gagtgcctgc

1201 agtgcatacc tgtgtggtgt ggggggcacc otgagcaccc accoccgagt tccacaggtt

1261 ccactcctgg gaaaacacat aaggagctgg tggcggaggc tctgggcctg aagtcagagc

1321 tcaagagtgg atggaaggtc aaatccttgg atgaaaacga caaaaatatc aggaatctaa

1381 gtgcggagac cccagcctgc tgcctccaga ccctccctgg gttgggaaag gccatggctg

1441 aataaggtag ttggccagtg tggcgggaga gaggcctctt gggagtaccc caaacctcgt

1501 ggcacagaaa agacccatgg atttgtaccc agggggttgg atagggacat tccagcacag

1561 accacaagtg gcttacactg ccctgtgagg gcaggtgtga tcaggacaca ccatggccag

1621 gaggggctgg acgaagtggc ctgggccctt ggtgggagca cggccagaac tcggccattc

1681 cctgggatct ggagggacat aggaagtaga acaaggagag tggggctcca ggagggcagc

1741 caagagggca gcggtggttg cagcctctag ggtgggtggg cccagagaac ctgggaggag

1801 gccccagttc ggcagacttt tgctagggag aggcagggaa ggcctgggct gaaatccagg

1861 cagagggggt gttgccaaga cactgactgg aagacgggtc ggcaggacac agtcagatga

1921 ttcctgccct ttctggggtg actttgcggc acctggtgat ggcMtgagct tctccatcac

1981 ctgcagtata gtccatggcc ccgagcatgc acactgggac tgctaggtct gcagaaccca

2041 ttagaaaatg cagaacttag gaaWctgcat ctccagggtt ggggtccagg aatctatttt

2101 tttacatcgc gaggtgattc taacgagcta ataggtttgg taactgccag aagaaaggac

2161 ttccaagtcc ctagctatgg gatcctggcc ccagggacac aagctagatg tgcaggctct

2221 ggttgtcccc agggaagtga ctgttctgcc ctcaccccag catacctccc aagttttagt

2281 gctcagcctc tcccagctga gtccgtgggc cggagtggtt ataRcccaag gagttattgc

2341 tgccMtaaat tcaaagaaat gaagcatttc ggaagataaa tttctttttg attcccagcc

2401 aggcYtcctt tggagagatg gctggaagtc catgctgtcc ctgagctgtg tctccctttc

2461 cttcctgtgc cacccctgct gtgacctcgc cggcgccggc tccggacagg ctgctgcttc

2521 ccgagtccct ggaggcttca tctgagccac tcagtttccc tccctggcag ctccaYggcc

2581 gggcaaactt cattagttcc agcacttgct caaRgatttt ctgtctctcc cttcactgtc 2641 ttgtttactt ttcttacctt ctgtttctac tttttttggt ttccataaaa attgcttgca 2701 caactggttt ggtccagttc tgcaatcagc atctgggcca ctgcctgctg cagggctgag 2761 agttgacaca atcagaaaca gtgtcctgct ggctggggca taatttagtt cagatgacac 2821 tctgtggcca atgtcgtatt ttcccccaga ttctactgga gccacgcaga ggaaaatcta 2881 ctgcatgtaa agctaatgac aRgtcgaata catcagggat tgctgagtct tggttggata 2941 atacaacaca tggatgcttg gcaagtacct tcattcattc cttcactcat tcactcttac 3001 agtgattcat tgaacaaatt tgactggtgg ctgccctgtc ccaRgtgctg tgttaggtag 3061 attccaccag agaggaagag aggagcaatg gaaagggatg cgtgtgtgca cttgtgtggc 3121 atgattaaat atggattgtg taatatatat gatgaagcaa acatgagtgg ctatctaggc 3181 ataaagaggt agttgcccta agagctgcac agtggaatgt ttcatgggaa agcatttcag 3241 atgagctctg agcaacccct gaagcaaggg caggtccacc aaccacaggc agtctgtatg 3301 tgtgcccaga gcaggatggg aagaggaggt ggtcagagac tggaggctgg ggacatgtcc 3361 atcccatccc taagcaccac cagccctcca tgctcagcca taaccttaac cccacatcct 3421 ctcctgaata tccccaggct ggaaccaggg ccctggcatg tgggttgatg aaaaccttat 3481 taatttgatg ctcctccttg gaggctggtg cttctggcat ttgctgagca ggtaggtagc 3541 cRtgtggtgg gacccagatg ttcataaaac caagaactgc atgggaaaga gattgttcaa 3601 agtcactgtc agctgaaaaa agtgacaagg gccctgagag ggcagatgat gtgctaggcc 3661 ctgagaagga accaggaaat gcttccagga gggatggatg gggcaggctt catggaaaag 3721 cagaggagga tgtggaacca gctagttagc aggaggcggg tgagttaggt gggtcacttg 3781 ccaggaacag ggaacaatgg aatggaccca gcagagaagt ggcagacata gcagtggcaa 3841 gaagggggca ttggagctgg actttcaggg cYttaagtgg caaattaagg actttgagtt 3901 tgaccccaag aaggtgaagc ggtcttggga agtggcttta atggctgggg atggcgtgat 3961 caacaccacg ttcaggKgtc ggagtcttgt ggcccagtgg actgggcatg ggctggaggg 4021 ggagggtgca ctaagaggca gagggatgtc ccttgggggc atgagctgag acaggctggg 4081 aatgtgaacg gagaggacga ggtgctggtg tgccttgccg tggctgaaca cagccttgtg 4141 gcttcactga aacattcctc agaggcaacc gaagattcag ggaagaagcc atgtccatgg 4201 gcttccagca ccagaaggat caactcttca ggoacatatg acaacctact ctcaggtcct 4261 tcctaccaat tcYtgatggg ccacctaggg ccatcttggt ttgtttaatt tgagttccct 4321 agctactaaa aaataaactg gattttttat tttattttat tattttgttt tattttttga 4381 gatggagttt cgctctgtcg cccaggctgg agtgcagtgg tgtgatctcc gctcactgca 4441 agctctgcct actgggttca tgccattctc ctgcctcagc ctcccgagta gctgggacca 4501 caggcacccg ccatcacgcc cggctaattt tttgtatttt ttttagtaga gacagggttt 4561 caccgtgtta gccaggatgg tctcaatctc ctaacctcgt gatccacccg cctcggcctc 4621 ccaaagtgct gggattacag gtgtgagcca ccacgcccgg cctttttttt tttttttttt 4681 tactttggat gattcagact ttcagtccta tgaaagattg gaggctgagt aagtggactg 4741 tcctgtcccc gtgtggacaa gtggcccagc cactgcaagc tgctgtgttc tggaaaaagg 4801 acaatttata tccaggtctg tattcgaatc ccactctgct gcttgggaag ctctStgaga 4861 ttcacggttt cccaacaaaa aagtggcatt gtgagggcca taatggtcta agaRgaaaag 4921 aggagctgag aaYaagcttg tcaccatcgg Rcacacccgt cagcattttc ttctcttctt 4981 cctgaacacc cagcagatcg gacagcagcc tcccctgcag ccaggtgagt tctagccaat 5041 aggatgtaag cca^'gggagca ctcttccccc ttctgtaggc tggatccaga tgtagacact 5101 gaggccctag agaacagagg agccacaagg tgggagaatt cctggaaggg atcggaagag 5161 ggaggacagc tacctgccag ccaggacctc gcattttcaa ctcttcaggg aataagcaat 5221 aaacttcata cttgggactt tggacattat ggggtccttt tgctatagga gccagcatta 5281 acccaaagga gacagatcat gtcatctgca gaacctcttc caaggcaagc agcatcaggg 5341 agatgtgtct gaacaaagca aggggattcg ggacagaaga atcttgacct agtcaagttc 5401 aactaaaagc acacacttgg^' gaaaggaagg aagccccgag atcacggctc tcccttaaga 5461 cagaaccttc cttctgccca gaacctttca gcattgaagc aaagcaacag gcccatgctt 5521 gggagatcta actccccaga ataagtgtct gaccatgtgt aagccttaat catctaatgt 5581 gattagggtc aacagcgtga cttagcctag tggtgaaaaa ctctgaaaaa gattcaggaa 5641 aacccagatg atcttgcctt gctttaacta ggagaaccag aacagcaggg caattgacgt 5701 taactacaag acccaggccc ggctgttgtg ctcctcctgg gagcatcagg cactcaccac 5761 acccccacat gccctggcca catccacagc tgctgctgca gacaccacac atctgggctg 5821 gctctgctgc agtccctctg tagtgacgca agccagaaag attcacttct gtgtggatct 5881 gccacctgca gcagggcacc tgtcgcctgt ggttttgaac ttgctaactg cgggtgcaat 5941 gcaactgcac cagtgcatgc agcacagtgt gattcccaca agccgcctct caactgtttt 6001 ctcccttcct agcccagtgc catggccttc ggcaacaaca cagggcagag gggtggggat 6061 catcaacttc ttaatcctgg ggcacaggca ggaaatgtaa gccagccctg ctcctgcctc 6121 tactcccaag catgggctgt gacagccctg aaatcccagt tcagccactc aattgccctg 6181 tgacctgagg caagatactc accatctctg agtttctctc ctccaaaaag tggagatgat 6241 gcctgcacct ccttcccagg ttgctgggat cctgagtcct agcccagtgc tgcccagtat 6301 cgtttgcacc cttgccaggt atgaggactg acaagtcgta aatgagctgt gtgagtcatt 6361 gttcctctgt gaacctcagt tttttcccct acctggtgat ggaataggct cggccctgcc 6421 tatccctgtt ggtgttgctg caggagcagc tgtaaaaccc agcagaccat ttactgccat 6481 gacagcctgc catcacccat ccctaaccaa ggaaacccca ggtgactttt gggatgttgc 6541 aggaggcaga ggggcctagg tgactctcag tggcagctac aggagcccag tgctcccagc 6601 actcactgcc tgaatcagat gtgggtgcgg aggatggacg tgcagggatg aRggccctgg

6661 gctcatcgga gcctgtggcc atggcaacct catcaggagc tccatgtggg gattattaag

6721 gaatatttgc attaattaag agtccaaaca tcttcctttt ccaggcaggg acYtgacaca

6781 cacatgcctc tctccagcct ctaagtaccc ttggctatgc cttgggcagc ctgctgggtg

6841 ctggagcggg tcctgcagca taaggattct ggctctgctc tccaacctct cagaacctca

6901 cttgcattga cgcatttccc tctactgctg tccccagcct tctaagtgag ccatcagcag

6961 cctcaagtgc atcatccatc tgctttattc acaaaacaaa ccatcgttgc tgggctggtc

7021 cggactccgc cctccctctt tgacatcatc atgaacaata gtcattgttt tgtttgaacc

7081 aaaattgtct aatgttgtac aaaaatagag tcactttgag tcttccaaag gacatgtgac

7141 atcctggaag ctggaacaaa acccaagccc cagaggcatc ccacagatga ccacagtgaa

7201 cctggatgtg cggggaccca ggtggagccc agagactggg gacaagaagg tggcttggag

7261 gaagaggata ggagccctcc tgcaaacacc cctgactctg cagtggggtc tcacctgaga

7321 actaccccca tagtttcagc agggcagttc tttgtggaga cagtgggtgc agagaccagc

7381 aggtcagccc cagggcgagc agcagacccc atggagagga gccccttgct ggggggtggg

7441 ggaactcact ccccataaca ggcatggtat agcccttcct tcctctaggc cccacctgtg

7501 gcttctctcc gtagaggtcc atcctgctct gagcctcagc cacataaaac ctccctccac

7561 acccaccagg agccccagct ctgctgttgg gcctgctcta gccaccttct cttccatttc

7621 ctgaagacgt tgcgggacct cccatcccca tttcatgagc acagaggact ggggagagca

7681 gcccagagtc aagtgggtgt gagtgcctgc tgctcagatg gggtccacac atgcccctcc

7741 ttcctgtttg ttcccccaaa ttcctgattt tcaccttcct tgcaggctgg ggatgaggaa

7801 caaccccctt cagagcccag cccttatcag agtccacacc tcccagacag aacggctaag

7861 aaggcacaca gaccccaSca agtcagacct ggaagcatac tcactgctgg aggcctgggg

7921 tccttggtac aggggagttc ccctggttaa gggaaacctt agcccttgtc tgggcccagc

7981 tgtatgacca aggctggtat ccaggccctt agcttggaca ctggcagcgc tgcccacctc

8041 cctgatgtct ttgtcccctg ctgttggctg ggttcctggt ctgaatgatc tgagtaaccc

8101 acagcagcat ggccgctatc tgttgccaaa atccatttca tccaatgccc aRaacctcct

8161 gctgtcccag tccacccctg gatattgaca aggcctgggt gagccaagga ccttccacaa

8221 caccctgcat ttgtgggctg gccagcttcc tggggaaccg tcctccctgg gaccctcccc

8281 agtctcagca tgttcagttc ccactggctc tcctaggaca gtaacttgtc cctgtgcatg

8341 tagcttgcat caccctcgat atcaacttcc taaagtggtg gcctggacaa tgaatttcta

8401 aagacagtga caccaaaata tgtcatccat cccctgtgtt tctctcatga tatgaggttg

8461 acctgcctct atttgagggg tgtctatgtc ctctgaatct aagtggacct tggaaaccac

8521 tccaaccaat agatcaaggg aagtcacact atgtggcttc tggaaccaag ttgcttctct

8581 cctgggtccc gtgcctcctg gagcccaggg ctaccacgag ggacattgco atgcaggagg

8641 ccatatggag agagcacagg gagccttgga tgcccacagt gcccagctgg tcaagccttc

8701 ctgctgcagc cccgggtgtc ctggagctaa gacaagccct cacacggtgc tcggcccatg

8761 tccccaaccc acacaccaag agagcagtac atacggtttt gcaaagcatt gaagtttggg

8821 gtagtttgtt atgcagccat agtgactaaa ataatctgtg tttctccaat acagaaggct

8881 atattagcca ataatctgtg ttgcttgggc ttgtagcctg tgggaagccc tgggtgtaag

8941 ctgggatgtg attatgctYa attataacat gagaggaggt ggcagctcac tgctcttcag

9001 tggctctgtt cgtccttgtt ctttcatatc tcttaatcca aaggcagctg aggctttttc

9061 tctgggtcac cttagagtcc tccattgtca gtaacagtaa aaaggcaagt gtgcaagagc

9121 tgaactagaa atgcctggta ttacatccct ggcctgtgca gatagtggga gtagacctac

9181 acaaacgtgc tctccccaca gaatcgcctc aaggaggggt gacagatgcc agcctgccac

9241 agcagccaag cacaggagac accaaggagc cagcatgtgc ccaggcccct ggatctccta

9301 ctgcacactc cataaggact tctggatttg ggccatgttt ccaggaagca gcatagtagt

9361 acctgagagt gaagaacgac atggccaagg tctagtcatg attttaaaca agttataaat

9421 gaatcacggt gcatccatcc actggcagac cgtcccgcag agctatatgt gcatgtgtgc

9481 ctctagaaag ctgtctgaca ctagcagtga aggaacactg aggctgcaaa acatcatgtc

9541 accttatatt tcatgtatgc acacacactc acacacacat atgctattaa gaagagaatg

9601 gttgtaaaga aatatgtgct aaatgattag tggtgattca ttctctccag caaaaaatta

9661 tacagaaatt cttcttttga tatactgtat ataaagctga gatttaaaaa aagatattaa

9721 aagactttta gaaagaaaat ctgctgcgca ggtaattttg cagcagcact ggggctctca

9781 ggaggtgagg ggctgctctc ctcccgagtc ttgaagtgca gtgctgccca gaggtggagg

9841 gcggggcaag ggacaaagga cagggaacag gggcaggagc aggggatggg gaggggacag

9901 aagacaggga gtgggacata gggggcagag tcaggagaca gggggcaggg agcaggggac

9961 aggggagagg agacaggggc aggggacagg agacaagggg caggctcgtg aatgaggtgc

10021 ccagggcttt cagtcctggg atcccctgac cagggccact gggaccaatg cttctgaagc

10081 ggatgcatYg ttgccaggga gtggggcggg gtggggatgg catattggcc tcagttcatg

10141 ctctccatca agcagtcctg agtttgaact gggattggta ttaatttcga ttccctacaa

10201 agcagagcct gagatgaaag catttgtgcc tgcactgtcc tgggaaataa gacctcaagg

10261 aagcagagct gccagggaag gaaagcgagg cagggaagga gaggggccaa aacccaaaac

10321 caagggatgc atagctggac ctgctgccgg gccKggtcct gtgggacttc ttcagggagc

10381 ctgagggtcg ccgtggcttg caatatgaat atgatgtcag cctacataga acaagaagca

10441 gtcatccact ggcttccatc tcctactgac caacatctac cccgtcacct agcagctctc

10501 tcacccttcc agggtgcagc atctggccgt cctgggcagc tacggggaga ctagatccag 10561 gaagggtctg tgtcctccaa gacataagcc accgggcggg caggggagca ccaagacagc 10621 aggtcccatc actgggggat ggagccccaa gagagacccc cactcagttc taccgaagtg 10681 aggaggagcc accttatctt cctggagggt catcagtacc acagggcaga aaaccaagat 10741 gccagggtcc gtcctgacca catggccaac tctgggagca ggaactgagc ctcgacttcc 10801 ttcagcctac ctgcctggtg gctgcctcca gggtgaggcg aggcagcagg caagctgccc 10861 gcacgcagga agccctctac atgctcctgg ctggaagcat ttgtgttgcc atcagcattt 10921 acatcgcaac aggaagactg ctccacatgg gcagtggcgg tggctcatgc agtctgcaga 10981 gagcccactg ttaaatgtct agcaattcga ggagccggtt gtcaaactat tggtagcttg 11041 aattctgcaa tagtgggagg gtttgcacca cagaagtcag aagatgctac aaattggggt 11101 ttgttggtgt ctttttaaaa ttttccttcc ggactgctgg cttactaggt caccactgct 11161 cagcgccatc attttttttt tatttatcaa attaaatggg agagggtggt cctagaatta 11221 cctgcattgt ctcccctctg gtgtctcgtt tacatgcaga ttttgggatc ccaccccaga 11281 cctctcagag ctaaatctoc aagggtaaac ctagcccctg tgttggactg gaaaaggtga 11341 tttgctttat gcacggttac ttgagggacc cacttgtcca ggcattcagg tgcccagagt 11401 ccaaRgtctg agactccagg agccctcagc catgtgcttc tgccccatca ctctcagtca 11461 cctctcaggt ggagcatttt tcttttcacc tccctttctc atcaacaaag cctcactgct 11521 ttgacagtta caaagcgtcc taatttaccg gcttttccta aggatgtcca cgttggccga 11581 gtaactcatg gctttaagcc tgaaacttaa aaggcccaca cacttatggc atgtaagtgg 11641 cagtgagacc Ytcaacgcat gagtcaoccc ctttcaaagg tactcacaga catctcagag 11701 aacagaggtc acagccatcc cagagcacag gccttggacc cacatcttgg catccccgga 11761 agctaacaaa tgccaaatct cctgacccag atctctttcc tccagaccag cacatctcaa 11821 accttaacct gcccacgaaa cacctggaaa tcatgttaaa aggcagatta ggttcacagg 11881 tctggggcag ggcctgagat tttagaaatt atcaagctct caggggatgc tgatgctgct 11941 ggtccaggga ccacacactc agtctcaagg gtctctgatt caccgttacc catggaacct 12001 tgtggaagag agagtaagag ctctgacacc attacagatg aaaggattca ctacattttt 12061 tatatttgtt tctgctgcct gctaccttct cttctaggtg tgtctcagct aggaccccta 12121 gactttagtt tcacttattg attgccacag aatgcttcaa aacttagaag cttaaacaac 12181 aaaaattaat ttgagctgga gctcagctgg gcagttcttc agctccaggt agcatgtgcR 12241 agagctggtg caccccatgt tcacatacct ggggcttctc tagagagcta gtgtggctgg 12301 gagttgatca gacatgtgag ctctctctcc ctgtgatctg accaccaggg tagtttgggc 12361 ttccttatag cttggtggtc tcagatcaSt tggagctctt atgtgacagc tgccttacac 12421 aagaaagcat tqcaagaaga caaaccccca tgaagaaaca ttgatcaggt ctctgcctgt 12481 atcgcacttg ctaacatcct gttctcaaca agttacatgg ccaagcccag agtcaatggg 12541 gaaagggcct acacaagggt gagaacgccg gatggtgtgg ttcactgggg ctgcagatac 12601 aaaagcctac catagcctct aacttctgat tcccacactg gtgtttattc atctgtcctt 12661 atctgaagtt caattcccat agaaattatc tcacctaata gctcatttga gggagtcttg 12721 gatctgtagc aattatcaga aaactgcttt ctgaattcag cttcattaga acatttaaaa 12781 ggaaacagtt cattagaatt tcagaaatac tcattttcat gcaagacttg cttgcttagg 12841 ttattacatt gaaaattaat taattctttt agtcatattt ttaatggagg aggaatttaa 12901 ttctttgaat aatatgacac atttctgctg aagactgaca gctgtgggta ttaatcactg 12961 ttctcatttc agaacctatt ctccctgccc aatttcatta tttcatggtg aaggaatggt 13021 ttagaattgc cactggcaaa aaaggaattt ggaccacaag ctagggtacY gttattacga 13081 atacggtgac aaagaggttg ggagcttcac ccaaaccctg aagatttcac catcccacac 13141 tctgtggccc agcagcacca gctagcggca tcatcgcctc acatttcaaa gttgctcctg 13201 cacttatatc tagggtggct tataagaaat gggcaaaaga tcacattttc cttaaaactt 13261 tttgtccaca tatttttatt aaaaaaataa agagcatgtt aaaaatgatc cagacagatc 13321 aaaagaatgt gcaatgaaaa atcattttct ttccacccag caaggctgga caccaatcct 13381 cagcatttcg gagacagtga gtccagttgc tcacattgtg tgtgtgcgtg tgtgtgtgtg 13441 tctgaatgtg tctgtttcac atccactttt gaatgtttgc taaagaacac ttcaaaactt 13501 agcagcttaa ataacaggaa ttaatttgag ctggggctca gctgagcagt tcttcagctc 13561 taggtgtata tgtgagggct ctagaaaccc aggctggaag ttactttctc tgagctcctg 13621 gaagatatca tcacattgtt tccaggtttc cattgcttct gttgaaaagt cagattaaag 13681 catatctttt tttMtggact ctttaaagat ttttgtctta gctttactat gatgtgccta 13741 gatgttgttt tcttcatact caaagcccaa tttctttgga tctgtggtca atgtctttaa 13801 ccagttttac agttttcagc agttatctct ttaagtatta tttctgccct atttattatt 13861 cctctccttt tcagattcta attacccata tattcSatat ttttcatatg ttctatgtct 13921 cttaaggtct ttctctattt ttaattcttt ttttctcttc atgctttaat ttagacatgt 13981 tcttcaaatt tatctttcaa ttcactttct ctttacctgt gtccaatctg cattaaactc 14041 attcattgac ttaattttag ttattttatt ttccacttat aaaatttgta tttgattMtt 14101 ttctaaagct tctgattttt gactacatgt ctcactctgt tctttaattt tctttaacat 14161 ataaagtgaa cttaaagtct gtatctaaca gctcctatat ttggatcccc atgggcctgt 14221 ttctaatgtc ttttgttgat gctgttgtta ttgttgtatt tcattcatgt tgtcttattg 14281 tgtgtttaat tattttaata aaaacctctt cctttagtta gaagttatgt ttttcagaaa 14341 gggttgatga gtgactgttc ttcaRgtcca ggcatgtttg aaaatatctt cttttgcttt 14401 tatatcaaaa taattgttga ggaatttaat tcttgcatta ttttttctct aataaactca 14461 atcatattac ttgacttgct acttgcattc aatattgctg taRgaaaaac tgagaccaag 14521 ctaatcttcc tgattttttg taacttgcat tttttttttt tttttttttt gagacagagt 14581 ctcgctctgt cacccaRgct ggtatgcagt ggcgccatct cggctcactg caagctctgc 14641 ctcctgggtt caccccattc tcctgcccca gcctcccgag tagctgggac tacaggtgcc 14701 cgccaccacg cccagctaat tttttgtgtt tttagtacag atggggtttc accgtgttag 14761 ccaggatggt ctcaatcttc tgacctcatg atccacccac ctcagcctcc cagagtgttg 14821 gaattacagg cataagccac cgcRcctggc cRtaacttgt attttttatg tgagaccgta 14881 ttgatttgtt tctttRtctt caaattctaa aatcttcaat tttcaccaag atatttcttg 14941 gtaatagtca ttctatgtca gtttttttta agttctaaca ttcctttcca ttctttcact 15001 caggctgctc ctaggagtac ttccttttgt tgtattttta acgtattgta ttctttttta 15061 cttcctSaat tttcttgttc tcagacacta tgtgtgtgtg tatatatata tatatataca 15121 catagttgaa tctcctttaa ttaatatttt ttctataatc attttctctc tgtgtacttt 15181 tctaagtgtg ttatccatac ttctgactgc aattttagtg ttagcttttt ttttaatccc 15241 ttttttctaa tgggactttt atttgatttc aYttactaat tctaatttct tttcttaact 15301 cacccagacc aatattatct ccttctggtg tcttatctct ccttcgattt cgagcatatt 15361 ttctttgcac tattttttct tacaacttat tgtaacggta catgtccagg aagaaaaata 15421 aaccacatca ggtatcttaa gaaaaacaaa tttaatataa aatattgtca accaagtatt 15481 gaaccaaaaa aagaaagggg aaaatactaa gataccttta agataacaac tcctgggacc 15541 cactgccata tctaggctag agaaacaaag tgaagaggtt gaaacattaa aatctatagc 15601 tctgatggag gagcattctc aagσtggaag ctagacttct gagtaggggt tgctacttgg 15661 ttagtgctgg tgtcttcgag ctcccaggaa tggtcctaag ggtctgtgac ccagatatct 15721 aaggatagga ctccttggct ggtgctggca catcaggaat tgagaggagg gaactgagat 15781 gagtgctctg cggagggggc cactgcttat caggagttgc tgcctgacct cagcagaaga 15841 agcccatgga gctaaggcca agagaagagg cagtgcatgg ctggtcctgg tacattagga 15901 gcccaaaaag aggtctcatg aaacagaccc aggctgggag gcagagttcc agctgagtgt 15961 tgtccatgtc tctgagtgcc atccagtcat cggttctgag tgtgagtaac tgtggaggga 16021 attcagctgc tgcagaggaa ggagctgcca caactggggt gaggacccat tgctggggag 16081 atgctgatag gaactgggag ccctcaggag ggaaggagca ggtcctgttc ctcctacagc 16141 catgacgcYt ccctctaaca ccgcttcttg gtgtccccca caatggggga cagctgacag 16201 attagaaacg tggctgcaga atcccagccc catcacagag cagaggttaa aagggtgggc 16261 atgcagccag aggaaacagc ttaagagaca gcactcttcc gaagaagcat ttgtccaaaa 16321 tccccttctg cgtcacagct cagctttcag atgcatgtcY tacatcagcY ttgcttgtta 16381 gcttcttttg ttgctggctc ctttccgagt tacccactga gggaaaaggg aaaoatggSg 16441 ggaaggaaag ggcatccact ggggtggtga aacatccacc caggtgtttt ctttcacgcc 16501 atgctcactt agcttttggt taactttagc taattggatt agttggttgc tgtgcacact 16561 ctccYtttat ccttccccta ctgccatctg cctcttgcag aaacagctct tctgtgcagc 16621 Ytgtcctcta ccccactccc tggcctgctt caacacaatg tgccagggtt tgggggctgc 16681 tcccatggtc tctccatgtt ccagatgttg cagtggcagg ttctaggtcc ttgactgggc 16741 Yttcgttgct atctaactct ctttgagacc tctgtcattc ttgggagaca tgaggggtca 16801 tctttatttc atactgtttt tctttctgtc caatttcact ctatttgcca gctattcttc 16861 acagtgggtg gtttgaggta gKgggcttct ttctaattta gttaaatatg gagttttctt 16921 ctccatttct tcattccttt tggctgtttt tggttgttgg gtaagagtat aaatatctct 16981 atactgatat tttcaactag aagccagaaa actgggattg aaacctttat ctgccattga 17041 tcttcaaagt ctatcatgat tgagtacttt gacaatgagt acaagaaaag acagtagtgc 17101 ttctctagct tactatgttt ccttttttct accttggctc ttaggcagct caaaacaaaa 17161 aagagaggtc aattttggta actcMagttt ttatgttagc tctccaacag acttcttgtg 17221 atttttttca caacgtagat agctgcttga agtctcttta tatgccactt gaaaccctgt 17281 ctgcaagcat gtcaagtgta cttgatcatt tttaaagttc gataggatct ctaattaaga 17341 tgtggacatc aagctgtagt ctttgaataa atgcaggaga aacctcctaa gagggatcac 17401 cccaccgctc attctggggg ttcccagtgg cagtatttta ggcactcaag ggatagtgcc 17461 tccgtggcat tggttaacat gtccatcatg gttagtattt actttagtct tagcYtaaat 17521 tagctcatgt ctgtaaccat ctatcttcct taKctgtgtg tcatcagagg gcatgcatct 17581 catttcggct ctcatttcac ccccatgacc tccccacctg aaatacagca aatgctttag 17641 taaatgaatt aaaatggtag aacttggcac agaatgcatg ttcaagatgt gaaatgtgtg 17701 agtgagtgag gaatggagca aatgagtaag tgaatgaatg ccgtgaagac atctggcaag 17761 ttttctgcaa ttaggcatac actctgggcc aagtgctatg ctaagttccg tttagaggag 17821 agatagaagt tggcatgcac tttttgttca caggaaagaa cactctctta ggcactagac 17881 aaggtggttt aactcacaga ggctagaata attccccggc actgggcata gcgctcttgg 17941 agaagaaaat gctatatggg caaagaaaaa taagtcattg taaatttctg tattgtatac 18001 cttttgggag cctagacaag ccaagctcct cactgggaaa ggcaaatcag ggcatacaat 18061 ttggcatcat cataaaaggc agcacatgaa acttcacaca acatgaaatt accctcttaa 18121 agtgtacaat tcacggagtt ttagtacatt cacggggttg tgcaaccatt accaccatca 18181 aattccagaa cattcttact accccaaaga aaaccccaca gctattacca gttacttcta 18241 agtctcccct acctccagtc cctggcaatc acaaatctag tttctgtctt ttatgttttt 18301 catgttgtgg acattttcta tcgggggacc atacaagaaa gccttttgta tctgccttct 18361 ttcactcagc ataatgtttt ctaggttcat ccatgtggta gcatgtatgg tgcttcattc 18421 cttcctatat ctgaataata tttcattgta tggacataca atgttctgtt tatccattca 18481 tcatttgatg gtcattggtc atttgggttg ttttcacctt tttgatgata tgaatcatgc 18541 tgtttgaaca ttcatttaca aggagtttta gtaaatatat gttttcagtt ttctagggta 18601 tgtacttaga agtggaattg ctggatcatg gagtaactct gtataYaact Stttgaggaa 18661 Ytgccaaact gtttccacag cagttgcatc actttatatt cccactagca ataaatgagg 18721 gttcaaaKtt tcctacatct ttgtcaacac ttattactat tcatcttctt attatagcca 18781 tcctataggt ataggaagtg gtatctcatt gtaattttga tttgcatttc cttgatgact 18841 aatgtcattc agtatctttt catgtgcttg tggccatttg tataccttct ttggagaaat 18901 gtttattcaa gtcctttgcc catttttaaa atgagattgc cttttattat tgagttgtaa 18961 gagttgttta tacattctga atgatagatg cttctcaact atatgattta caaatctttc 19021 ccccatttct tgggttgtcc tttcactttc ttggtagtgt cctttgattt gcataagctc 19081 ttaattttga ttgtcttata catttattct gggtttcctg tgctttttta acattttatt 19141 ttttatttaa aaagtttttg aggaacaggt ggtatttggt tacataccaa atggtggtat 19201 ttggataagt tctttagtga tgatttccaa gattttggcg cacccatcac ccaagaagtg 19261 tacactgtat gcaatgtgta gtcttttatc cctcacccca ctcttaccct ttctcctgat 19321 tccccaaagt ccattgtatt attcttaaaa ttccaggaat ttatccatct cctctatgtt 19381 ttctagtttg tgcacgtgaa ggtgttcata gtagcctYga atgatctttt gtatttctgt 19441 ggtatcagtt gtagtagctc ccatttcatt gctaattgag cttattaaga tcttctttcc 19501 tgttgtcttg gttaatctca ctaatggtct attaattttg tttatctttt caaagaacct 19561 gctttttgtt taatttatct tttgtatttt tttttatttc aatttcattt acttctgctc 19621 tgatctttgt tatgtctttt cttccattgg gtttgggttt ggtttgttct tgtttctcta 19681 gttccttgag gtgtgacctt agactctcta tttgtgctct ttcagacttt ttaatgtagg 19741 cattcaatgc tatgaacttt cctgttagca ccacttttgc tgtatcctgg agattttgat 19801 aggctgtgtc actattataa ttcagttaaa aaaatttttt tatttccatc ttgatttcat 19861 cattgaccca atgatcattc aggaacaggt tatttacttt ccatgtattt ggatggtttt 19921 gaaggtttct tccaccgtgg tttgagagag cacttgatat aattttgatt ttcttaaatt 19981 aatcaaaact tgttttgtat cctattatat gttctatctt ggagaatgtt ccatgtgctg 20041 ataaatagaa tgtatattct gcagttgtta gatagaatgt tctgtaaata tctgttaagt 20101 ccatttgttc tatggtatag tttaagtccR ttgtttcttt gttgaccttc tgtcttgatg 20161 acctgtctag tgctgtcagt ggagtattga agtcccccac tattattgtg tttctgtcta 20221 tctcatttct taggtctagt agtaattgtt ttataaattt gggcgctgca gtgttaggtg 20281 catatatatt tagaactgtt atgttttcct cttggactag tccttttatc attatgtaat 20341 gtccttcttt gtctttttta accactgttg ctttaaagtc tgttttgtct gatataagaa 20401 taggtacttc tgctcgcttt tggtgtccat ttgtgtagaa tatcttcttc caccccttta 20461 ccttaagttt atgagacctt atatgttagg cgagtctctt aaaggcagca gatacttggt '20521 tggtgaattc ttatctattc tgccattctc tgtctcttaa gtggagcatt caggacattt 20581 acgtacaact taaatatcaa gaggtgagat actattctat tccttatgct agttgttacc 20641 aaaatacctt tttttcattg tgttcttatt ttataagtcc tttgagattt atgatttaaa 20701 gaggttttat tttggtgtat ttoaagaatt tgtttcaagg tttagagctc cttttagaag 20761 ttctggtatt gttggcttgg tagtggtgaa ttctctcagc attggttttt ctgaaaaaga 20821 Ytgtattttc ccttcattta tgaaatttag ttttgctcga tataaaatta ttggctgatg 20881 attgtttgat tgttttgttt aaggaagcta aagataggat tccaatccct tctagcttgt 20941 agggtttctg ctgagaaatc tgctgttaat ctgataggat tttcatttat aggttacctg 21001 atgattttgc ctcacaggtc ttaagattct ttccttcatt ttgactttag ataacttgat 21061 gactatgtgc ctaggcaatg atctttttgt aatgaatttc ccagatgttc tttgagtttt 21121 ttgtattttg atgcctagat ctccagcaag gccagggaag ttttccttga tcattctctc 21181 aaatatgttt tgcaaacttt tagatttctc ttcttcctta ggaacaccaa ttattcttag 21241 gttttgtcct ttaacataat cccaaactcc ttggaggctt tgttcatttt tttattcttt 21301 tttatttgtc tttgttggat tggatttgaa agccttgtgt ttgcattctg aagttctttt 21361 ttccacttgt tcaattcgat tgctgaaact ttccagtgta ttttgcattt ctctaagtgt 21421 gtccttcatt tccagaagtc gtgattgttt tttatttatg atatctattt ctctggagat 21481 ttttccatcc atattctgta tctttttttt taatttcttt aagtgggtct tcaccattct 21541 ctggtgcctc cctgattagc ttaatagtca gccttctgag ttatcttttt ggcaattcag 21601 atactttttc ttggcttgga tccattgttg gtgagctagt gtgatctttc aggatattaa 21661 agaaccttgt tttgtcatct taccaggatt ctttttctgg ttccttctca tttgggtaga 21721 ctatgtcaga gggaagattt gggactcaaa ggctgctatt caaatttttg tcccactggg 21781 tccttccttg atgtggtgct ctcccctttc cttcccctag ggatggggct tcctaagagc 21841 caaactgtag tgattgttat ttctcttcta gatccagcca cccaRtggag ctactgggct 21901 ctggcctggt actggggagt gtgtctgcaa agagtcctgt gatgtgatct gtcttcaggt 21961 ctcttagctg cgaataccag cacctgttcc agtggtggta gcaggggagt aaagtggact 22021 cagtgagggt ctttggttgt atttttgtta agcgtgctgg ttttgtgttg gttgtcctcc 22081 agtgcatcag ctgcagtagt atagggagga tccgggggtg gatggagcca tagagctccc 22141 aagagattat gtcgtttgtc ttcagctacc tctaccaggg caagtagaga aagaccatca 22201 gatggggtca gagttaggca tggctgagct cagactctcc ttgggtgggg tttgccatgg 22261 ctgctgtaga ggatgggtgt tttgttctca gaccaatgga gttatgttcc cagggggatt 22321 atggcggcct attctgtgtc atacaggtca ccagggMagt ggggaaaacc agcatgacag 22381 gcctcaccca gctcccagac agtccaaaag gcccgtctca cttccactgt gcccccacaa 22441 gagcatcggg tttatttcca ggcagccagt gagcagggct gagaacctgc cccagactac 22501 aagcctcccc aotgagaaat caagcagggc tttcaggctt ctggcctccc tgcctgccat 22561 ggtttctgtg tttatatatg cactccctgt tcacctcctc ccctggattc tgtccaggaa 22621 acttcatgtt tggttgaaat tgttataaag tctagctgga agtttccttc tccctgtggt 22681 ctttccccag ttccactggc acacctccgc agagacgcct gagagacaaa gtcaggaatg 22741 gctttcctgg gcaccaaaag tgcctacagg gttcttccca ctgcttcctc tacccctata 22801 tttcacttgg ctctctaaat tcatctcagc cccaggtaag gtcaaattct tttcccatca 22861 tctagacctt caRgctcccc agtgaggatg tgtgttcagg gacagacatg accctctcac 22921 actttgggca ctcagttttt cagctgtctc atggatccta ccatggcaag ctgcttcctt 22981 caaaggggct tgtgcttttt tgtcatatct aaaaaacgat tgcttaatcc aacttcacaa 23041 agacttaaac gtatgttttc tctaaaaatg ttacagattg gcttttacat ttaRgtcttt 23101 gatccatttt ggttaatttt tctatattgt ttgaggtggg agccaactta attttttcac 23161 atcttagcac catttgttga aaaggttatt cttttctcat tcaattgtct tggtaacttt 23221 gttgataatc aattgcccat agatgcacag atttatgtct ggactctcaa ttatattcta 23281 tcatccatat gtctatcatt gtgccagtac cttattgtct tgattaattt agctttgtag 23341 taagttttgg aatgaggtag tgtaagtctt ccagctttgt tgttcttttt taaaaattgt 23401 tttggatact ccaggttcca tttccataaa gattttagat gagaatttat attcctggaa 23461 aacataaagt tggtatttta atagggagca catgaaatct ctgtatcaac ttggcatgta 23521 ttactacctt aacaaaattc attcaatcca tgaatacggg atgtcttttc attcattttg 23581 ttaYacactt tattctagtt atcttttgta gctttcagtg tataagtctt acacttcttt 23641 aaatttattc ctaagtattt cattcttttt ggtgctacta tacatgagat tattttctta 23701 atttcatttt cagatggttt attgctaatg tatagaaatg caactgattt ttatgtattg 23761 attttgaatc ctacaagttt gctgaagtca taatagttta tttgtgcatt ctctgggaat 23821 ttctatatat gaRgtcagat catctacaaa tactgataag tgtacttctt cctttcYaat 23881 ctgcatgtct tttatgtatt tttctgacct aattgacctg ggtagaactt ccagaacaat 23941 gttaaatgaa gtggcaagag gagagacatt cctgttttat ccctgatctt ctaggaaaga 24001 ttctggtctt ttgctattaa gtatgatatt aactgtgggg ttttcataaa tgccctttat 24061 cggtttgaga aagcctcctc acattcctgg tttcttgggt gtttttcatc atggaaaggt 24121 ggtggactgt gtcaagtgtt tgtctgtgtc ctaatggtcc taatctgatg tggtttttac 24181 cctttatttt attagtgcag tatattacat tgattacttt cfccatatgtt gaaccaaatt 24241 ggcatcttgg ggtaaatacc acatggtgaa tactgctaga tttggtttgc tggtgtttca 24301 ttgagtattt atatatatat atatttataa gatgtattgg tttgtggttt tcttttcttg 24361 tgatatttga ctttggtatc agagtaacac tggaataata gcaagaacgg gggagtctta 24421 ctcttattct gctttttaga agagtattta aaggattagt gttaattatt ttgtaaaggt 24481 ttagtagaat tcatcaaatc actggtgaag ctaacttgtt ctgggctttt ctttgcgaga 24541 agtttgtttt tgtttttgtt ttgtgactaa ttcaatcttt ttacttgtta taagtctatt 24601 tctttgtgag tccattttgg aggttggtat ctttctagga atttgtccat tttatgtgaa 24661 tgtctaatac gttgtcacac agtttttcct ggtattcctt tataatcttt tttcttttcg 24721 aatggtctgt gttaatgccc cctttttatt cctgatttaa taatttgagt cttctctctt 24781 tctctcctgc tcagcctagt tacagatgtg tcaattttgt taatcttttc aaggagcaaa 24841 ttttattgtg ttcattttct ctgttgtttt tctgttctct attttattta tttcttctct 24901 attgtttact tcctgcagct gctttggatg tagtgttctt ccttttctag tttcttaagg 24961 tggatggttt agttatgaac ttcaagtatt tctccttttt aaatgtagac acagatggct 25021 atatatttct ctctgagcac cattttcatt gtatcccata aattcagcta cattgtgttt 25081 taatttctat tcatctccaa gaatttccca atttcttgtg atttctcttt gacctattgg 25141 tcgtttttta ccgtgttgtt tactttccat atatttgtga cttttcaaat ttccttctgt 25201 taccaatttc taactttatt ctattgtggc cagagaacat acttggcatg agtttgacca 25261 tttcaaattt attgggacct attttgtgac ttaacatgtg ctctaccatg gaaaacattc 25321 tatgtgcatt tgagaggaat atgtgttctg ttgttgggta gggtgctcta taggtgactg 25381 ttgtcattgt tttgcgttgt tcaagttatc cattattttt tgatcttcta attgctctaa 25441 tcattattta gagtggagta ttgaactatc attgttgaat tgtccatttc tctctttaat 25501 tcttttgttt ttcttcaggt aatttgggtc tctgttgtta tgtgtatMat tgttatatct 25561 ttttgatgga gtttccattt tatcattata aaatgtcctt tgtctcaaat accagttttt 25621 gtctttaaat ctgttttgtc tgacattaat ataagcactc tgattctcta taggttactg 25681 tttgtatgaa atatattttc catactttta ttttcaacgc attcattttt ttgaatctaa 25741 actgtgtctc tttttgttat catatcattg gatcatgttt tgatccactc ttccattctc 25801 tgtcttttaa ttggagagtt aaatctattt acaaacctgc cttcYccact ggagatgaca 25861 agagtggagc tctggttttc ccttttctct acacagtgtg aactattact cacttcactt 25921 cttgccaggg caacttaaat aaaactgtca accagctagt tatgtaattt gattttcaca 25981 ttctctctct gggactcagc tttcttattt gcaaaataac ttgggacaga catttaacat 26041 tcttttgacc aatgtgcaaa tgacacactg cacacctgtg cagggaatgg cctgactcta 26101 gacgtctccc actagtcctg tgaatagaaa tgagtggaga gactgaaaag ctcatatttt 26161 tctgatgggc aaaataatag caattcattt tcactaRgcc caaaatagtc caaggtatca 26221 tctaaagacc tcaRgttgct tccagtttcc cccacaatat ttgtgcccaa agcatcaRgc 26281 agaaacctga gactgggtcc tttccttcat gcaRgccctt gatgtgagtc accagcacct 26341 gtcacttcta cttgccaaac actggccctc ccacctccct cctccctgct gccacccctg 26401 cctcattcct gcctttctca tttctcatgc tcctgcttcc tgtccctctg ccctctccat 26461 atgccaattg atgcactgtc acagcacccc aaaaatcctt ccaaaatggc cttcgtcatt 26521 gctgcccact gctggcatac tctctgcaaa ctccagactc tcctcggctt cccacccaag 26581 aactccatga ttagacacct tcccacctgc cgggcttatt gcttctcctc cccattcaga 26641 tcctccacca atctatcaca gtttcctaga aacagtgggc tctagccagc ttctctccct 26701 ccctctgcac cagctgctcc tcaccgagag ccccactccc caaactgcag ttctttaacc 26761 actgtgctct ctccttaaaa gaattttgac aaagtcgtga aacttctttc acatatgttt 26821 gaggtaacat ttaacttttt cacacaaaca tataattttt catatattat aaaaactggt 26881 attttaaaat aaaactgtta gtgctctctt tagaatttat gcaatagaaa ataaatactg 26941 gccaggcacg gtggctcacg cctgtaatcc tagcactttg ggaggccgag gagggcatat 27001 cacgaggtca ggtgtttgag accagcctgt ccaacatggt gaaaccccgt ctctactaaa 27061 aatacaaaaa ttagccaggc gttgtggtgt gcgcctgtaa taccagctac tcaggaggct 27121 gaggcaggag aatcatttga aactgggagg cagaggttgc agtgagccga gatcatgcca 27181 ctgcactcca gcctgggcaa cagagtgaga cttatcacaa aaaaaaaaga aagaaaaaag 27241 aaaataaatg ccacagcaat ttaaaactta gcattatcca tttaaaaaga atacatgagc 27301 agcctgtaat cccagcactt tgggaagcca aggtgggtgg atcacaaggt caagagtttg 27361 agaccagctt gaccaccacg gtgaaaccct gtctctacta aaaatacaaa aattagccgg 27421 gaatggtggc acacgcctgt aattccagct acttgggagg ctgagacagg agaattgctt 27481 gccaagaggc agRgtttgca gttaaaaaaa aaatacatga gcaatctcca ccttaaatgt 27541 cagaaatttt accccttctt ttttttctac tggaactcac agttcaattc tacttccctc 27601 attgaatttt attctaatgt cacagaattt tatgcttgaa agagctttat tatcatctca 27661 taaaattctg gaaaagaaac atgtatatca attgaaatta ttttgtttcc tatgaccaaa 27721 tggctctaga tgttcaattt ttttaattga gttatcatga caatgatcat taactgagca 27781 attcaaggta tataataaaa aattgataaa ttattatatt aaaaaataag attgcattgg 27841 ggatgttcct tgtgatgaga tgattttgtg gttgttgctc tgtttcttga gtcacttatg 27901 tatctgtccc ctggatcaag aagtggacaR cagggatagc aggtgcccgt gactggtgca 27961 gttgtccggg gagagctcag ggtccccccc aaccacctac ccctgtggtt catattaata 28021 ttgaccttta ctgggggcct ataaattgtc tttttgggta aggccttgtg ataRatgaat 28081 agtgcttatt tttagaatta agcaaaggag acctcacatc aattttattc tcaccttttg 28141 ttttttgtgg ttttgtttta tagttgaata cactgagaaa ctttattcac gtctaagagt 28201 aggtgagaat tttgttatac caatggcatt cagttctgag gactccttct cggttatagc 28261 cattagatct gcctttaaat gtgttgaaag caaataattg gaaaccacct ccctcagaaa 28321 gggatttgtt ttccaatcat tcaaatcatc attgctcaat ctcttggacg tctatgcaaa 28381 gggcactatt acaagactct cagaRgactg tacaccaScg tgtccctcgt aggtacttgg 28441 ttcaacctgc taagagatag tgctgaatat tattttatca tatgctttga atatattttc 28501 ctgaagacYt tgaggctgag gcttagccag cYtgaatgat ggagatgcca ccctgatgac 28561 atgcttggaa agccagcact gcagcttctg ttggcacaat tcaactgcca gatgggactc 28621 cctaccaggt gaaggcatat ggcgtttctc agctcaagca aatgtgtgaa ttgcatgttt 28681 caagaaatag cataaaaatc actgagaaat aaattgcgaa atgtgtctta taagaaaggt 28741 gactaaaatc agtcaatatt aaactgataa aaattgaata caataattcc tatttatttt 28801 ctaataagtt gtaaaaaaac aagataagtc taaatactat ttgttattat tgaatgtggt 28861 ataatgctgt catgtagcaa aattattata tatgatataa aatgtatgat aaaagcttca 28921 gtaagcctgt ggcaaaggta tgcttctgga cattttgggt tgttttgcta attttgagaa 28981 taatcgaaat catctaYtaa agtcaaaaac aacttcaaaa attttatggg acgtaatcaa 29041 agtttctctt tatacttaag aaaacagaag gtaaaagtcc caaagtacta aggacttgaa 29101 tgtttatgta caattttatt tttgttaatg agaagaatac agtaaatgtt tattttgatt 29161 aagatgagga ttgactataa ttagaataaa tatttcaatc tatggtttga caaaatgggt 29221 tttcacttac tttggaatac tgcacacata attttaatca gtgaatttta ccttgtatgt 29281 cttgaaaaac cttggtgatc tcccctcacc aaaattcaaa tgacacttaa catcataatc 29341 ttYattaagc tgtaacccct actgctctgg ctgttcaaag acactttttt ttctggccaa 29401 tggcataccc agatagcaaa catggccaag agcaggggaa agctgctccc tttaaattag 29461 tcatgggaac aattgagcca atgtttttta ctgatgtttt ctctgctttg ctcccacagg 29521 ctMtccccca agggcacagt aatctttggc aactgtctgg gcatggaaga ggcatgctca 29581 ctaatggaca agttcatcaa gccctctgct ctgctctttg atgtgtctaa attcagaaca 29641 tccccacact ggcgcYtcat gKRtaaggtt taaggcagga agggtccagg tgggctggag 29701 tccctacatt aatctgcagc cctcaagtgg ccctgctttc cagatgggca gggtgagggg 29761 tatgaggcag cattaatgtg gagcaggaaa ggagcctttg tgtctccKgg tgtgatcatg 29821 aggcaggtcg gattcaggaa gaccagcctg tggaacctca ggctctggtg agttgccaag 29881 aaactgagct caagtagcca gatgacaatt cacatctcct gcttgtttcc aaattaacat 29941 agaatcctgt ttccctccag gccatcactg tctcagtatc ttacccagaa cccagccaac 30001 attcaagaaa tgtgtgttga gttgaaatgt attaagtgag ctaccacttg ctaagagaaa 30061 gccccaccca acttttggta gaggtctggg tttggagcYt gaagttgtct cagctctggg 30121 gaagaaagaa tgacatatcc tctgtctggt aggttctaag accagcccag actttcccag 30181 gcacaagctc agagccctca aacacaacct ctggtctcta ggctgtgtgt ctccagggca 30241 ggctagaagc atcccocctc ctccctggag gctgatcagc gcctggggaa atcctctctc 30301 ttgccaccaa gcagcaggct ccagacttgt caatcttggc ttttctgata aatcattcac 30361 aaactttcat tcccactggt atttgctatt tgctaattga ataattagat ataattaata 30421 acatcataca ttaccataat tttaacatta taggtgtcaa gaggatataa tttaattaga 30481 ggttaacgtt ttgggcttgg aatcagatgc ttaagtgaac tgtagcttgt gcttctgcca 30541 gctggagaag catgaactgt gcccttctga ttcattctgc tgtgtttcta aRgtctggaa 30601 aagcagagag ggaaacacat tgatttcttg aaatttggtg Rctgaagaga aattccctga 30661 aaacagcatt ggtgtttgtg tatgtgtatg aacatctgct gcagctctgc ctcaaagagg 30721 atatatacta gctgctctgg gggacacaaa agaccccatc tttatgtcca cagtcagRaa 30781 ggtcaaataa Rgcttgcaca gaagtccctg cagcaggaag taacgagtga caacctccat 30841 tgtcacatgg ctgagttatg acagattcgc aggatgcatg caatcaggaa atcatatgct 30901 ttttgataag aatgactctg gaatatactg ctaagtataa tttctaaaat ttataacttg 30961 ctaagacttc tcctgtaatc gaatttacag gtgagaaaaa gaaactgaca agacattaat 31021 catgatgtca gacttagaaa agatggctgt taaggagatc acgacagatc agtgttgtgg 31081 gaattgaaag gatggggagg ctgcccctgc gtgaaggtgg gaactcacaa tcacaagtga 31141 gggagcccca agtcaagaaa ccccttttat ttccagtgca tctcggagca tgtctgctgt 31201 ctgtgtatgc gtttactctc tgggtttgat gagttgacgt ttctggtgag tgtggtcagt 31261 gctgctgtct gggctgacct gatctgggta gaggactgta ttctgaagga ggcttagatt 31321 cccggttagc gctgcctgct gcctgatcac ctccaggttc ggttgtgagg cacaatccat 31381 catgttaggt cagggttctt gatagcgtct caaaatctga gtgtggggca gagggctccc 31441 agcttaggaa tgatcatcaa gaggagcctg tctctgggct ggggcaggag agtggcaggt 31501 tcaRggtgtt gctgcggtga acgctaaagt gagggggagt catggaattt cYtgagaggt 31561 tggtgggccg gctgagaagt gaagtggtgt ctgtgctgca tgaggagccg tgaggtcagg 31621 cagggagcct agagctagtt cagaggaaac accagcagcc tggtagtgcc agctcctgcc 31681 ccgaggcaag agggataaSc tttatcactg ggtccaggct acagagtcca caacaggctt 31741 ttgatggagt ggagacaaaa gagactccat cctggatgct ggttacatgc tgacttctgg 31801 tcagccccag tcccaggaat gactcccaat tctactgtat tcactgtccc tcgcataaga 31861 gcatgtcaac ottgatgtta ccatacaaat ggcaggctct gatgcacaca gcattctttc 31921 ctgttctggg gggctgcctt tcatcatctc gatagagcaa ataaaatctt tccctatggt 31981 atataagccc tgggtctggg gagtaacggc agggaggtct acctgtcttg tagcctctca 32041 agactgtgct tctgtttgaa ggttctaatg aatcatccta tatccacaaa aactggattt 32101 gcctgcctca tcttttggtt tcctggcact tttggcattt ggggRccgct tggcatattt 32161 ggcccttcca tgaggttgat tcagaacctt aagggcatgt ccagatctct catgcacaaa 32221 tagatgattg gctttgatag ttaggaaagc acccggaagg aggccactga ggagacttct 32281 tcaggtccca caaggcctac tcatgttgga gcccccacag cagagggtct tcctgagaac 32341 tgagttcata aagaggtatc gtaacctcag aaaaacttgg cacccattgt ctgcaatatc 32401 cagttaacct agaaatcctg tccattgttg ctgtgagggR tctaggacaa gtctgcatag 32461 ctttttgtct attgtgaggg aatgcctttc cctcttctga taggctgtgc cctgaataat 32521 gggctgtgct ctgacaattt tKtaaagtct tgactgtgga cctggggaag gcaggaggga 32581 cttcagtgaa gccctggggt gcgcccggcc cggtgcactg ttgtcctccc aggtgaagga 32641 agaaaaagtt gactgatctg gggcacactg agaagggctg accaaagctc cactgcagtg 32701 gagcaggcag ctacaggagg aaatgatggc gggatggtgt ttgggttagg aattactggg 32761 aagtgagaaa tgacaaatgt gtcgatgccc tgaagtcttg accacattga tttctcatcc 32821 attcagtttc ttggcaggac aggagggttg taagggtgaa tgcagggcat gggaaggcct 32881 ctggctataa gacttttaac tttagtttga gcctttcctt cattcccagc ttcaggggat 32941 aatggagaaa tttgggtaac catttggtag gatctatctg aattttaata agttctactc 33001 aaattaattt ctgtatgttg gtggaagttt tagcccatac agtatcagat acggtgtcaa 33061 ggcctttatc tagggctcac atctgatgtg acagaagggg caaaggtaga tcgagagcag 33121 acacagcttg atgatgaaca gaagagttct ctgagactgc aggaaattgt ccctctggtg 33181 tgcaaatgtt ctgtttgtaa tgtgaatgtc tcgctattaa atttgcatag gtgggatcac 33241 agaacaggaa agaatgtttt caaccaagga cctgaaggtt ataYagttca ggaccaggag 33301 ctcaggaaaa tccatgggtt atttgaaata tcagccactt gtgtggtgtg tttgctctga 33361 ggtgaaggtt aagcaaaggt ggcaagtgta gcttagaaag aggagctccc atatcaactg 33421 ggaataatga aatggaccat ctatattttt catcaactca ccttgagtat ttaaggtaac 33481 agcaagatat tgggtgcacc ctcatctaac tagattttct gatttttctt tgtcttgtct 33541 tttcttttcc aagatgggat gatctttatt ccagcttccc ttttgtttac atatctacaa 33601 gtatccttat cagtttgtca gttggctggg agtgggtcac cctgctgttt gatctgtagg 33661 gacatgcgtt tattttgggt cgtgtcttcc ttttgttcta aagccctttc aacatgctct 33721 gccagctatt gtagttgagg tgaaaagact accttccatt ctaatttctg tttttgaatt 33781 acatatacaa attgacaaaa tgagatgaaa gagctgcttt cccatcaccc tcttctttaa 33841 ctcccaaatg caacctcaat atactttYta gtttagtctt aacattgcct atatttttat 33901 attttattat ttgcatgata taattaKggt ccaatagatt ttattggaaa tgtttcaggc 33961 atagcatgta gaagacttaa tcctaattta taggcccttt ttgggccctc aagcttattg 34021 tggaaagagg gatcatatag gtccctttcc agttcagtcc aattagctct taccatctag 34081 aatttagtat ctgaggctct gatcagtatg tgtacaactt aacataggtY gggtcactgc 34141 atcaaccagt gttctccagg gaaacagaac caatatgggg agtgtgtgtg tgtgtgtgtg 34201 tgtgtgtgtg tgtgtgWgac agaaagagag agagagattt taaagaattg acctgataga 34261 tgatggaagt tgccaagtcc aaaatctgca ggatgggccg gcagtctgga gacccaggca 34321 agagccaatg Ytgcagttca gtccaaaggc tatcagctgc atcattcatc ttgctctgag 34381 gaKgtcaggc tcacattcca tttaggcctt caactgattg gaaaaggtgc actcacatta 34441 gggaatacaa tctgcttcac tcaaagacca ccaatttgaa tgttaatttc atccataaca 34501 acctcacaga aacagctaaa ataatgtttg accacataaa tagggaacca tggcRcagcc 34561 agctggactc ataacRttaa ccatcacagt agccctgggt cctaggcacc caaaaatttc 34621 tctaggaata gttgctggct ttgtctagat ttagggaaat cctcaatcag agctttcaat 34681 tcagcctggt tcccgggttt acattctgca gYtgtcagta tacctggttt ctgggagcaa 34741 taagactttg gagacaacaa ttatttgggg ggtcatacaa gagtcattgg taaaagctag 34801 acagacaagg goaagaggaa ggaggagctg atgggagtgc agaggagagg ggccagaagg 34861 aaagtaaaca acgagatatt cgtacaaggg gctgccacac agcaatcaaa agaaacgaac 34921 catgctacaa acaatgacag tgaatcccac agataaccag cagggcaaag aggtcagaaa 34981 caagagataa cacactatat tacaccattt gtatgaggag aaggccagga aatcYtacac 35041 gttagggaga ggctttagaa tagtggttac cttgtggcaa gggggtgctg tgcactggga 35101 agagacatgg ctggttccct ggggactgtg tgacYtacgt ctcaagcagg tggtagctac 35161 atggactggc agttatgtgg ggtggtagtt atgggggggt ggtagttatt caaggtggta 35221 attacacaga atggtagtta catggggtgg tagttacatg gggtggtagt tattcaaggt 35281 tgtatttgca gggtgatagt tacatggatg gtagttgttt gaggtgtagt tacatggggt 35341 Rgtagatatt tggggtggta gttacagagg Ktggtaaaca cacagggtgg tagttacatg 35401 tggtggtagt tacatgggat agtagttaca cagagtgata gttacatgag gtgttagtta 35461 tttggggtag tagatatgta gatggtagtt acttggggtg gtagttattc agggtggtag 35521 atacataggg tggcagttgt gtgaggtggt agttttttgg agtggtagct acatggagtg 35581 gtagctacat gagttcgtag ttatttgggg tggtagttac acagggtagt agtcacatgg 35641 ggtKgtagtt atttgggatg gtagttgtta catggggtga tagttatatg cagtggtagt 35701 tatctggggt ggtagttaca taaggtggta gttatgtggg gtggtattta cacggggcgg 35761 tagtaacatg cggtggtagt tacaaggggt ggtagtgtga acccagaaaa tctgagacag 35821 gtctcagtta atttacaaag tttattttgc caaggctgag gatgcgcacc tgtgacacag 35881 ccccaggagg tcctaatgac atgtgcYtaa agtggtcaca gcacagtttg gttttataca 35941 ttctagggag acatgagaca tcagttaata tatgcaagat gaacactggt tcggtctgga 36001 aaggcgggac aacttggagg aaagatggga agactca'aag tgaggagtgg gctcccaggt 36061 tgtaggtaga taagagacaa attgttgcat tcttttgagt ttctgattag cctcttcaaa 36121 ggaggcaatc agatgagcat ttatctcagt gagcaggggc gactttggag agaatgggag 36181 gcaggttggc tctaagcagt tcccagcttg acttttccct ttagcttagc gatttgaagg 36241 ccccaagatt gattttcctt tcacagtagt tacatggggt ggtaattaca aagggtggta 36301 gttacatggg atggtaataa ctcaggatgg tagttacatg gggtggtagt tacatggggt 36361 ggtagttaca tagggtggta gttgtcagag ttgtaattat gtggattggt agttattcag 36421 ggtgataatt aaaatgggtg gtagttatgc aggatgttag ttacacggcg tggtggttat 36481 tgtgggtatt acttacacag ggtggtagtt attcggggtg gtagttacac tgggtggtag 36541 cgatacaggg tggtggtcat tcagggtggc aattattgaa ggtgatagtt attcggggtg 36601 gtagtgacac agggtggtat ttaggtgggt tggtggttat tctgggtgat agttattcag 36661 ggtggtagtt acactgggct gtagttaaaa gggttggtga ttatttgagg tggtagtgac 36721 acagggtggt agttattcaa agtggtagtt atttggagtg atagtgatgc agggtggtag 36781 ttaggcggat tggtggttat acagggtggt agttattcag ggtggtagtc acatgggtgg 36841 tggttatatg ggtgatacac agggtggtgg atatgcaggg tggtagtcac atggtgtggt 36901 agttattcaa ggtggtagtt atttggggtg gtagtgatac agggtggtag ttaggcgggt 36961 tggtagttat tcgaagtggt ggttacacag ggtggtagtc acatgaggtg gtgattattg 37021 catggtactc acacgcggtg gtggatatac gggtggtagt cacacggggt ggtagtgaca 37081 cagggtggta gttattcaaa ggggtagtta tttggggtgg tagtgacaca ggatggtagt 37141 taggcgggtt ggtggttata caaagtggta gttattcagg gtggtagtca cacagggtgg 37201 tggttatagg ggtggtactc acacagggtg gtgcatatac ggggtggcag tcacacaggg 37261 tggtagttat tcgaggtggt agtttttcgg agtggtagtt attcagaggg tggtagttag 37321 gcaggttggt ggctattcgg ggtggtagtc agttattggg gtggtactca cacagggtgg 37381 tggctatgca gggtggcagt cacatggggt ggtagttatt ggggtggtgg ctatgcgggg 37441 tggcagtcac acagggtggt agttattggg gtggtggcta tgcggggtgg caggtggggt 37501 ggcagtcaca cagggtggta gtcagttatt ggggtggtac tcacacaggg tggtggctat 37561 gcggggtggc agtcacacgg ggtggtagtt attgggatag tgactatgtg gggtggcagg 37621 cggggtggca gtcacatggg gtggtagtta ttggggtggt ggctatgcgg ggtggcaggc 37681 cggttggcag ttgcgtgggt gcagctctcc agttttgtgc actttgtgtt tgtcattccc 37741 gctggtgcgc ttgtaaatgt ttaataagca gctgtctggg caagaaagct ctagtttgca 37801 gtgtttgccc YttcYgaggc atgactcttc tcacctgtgg ccacttccag gctgcacatg 37861 tgacgtccat gagcacagtt agggagggcc gtggatccgc atcaccttgc gagcataaat 37921 gcagtcaaat gtgaatgagc tgcaagtgac aagtttgagt attttttccc ttcattttaa 37981 tacaattcat ctaatagtaa gtttttaacg tttaattttt aatgatKtct gtgttaacaa 38041 ctggctccca agacccctga aaatttagca cttaggtttc aggagctgga gcaagctggc 38101 tccagcatcc actggtgWta tctcaatgca attacttaag aaacaaaatt tttcctgctt 38161 aagagttgaa ggaacaaagg gaagtacaga gtgaagaaat gagtaggtgt ctggctcttg 38221 tgaggaaagg agaggaagag agtgccctga agaatctgag cattggagcg gacacggggt 38281 tccaatgccg gaccctttgc tcgtggttga acttgaactg tgcctgcccg ctgccggctt 38341 gagcttgtgg gcctgcacag ccagaggcgc acacccctca gagctgcttg agagaccggg 38401 ggatgtccct ccacccagtt acccagcccc gaaggcccac catgctgaat caacactggt 38461 gtcgggttta ctaattatgt atatcaataa ggacaagagt cattcatcta tagcagcagt 38521 gcactcagaa ttttttatac atacacaata tcaagtattc tgctttactg tgtcagaaat 38581 tttaacccag tatttttgaa atccaaagag catctttcag acaggccttt gaactgggaa 38641 acaacataaa aatcctctgt aagacacagg tgcctaggtt agtatcggag acatggcaga 38701 agaagattcc attcctcaag gtggtggttg ctgtcaggat gtggctgctg cggctgttga 38761 tattggcaga ggctgtgctg tgaggagccc atgaggcccc ttcgagggct caatcgatgg 38821 gaaagtaccc ccagcacgga tggcccaaaa gtggcagcac ggaagccaaa gtggttggta 38881 cSggaaagtc ggccaggggg tctggctggg ctggggattc aagttcctga ggaagccccc 38941 aggctcacag gagctgattc tccatatcat cccactgttc caccctccac tgggcctcct 39001 gccccacccg ccgcctccct tgtctggcag atgcggagag cataatacag gctcttttcc 39061 actgctcatc ttcctgagag agaacttctt ccctgcaaca tggctgttta atgactgtgt 39121 ctgcaggaga gaaacagcat cacatccggg tagggctgaa ccgctgggga gtcctgggca 39181 tttggcggaa ttctgcacat catcctgtgt gcaggcaggg ggtactgggg tttggaatac 39241 agggattttc ctgtccatga taaaatacct ctgactctac agggaagcag gcatacttca 39301 ctcaattaac atactaaaaa gtataagctc tggccaggaa aatgaagcct ctttactcga 39361 aagtagccgt cctcatagtc agctcccaaa ggcaggcgcc ggcttgctYt gcaggcagca 39421 gataagcaga cagtacattt gggtaccatc cgaaagataa ttggccattt gcttactgct 39481 ctcaatttct atctctggct catggatgct tttctctcgt tttttctcgg ctgagaaccc 39541 aacaagggct ccacactgag ctccagtagg gcagggcgtt gaagccattt ccacccaaca 39601 ccagccagca ggggggagct gcccacagca ctgtaaRgag ggatgagggg caggccacag 39661 atatggcctc agtctactct caaaccccct cccagtgtcc cctccactgg ttgttgccac 39721 ccttagaccc ttggaggacc acttgaggtc actgcaagca tgatgatggc ccagacactt 39781 ccaagacagg ctgaatcaga atatctgagc aagtctgatg cagaaacctg cgttgtaaca 39841 aaccctggat agatttgaag tttgagggcc actgggcacc ccgctagaat gcaagcttcc 39901 agtgaggagg gactttgctt tgttcattgc tatctcctca gcacctcaga gatagcaatt 39961 aaacattttc aacatttaaa catttσtgga aRgcacctct ctgggggaga gttccctaat 40021 cttagccatg aaRgagttga tcaggttaga gttggcaatg tgacaatcat cctcccactc 40081 cccagtcctg ctcagggcag acatcactaa tcaattacag cactcttaat gcctacagcc 40141 caagcagcac caccctgcat tccaggctgc cacagcaaac ccagcaaagg cagtgcctga 40201 gagagctcat ccttaccatc tgggagtcac tgtgttcctg atccttccca gttcggagac 40261 cctgtggaca ttgtgatgag gctccaaaac tggccccacc acacggagac atctgccagt 40321 gggcgtcttg ctgctgctct gaggagtgta gggcctgggc cttccctgtg agaaggaggc 40381 gttctggtca tcacaacaga atgcagtgag gggcaaagcc tgtggcccca gagagccagt 40441 tgcttggcct cgggaggcct ccatgtttcc atgggtttac atcatggaga atctctggcc 40501 acatgtttaa ggtgaaggag cacaaatgat gattgtgagc atttgctcaa catgatttac 40561 cacccttggc ctattttgtg cctgccagtt gctgttctag aagctggaga cataggatga 40621 acRtggtagg aaagctacag cctacggagg agcaatttac tcaacagact tctccctgag 40681 ccacagggac ctcagcagcg agcccggcaa gRatgccatc catcggcctc tgtcagccgt 40741 ggaactcatg gattatttct attcttttcc ttagactttt aactgcattc tgaatagcaa 40801 ctcatctgag gaggagaata ttctagactt tgcttaagat ctgattctcc ctttaacctg 40861 tcctatgaaa actgagcctg ttattggatt ctccagactg ttttcttcat gggaaatggg 40921 gataagaatt tctgcctgct ggggaactga gcacaatata actatgaaaa tgctaaaaat 40981 ataccattct tctcaaagga gWtgagatca cctaaaacaa atgacatagc cacagtatag 41041 tcagtaaagc agaactagag tgtggaaaat caggaactag ggaagaaaga cagagacacf 41101 aatgggcttt aagaggttga gcagcaaaac ctaaaaatcY ttgacatcaa gtgatgtcca 41161 gttaatgaaa agaggagatc ctcacaacat atccagacac ggaaagttct ttttccttcc 41221 acaggatagc tttggcataa agaggaacat atttcacaga gtttatgaag gacagtttgt 41281 ctccagaagt ttctgcatgt gctcagcctt ctgcggcagc aaatagcagt aggcatatgt 41341 ggaactctct gcagagatct tcagaagact cagccctctg cagtatgaac tgtgaacaat 41401 gatggcggga gattctctgt ttgtcaaaac caaccaagRg cagggactag tcccagctga 41461 gctggcgtgg agcttcagag aaatggagtt taactgtggc catcagagga atttctattt 41521 cagaattact tagaagaaga attcaatctg ggtcagaggg caggctctgg aaaggtgggc 41581 tttctgagag gcaggaaggt ggggaggRgc aaacactgtg ttcagggacc cctgagtaca 41641 agcagtgctt tctccccacc tccccttcca ggtctggggt ttggttttag agcagggagg 41701 accaggagtg ggtagacacc caacattcgt atgcacagcc acgtaatgtg gtcatcagca 41761 ctgtcctgct gagctgccct ggccacatgc tgagctgccg ccactacatg ctgagccgcc 41821 cccgccacat gctgagccgc ccctgccccc acgtgctggg ctttgggatg tccctaccat 41881 gggcccatcc cctcagtccg ctcatgtggg ccactgtcca aaccactggc ctggtctctt 41941 cagaagtgtc caggcggcga aggacagtga aggctgagaa ggcacactcc agaggaaaag 42001 tggacagagc cacgcggcaa gcaaaggtaa cactccacgc acgcatgggc cccagacagg 42061 gcagaaagac tgatcattgg catctctgag aaaactgaca aagaatgatt agatggtagt 42121 attaatgcta agtttcctga gttttgatta ttatactgtg actatgtgat aggaagggcc 42181 cttgctctca Rgccatatgt tgaaatattt agggataaaa aatgacatta cctatgcaca 42241 cagaaagtta tactgggctg gaatgYacac ggttggtgag tggagctaaa gggcatagaK 42301 gtaaattgtc ttaaacttac cgaaaatttg cggatttagg acaMagagct cctacatacc 42361 ctttaccctc attcaccaat tgtgtacRtt ttgccgcacc attttctgtg tgtacatatg 42421 taatattatt ttacatacga ttcttatttg tcaattatat ctcaataaaa ctggaaaaat 42481 tgttgagaag gcagatgtca tgtgatctct tacccctccg ccccaaaaag acacagagaa 42541 accaatccct cacccaggca cagggtccgc taggctcacc aggtgctctg gcagagaagc 42601 actcccccaa agtacaggca ggaagggccg agtcaRgcag gcccaattcc ttcccaacac 42661 tccccagcct aataactcag cctgactccc tggggaggaa ggaagacacc agcRtgttac 42721 ttccRagaag aaaagtcgtg agggagcggg gagggccacg atgatgtctg cggccatcac 42781 caaRgctcca tttctaacag acagMtctgc ctccaccagc tggcacgtcg ggtggctctc 42841 tacagcctag agccaagctg tctgaggtct ctccttatct gcttaRgaat gcatgcttta 42901 cagtgagatg gccaagtgta atccttagct taatcaagtt catccagtgc cccaggggat 42961 agggacagcc tgggagccat ttaaatcaca caagctactg ccccttggag agaStggggg 43021 tgggggaatg ggttctttca tgtaggtgat ggcttccctc ttcatccatg ctgctgcaaa 43081 tagaaatMat catgtatata ggccacaatt tccttattca ctgtgaaata agccagacac 43141 agaaagacaa ataccacatt atctcattac atgtggaatc taaacagatt gaactcacag 43201 gatggaggag aatggcggtt accaggggcc gggctgaggg agtggaggYg gaaagRggag 43261 ctgttggKca aaaggtacta agtcacagtt aagcaggagg aatcggtctc actgatctag 43321 tgcacagaca ggtaacctta gcgaataaaa atgtattatg tatttttaaa ttgctaaaag 43381 agtagatttt aaatgttctc accacacata cacacatgca cacacacatg cacacacaca 43441 cgcacacaca cacacgRtac tcaagtgagg aggggSctct gctaaggcac ctgcaaacRc 43501 atgcacaccc caccacagca caccccccac aaacttacac aattactatt tttccactta 43561 ttttttaaaa agattggaga gggcttatga tcctgacgtg tgtacatttt tgtgattctg 43621 aatgtgattg tactgatgaa Rcataaagca ctgtttactc tgtaataatc cacacRtgac 43681 ttgtcccttg gacaYgccag tggtatgggc gaaaaaggcc ctgaacaccc aggcccaccc 43741 agacttgcct cttgccRtaa gggtcatggc ttatcttccc aggaagcaat gccacagcat 43801 ccaagagttt cttagcaaac agcaaacgat gctgagtcag ggaggtaggg gggattcctc 43861 ccctctgaaa tgaataaaag acttMctgca attgcYgtgc ttcaaacRtc cggtaccatc 43921 tctgYttacc aaggtgttta aagattgctc attttotcca agtttctaat agcataaatt 43981 atcttactgc tctaaataaa gaggttatta tatattattt tagattttca gcaaccacat 44041 gcatttagca gttagagata ttagtgctgc caagtgactt tgaaagataa atactggtgg 44101 ttagaagaat gccaKgct±R cgcttgtttt attaaacaga aatccaRatc acaatggctc 44161 tattYcagtc ctctactccc tgagtgtcca attaactaga agacagaaaa tacacttttt 44221 otaatttaaa tagactctgc tccatattaa ttccaagggg ttatacattg gtcacctatt 44281 tccaaatcct ctaatacaaa tggtggagcc gtggtttctg ctggtgccct ggtgactccc 44341 caggctcatg gctcgaggca ctgcgcaggc cctctgcagc ccctggagaa tctgcctgag 44401 ggctttccca gcattgtggg gtcggcctca caagcatccc ttagctgatt acaagtggga 44461 attggagggt gaaYagcccc agttcctggc ccttgggctg ggaggaccct ggggtattac 44521 ctaYccctct ccccgtggct gaaccctagc tgcccacagc tttgtcctgg ctccttccca 44581 ctccccatac cccRgctgga gcttcctgag atcagctccc aaatgagcta ccactctcca 44641 accttgtcat ctacttttgt gggaaaKtca cctgagttac ccaaaaattc cccctaaaga 44701 tcctcttctt cctgcagcca gcaggcaagg aggaggctcc cagtgtgggg gaggggaggc 44761 gaggaaggag aKagcacagg gttttgagcc ctgcaggtag aagcacatcc ttacactgga 44821 gcacgaagga ggaagctgcc atatgcaggg ctgggattcc ggggtccctg gagctgcaga 44881 accgactctg ccctgggccg agagctgctc tcgagagtca gtagatgact gacaagtctt 44941 agcagaagcc atgaaaagct tccctccttc ctttcctact tttctttcca ggcgttcagc 45001 aaacaccccc tggggagagt actactggtg gccaggccct gtgtaggaca aacattggtg 45061 gacgaggcaa caccaccctc cttgtggagg caccaaRgcc tctgtcctgc cccctgactt 45121 ccctggagcc cctcatcact ccctggacac aggcggcatg gactgagggt gctctgcaac 45181 agggcccctg ggtttgctgc accagcatcc tcagcaggtg cctctcacct RcctccaKct 45241 cagatcccca ggataacacg gttggtcctg aggagactcc caccaagaac ctgggtagca 45301 ccgtccagcc aagatagagg agggtcctca gcctgagagc tgggaggagg ccttgtcctt 45361 gctgaRgctg cctcagaagc tggccctgag ataaggattt ggtttatctg ggaggggatt 45421 ccaggaagga cctggaaggg agtgaggaag gaagggaagt gcctcaagga agggaccaaa 45481 gtcaaaaccc aggagSagga aatcagtaac accgaggcca gtgggatcRc gagcctgggg 45541 tcaacttcgg gagacctgag gtctatgcct caggKtctgt gccttggagt gtcctctcca 45601 gagagccagg cacctgggct ggatccagca gctccagtag gtctgcagct cagggcagct 45661 tcctggggcc tgactctcca gcccttcagg aaagaactct gagaaggagc atatggtaag 45721 aggccatggg cacStgccag acccacagtg ctatggatgc ggggacttgg acagagacct 45781 taggtctggg gtgcgggtgc atgtgcacta cactggccct cccgacccca ggagtgaggc 45841 caggaagtga gagcctcagg gcactgaggt gtagtccctg catccctcct cctgcctgca 45901 gggtcaacgc aggatgaact gcatggacca tcattgcttt ccacaacagc acaggggcct 45961 agggattcac ccatcagtgg gaaatcaagc atcagccgtg tgctgggaag ccagggtgct 46021 gtggtcgcat gtttgtgtgt ctgtgtccct ccaWatccag atgctgaaac ctaatcacca 46081 aggtcctgat gtgaggaggt ggggccttta gcaggtactt agatcatgat ggggagcYct 46141 catgagtgtg attggtgctc ttataaaaga ggactgaagg ggttgttagc cccttttggt 46201 gtttccacca tgtgaggaca catggaaggc cctatctggg aggaacaggc cctcaccagc

46261 ccctgaatct gctggtgcct tgaccttgga cttcccagac tccaaaactg tgagcaatat

46321 acattgctgc ttataaatct cccagtctcg ggtattttga tacagcagca ggagcagatt

46381 aagacacagt gaaaagtccc agcatctgac tttagacagc tgacctggtc agttctcaaa

46441 gtggggtccc aggaccagta aggcattacc tggaaacttc ttggatatga agctctcagt

46501 ccccacctcc cagacctcta aactctaaag gagctgtgac acctgttcac aggccctcgg

46561 gactctgagg caagctggca ttggaaagcc actgaaccag ggcgattggg gaggtcttca

46621 ttaactgtgg gaagaaaccg aggggagggc atgtttgcta ctgacacagc ctcttcacat

46681 tgctccccaa gagacaacca tgccgcccca gtggttggcc ggacatggag acactaactg

46741 ggtcttaagg tacttaggac aagagcaagM gaagattaca tctcaacacc gcacagggaa

46801 ggattgaagc aatctcttac accccRggga agcagaaaga agaacgttaa aaaggaaagt

46861 aaaactgcac atggctcaaa acttcaaaga gttctgaaca ttttcaaata aaaagtgaaa

46921 gcctttctct tattttctag gctggttcat cacttcttag atgtcctttt gagagaggct

46981 tctgtgcata tgccaacaca ggtattttat agggttagtt atttatttgt tattctgttt

47041 ttacactgtt ctgccttttg ttattccctt aaacatatgt cttcgaaatg tttctgtatt

47101 ggtagagaga gggtcatttc attctttgtg tatgttaata acttgttact gaagtgtata

47161 cataaacaca agtgaacaaa ttgtagtttt Kccatctgta gaattgtcat aatctaaata

47221 atctgtttct taatgataga ttatttgatt tttttgttct ggtttcattc ttgcaacaat

47281 atttgtaagt gtttcttttt cctggctaac ttatgagtac agccaccagg tcaattcctg

47341 gcaggggtac tgctaagtca aagggtagct gcatttttta actttgatgg atatggccca

47401. ttaactttcc agagcagccc tctgcaactt acactcctgt tgacaattta caattgcacc

47461 cttttcccta tgctcacagc agccacgagt gccattgcat ttttaatttt gctactttga

47521 aattatattt ctttgttctt tttatatgtt tctttaattt tgagagaaat tgagcaagcc

47581 ttttaaaaac tRtatttatt aaccaatttc atttatattt ctgtgggctt gtttttcagt

47641 ggggtttgta aatgtttttc ttaStgactg atgagcactc tttgtaaaac gtgttgctca

47701 atgaagcYta caagcctttt cccatttggR tttcaaatat tttcttcagt taattgttca

47761 ctttttcttt aattgtgggt ttttgtgtcc tcgatgatga tttttatttc tagtcaaata

47821 tctcaacatt tcccattaaa gttttcaaat atatatcttg cttagaaagg catttcacat

47881 tcacaactat aaataaactc accttttaaa tttcagaatg ttttcatttc actcttgtac

47941 actcacatct ctgatacctc tggaacttat tttggaacaa taaggcagtg ggtcagaatt

48001 ctgtgtggtt ttccaaatac cacattgtct ctaagccatt tattcaatat ttcctctctt

48061 gccctctgat ttaaaatgct tcctatcata cacactcgat ttgagtatac atttgtatat

48121 atcctggggc ctctttctgc tccacacaaa ccttcgtgtc catctgcttt cattcttgaa

48181 ccttcacggt gcatttgaca tttcacagga ctactcccca attcccttct tccacctgac

48241 tcttcctgYt tattttccca catcgatttc ccttcacata gcatgttagt gtttcaactg

48301 ggattgcact gatcctatga gtaatttagg gttaatgRtc accttcataa tattgatgca

48361 ttctagccaa tagcaagtta tcgctcgcag ttttagttta tcccttagca gaattttcag

48421 gttttgttta tataggtcct acatatttct tttaaagttt gtattttgct attgtctcaa

48481 ctaaatgcta tcttaaatgc aatatttttt cattattttt tttgacaggg tctcactgtg

48541 ttgcccaggc tggagtgcag cagctcagtc ttggctcact gcaaccaccc gctcttgtct

48601 caagtgattc tcctgcctca gactcccagg tagctaggac tacaggtgca cacctctatg

48661 cctggccaat ttttcatatt ttttgtagaa Rcagggtttg ccatgttgcc taggctagtc

48721 ttgaactctt ggactcaagt gattcgccca ccttgacctc tcaaagtgct gggattatag

48781 gtgcgagccg cagaacccgg ccttttttca taatatttta acaagttatt tgtacataga

48841 aaagttattg gttatgcata ataattttcc tacctgagtt attgttttcc ataggttcag

48901 ccagttctcc tgggtattcc aagcacacag tcatgtgatc tgtgaacagt ggtaacttag

48961 ccttgacatc tcactatttt actggcactt ctgactctcc tctgatttta ttgtctagcc

49021 ttctgtaacc agcctacata agatcacagc ttcggtctgt attcacagaa ataaattccc

49081 aagcttgaga acgttctttt catttgYgca cgttacttga tgtgggctca gaagtaggcc

49141 actgtggttg tgagaggtag tgtYccaggg acaacagaag gtggctcatg cgagcaaagg

49201 ccagggaggc agagcctgag agaggggccg gccactctgc ccctccctgg agtccatgcc

49261 cagtgggσtg tgggggacac agatcccacc gaggcaccca ggcaggagct gtgcggttcc

49321 agcctcttta cctcatggtt ggcaggcccg ggcgtctctc tccacctgtt ttgtctcctc

49381 tttgccccat cggcaacccc agcctctcca tttctgaaaa gagcagagaa aggacaacat

49441 ttggggaatg acaKcaataa gagagggtag ccttcacctg cagagggtga gcagcctgcg

49501 gccccagcct ggacttgccc agaggaggag gtcaagaggg caccagcaag gggttggctc

49561 ggcaagatca gaaccctcag tctccaggaa gcaagatgcc aacagcatct gtggctagga

49621 gtcaatcacc agcgtcccct cagaccccac gtctgcccct cccagccctt tcccatggca

49681 gcttcctggg atgacYttcc tccaggcaca gcaggggctg ccatcgcagg gcagcaagtt

49741 ggaagggtgg gctccatgca cccaccgagg ggccttgcct ccccagccct gaccacagcc

49801 agttccatgc acatgctcac cagcctgaca gggacctggg acttattggc catgagcctc

49861 agacgtattt gaaggagaaa atgtattttg gttttctgcc aaccttatag tcttttatca

49921 aagagaaRgc acttgaaggc gcttctcaga gggagacttt ggcagggcac cctgccccga

49981 ggtggagtcg ctcacccctt ccgcttccca gttctgctgc tgcagcctcc gaRgctggct

50041 gaaRgctgat ggcccatcgc aaggtgtctg tggctgctgt ccttttactt ttaaaaagtc

50101 actcaRgcct gagagctggg gatgggtagg cagcctgtgg caagacctgc ccagggctct 50161 atctccagct gcctgcccca cccatgcccc cagcccatca gctcacacag acacacagca 50221 cRgcgtggag agtgttccta gaagcagcca cYttggagga ggggtcccct gttcYtgaga 50281 actccaaggc attccgctcc cacccttcaa agggcacagg tggctgcttg tggacctgat 50341 ggtgctcaca cccttcacag ggcacaggtg gctccttgta gacctgatgg cgcttggtat 50401 cctgtcctRa aaccatggcc tctcattcat ctataactgg gttacagtct atcagattta 50461 aaaaaaaaaa ctcaaaataa taaccaccta ttacaatggc cttggctcca ccgcacccac 50521 cagttcagca tcgcagggtg ggctgtgcat gccatgggct gctggagacc aggaggccac 50581 ctgaaaggca gtgtgaccat caggctgcct ccaccactgg gaccctggca ttggaccaca 50641 ctctcacagt gggatgaagt gtttctgcat gtttctctgt cctccatcca tccagatctc 50701 agcgggacct cctgcccatc ctccatgtga ttcagagtcc tcgaatgcac tccatgcagc 50761 agtgaggtgg ttcttccatg aacagttttg tgcccgccac aggccaggca ccataccagg 50821 tactgggaca ccaccccccc accaccacct ctatgcgctg aagaccctaa tacctttaaa 50881 gctgtttgct gcacattaca atcacccaca gagcttttaa actcccctag tccagattac 50941 ttccattcca attaaattag aattgggggc agggcagttg aggattttta aagctccctg 51001 ggtgattcca aagtgcagcc aggattgcga atcaaccctt taacatatca cttttatttt 51061 aatttctatt tacttgcaaa acagtgcctt ttcaaactcg aatgtgcctc tacactcctg 51121 ggagtctcac tccaggacag gttctggct^'c agcaggtctg gagcaagcct gggattctgt 51181 gtggaccaca agctcccagg tgatcctgat gcttgctttg agccatgcag ctttgaactc 51241 attacctcat ttggttttaa tgccaRctct cccaggcagc aagccacaag acccggagtt 51301 gaggccacat ggtgggtatt ttgaatcttt gatactccac agagaagcag gtctaaatcc 51361 ctgtggataa aggagggcgt ctgtgaataa caagggagca agtgtgtctt gggaactggg 51421 cacggacagg gtccctcacc caggagacac ctgtttgcct gcctgcgtcc tctaggaggc 51481 tttgactctg tggggcctca cagaacactg agRatctgct ctctgagacc Rggaagactc 51541 gatatcctct ttcccctcct cctgggctgt gggatctgtg tacatctccc acactgctat 51601 ctcatgaaga gtgagttcct tgagatccYa atagtagcac tttgggaggc cgaggcgagt 51661 ggatcatgag gtcaggagat cgagaccatt ccggctaaca cggtggaacc ctgtctctat 51721 taaaaaatac aaaaaattag ccaggcgcgg tggcgggtgc ctgtagtccc agctactcgg 51781 gaggctaagg caggagaatg gcgtgaaccc gggaggcgga gcttgcaatg agccgagatc 51841 acgccactgc aatccagtct gggtgacaga gtgagactcc gtctcagaaa aaaaRRaaaa 51901 aRaaaaaaag aaatgctcag aacatggttc atgctcaaac aagttatgga aggcatccat 51961 ttccatatgt taagcaagtt tcttcactac aggacttctc agggccttta aattgctaaa 52021 ccgcaagaYg atgatgccat gtacaacttt tccagacttt ttcaggccat tcttactaat 52081 atttcctcca agagtcttgc ccagggtaca ggttgggaac actgaagttg gccacagtta 52141 agcatttgat gaatccctgt gggttgcaat ccttgagcgc catggggctg tgtgagctcc 52201 aaggcagcct aggMccacac cagcgcagga gatcatttat ctggggaaat ctcaggtgcg 52261 accttagtct aggctgccag gttctcagac cttaagcacc agctctggcc aggaggaaag 52321 caggcagcat tcgcacagca cttcctagat tagagaaaat tatagattgc cttgaatttg 52381 catactggga cccacccaga aaccctgggt ttcagtcata gccagtgcca atgcctgaat 52441 atagcaaact tctgctgcaa tcagggccca ggtgcagggg aattagaatc aaaggaatct 52501 aatattccat atggtgggtt ttagccaaaa gtacctttgt ttcttttctg ttttctcact 52561 gattttctct gaagttgctt tatcttggtc atttgaccag tgttaacgca ttgcccgaag 52621 acccccagaa acattgacat tgYctgaaaa cttgttggaa atgcaggatg tcagacccct 52681 ccctggactc aggaagtcag catctctggg ggtgaggact gcagcctctg aacacgccct 52741 ccagcagact ctgtgggcac tgaagctgaa aaattgctgt tttaaaccaa agtgcccgct 52801 attccagcat ctgcaaaggc cccagcgtgg ccacctttgt ttcttcattg cttttatttt 52861 tctttgcaag cttattttgc tttatctttc taaccatttg cctctcatta tgaagaactt 52921 ggtgccagcc aagcgcatgc caggccctgt gggtgggata cacaggacgt ccggagatcc 52981 tgaagagcct gtccaggttt tcaaagcctc ttagcaagtc ctattcagtg catattcctc 53041 ctggttttca ccctgctctt ggccaRggaa acaactggtt tatgcctcaa atccccagaa 53101 agggctRctt ttacMcgtgt tcagtcccct ttagagctgg ctctgaaacc tggtggcgaa 53161 tgtgcctttt ctttggggca gtggcaccac ctggctgtac gttccaatcc cctgggggat 53221 gcaKgcagag actcacYcca ggacctccag ggcagggacc tggctgtcaa tatcgtttaa 53281 ggctcccggt gattctattg tgcaccaggc ttgagaccct ggcatgagat taaagactaa 53341 ggaaaacaaa accaagagtt ttacaggaga gctggcaaaa ctgctgacgt gggtcacagc 53401 tctgagaaac atggaactga agcaaagaMg accggtccca cagtcggatg ggaatggaaa 53461 ccctccagct cctcctagat ggtgtttggc aacagagagg cagcctgcag tcctaccgtg 53521 cctacgtggt cctttacggg aaggtcaggg ttcaccagcc attcttgggg gccaggtggt 53581 gtctacctcc agtgcactag ccacagtcat cgggcccaag gctggggtgg agactgagga 53641 ggccactccc agccacagtc ctacgtgtga tccttcagga gggggcccca ggcactgaca 53701 agcctttgcc cRgcaggccc aacagggaaa gctgccttcc ccccccccag acctgtgcca 53761 agcccatgcc aggaagtctc tgcagggagt caaggactca gccacgatcc tgtaggcatc 53821 tgcagtcctc acccaggcac ctccctccag gcctcctcac cgggggcgtt ggctaaggcg 53881 tattccacag tctgactcag cRcttttccc atgccagccc gtgccacgcc ccagcctccc 53941 aggttccttt tgttcagggc tcctgggcag tgaggattcc ccaacctgca ttgcagaccc 54001 tggcccaggg ccaaaccgca ggagggcgag gaaactccgc cttgctcctt ctcccacctg 54061 cacagtcccg gggaggKtgt gctccagagc agggctctgc aggccatggc cacggctctg 54121 aacacStcac cgttgaactc cgggtccaag ctctcggact caactcccaa cgtagccaca 54181 gctaagattc cctttctttt taacaaatta gcattaaaat gaactgaaat ttgttgatcc 54241 tgatttaagt ttctttttaa taaggtcgtg gataaatttc acagWtggag atgtgagggc 54301 aaccaYacat gtatgtggcg aggRccagaa aacagctgcg gtgataaata aatggtgggt 54361 gcaagcaaga atcaaataaa tggtgtggaa aagaccagcc ctctttctct catctttcta 54421 gtcaatgatt ttagtcctca gctgcctccc taggatctgt gtcttacaag agctccgttc 54481 tttcYtgaaa actgtatttc tctaaaacac tYccagagcc cttatcacag ccRaggcctc 54541 ttttccagtc agtggcctga gagtaaggca gtgcccttgt cagaagctgt tgatgctggt 54601 aagMagcagt gacctctgac ccttctggat gctgctgact cctgctgtca cttttaattg 54661 cagagaaagt aaaaYaagag atttYtactt tgtggactgt gctacttcag cagtccctct 54721 tcaggcagca tgcacatatg cccacactga ggtaaggaac atgagcccag aggtaaggaa 54781 tatgaccaac ctgatcccct cagccatcac aggtggtggg aaaagacttc aggtgattca 54841 ctcaaaggca caaaccaggg tccgggcaga gctggactKg aacacacggc tcctatctct 54901 caggctgtgt tcgttgctct gcacRcactc ccgctgcgtg tttactcctt ggcaatgtgt 54961 tgagcacctg ccRtgaacca gctactgctg ctgtggatgc agtgacaacg .ggacaggcag 55021 agtccctgct gcagagggtc tgtgctttag tgcagcaggc agctctgcaa cgtcaggcac 55081 tccagctgtt aagggcaggt gctacaaagg gacccacatc cgggggtggt gagtgtccct 55141 tctctggctc actcgggtac aagaaaggga aattctggga aaaagtggca gcagtgacag 55201 agtgcttacc ctccctaaac ctccccctaa aaatagatgg catgctatgg gctgaatggc 55261 ctcccWgcaa cattcatatg tttaagccct aattcccagt acctcagaat gggctctgta 55321 tttggaaata gagcctttaa agtggtgatt gacttaatgt ggggtcatta gagtgggtcc 55381 taatccacct tgttgatgtc ctcataagaa gaggaacttt gggcacagag agatactcag 55441 atgtgcatgc acagagggaa ggccacggga ggtgcagcaa gccaaggaga gagtcctcat 55501 gagaaaccag ccctgcccac acctggacct gggacttgag cctccagaac tgtgacacaa 55561 tagatttctg ttgcttttgc taccaggcct gtgtcatgtt gctatggaag cctYaatgcc 55621 cagaacaact tgacagtgaa atccaaaact cgtggacagc aacccaacat tcaagtgggt 55681 gggacaaaca cccacgagcc cccRaccaga tagtgtggga gcagcagaag gaaacaggag 55741 acaaccctcg cacctggaaa cagagcctcc aaaaggcaga gggcatgggg gtgatttgga 55801 aacagcagtt gaagcctagc atttgtctaa tgcttcagca agtacaagKg tgagcctgct 55861 gggccgtgga tccttcaaac tggcctgtct gggctcccag ccaggacaga gcccacactg 55921 aggagagatt gggtgagaaa aatcaaaatt gagcaagatc cccatatcaR acctgaagtg 55981 gggaggggaa cccacccagg acacctcaga gggcagacca ccctgttctt aatactacaa 56041 ggaaagtgcg gaagagagag ctctgcagag ttaaaaatcc tcccctgcaa tcagtctcct 56101 tctaaaatat caggaaaacc atttcacata aaaattgagc aacagaagtg cattgaggtt 56161 caataYgaca caaaatacaa aattaacaca agaaaaagag acgaagcRgc agaaaacctt 56221 tcctactaac aatcaaaact tgcctgacaa atgggaccac aaaaatcaga gctatcatct 56281 attatttcaa tataaactaa aagacattag gaacaccaca tgacatgaac actcttaaat 56341 gactttggga gaattcataa ataaggtaac aaaactctag agaatttgaa ataaaagaaa 56401 attattgcag aggtaatgat taaaatgaaa ggaacataac accaaataca cacaagggat 56461 aatgccatag aaaaatagaa ggcaaaaaga ggaaatttgt aaaaactgaa aaacacgagt 56521 ccagagatga aaagactgag agaaagtggc aaatatgaaa gatagacaaa ggaaatctaa 56581 tataaagaaa ttaggagcct gagaaagaca atcaaagcag gagaaacgat tatcaaccca 56641 gaacaagcaa tgccaaaaca tatcctagta aaattattaa actgtaaaga aaagaaaaaa 56701 aatcttttga gcattcaggc Raaaagagca aatgacttgt aacgagaaga aagcaaatta 56761 tcatcaaact tttcaacagc aacactgtgt gccagaaaat aaataaataa ataaataaat 56821 aaataaataa atgcattaga atactcaagg aaagaaaatg ttagccaagM atttcatatc 56881 cagcaaaact gactttaatg ataaaggcca tgtatagact attatcagta tgtaacaact 56941 cagcaaagat cattcccgtg aacatttcct gaggaatcta ctaaacacta agcctcagac 57001 gagcgagctg atgagagaga cacccattca gggacYggtg ggcactgaag atagagtcgc 57061 ccctggaacc cagcctgggt gatggcccgt gggagggtct ggagctcagg cagcatagat 57121 cccacacaat caaaaaagtg ggggagggag ggagggagga gtggtggtat tgttattctt 57181 atttcattga ctttaatttg ggataaaata aataattatg ttatattcta tcaatcactg 57241 taggcttgag aatcagggtt cttgttgtgg aagaaagaag atacagatgg aatagaagag 57301 ggttgcccct tttctaaaac cttgtaaatt ctaaatttgt atagagaata aaactoatta 57361 ggtattttac cttcaaagta gatagttaca taggtagtca gacagtcaga cagagagaga 57421 gatacagata gatagataga cagatagata gatggataga tacatacgta catacataca 57481 tacatggaag gaatgaccat tccaatagca atgagtgcat ccagcatcca gacagtggtc 57541 ttgaaatgtc atttcccact aaaaaaaaaa ataataagga gggcttcttg ggcttcatgc 57601 ctcgtcccat gtctgagaga cgaaatgcat gagatgagcc tggagcaccc tagcagatgc 57661 caagataccc tcaaagacca cgagggtcac atcagaaggc tcaggtgcca gcatggagag 57721 actctcatta tgaggtcaat cttcaaaRag gagaataatt gcaatatgtt gaaaacccat 57781 caactataca ttcctgaatt catagtattt ttaaaatatt aattgggcac cttttgaaga 57841 tgttgtaaaa ccaattcaat gttttaaata aaagaaagta cccagtgttt gtcctccttt 57901 tcctgtacga atggtacccc tgggtaatcc aggcataggt gaggaaaagt ctctttaaga 57961 aactatccca gctaataagt gaaaaaaaaa Ngatggaaac agacaatcac cattttgcag 58021 gcatgccagc ccagtggctg ctgatgttac acaaagagaa Ycacccagac atcggatgcc 58081 tcctgatgag acaacacacc tgtctggtct ggaagatgaa tggtgcctgg gtctgatccg 58141 gctctgggtc cagctgtgag aaacagaggg tagcacaggc cttggtctac accacgtggg 58201 cacagcctgc aaaacccaga cgggaaaact gcaggcgaac cagcctgtgt tcctcaacag 58261 aaagggaaag agaggtgtac agggaaccta taaattgaga catcacagtt taaaaaagga 58321 agatgaaact ctaggatcca aggactgcac ctggatgcta agctgtggag aagtgcaaag 58381 agctggtcta gtcagggcag gcataggaga ggctgcaggt ctgcttcttc acctgtgtgg 58441 tggctgtaag gtgttgaccc aaaataattc actaagctat atcttttatg gggttttctg 58501 tatctgtgtt ttattttata atagaaaatt taccaatccc agcactttgg gaggccaagg 58561 caggaggatc acttgaggcc aggagtttaa gaccagccta ggcaacatag tgagaccttg 58621 tcttcacaaa acttaatatt aaaaaattag ccaagcaggg catggtggct cacacctgYa 58681 atcccagcac cttgggaagc caaagcgggt ggatcacctg aggtcaggag ttcgagacca 58741 acctggccaa catggtgaaa cctcatctct actaaaaata caaaaaatta gccaggtatg 58801 gtggcatgca cctctagtcc cagctacttg ggagggtgag gcaggagaat cacttgaatc 58861 caggaggtgg aKgttgcagt aagtcaagat tgcaccattg cactccagcc tgggcaacag 58921 agcaagactc tgtctcaaaa aaaaaaaaaa aattagtcaa gtatggtggt acacacctgc 58981 aatctagtta cttgggaggc tgaggcagga gaattgcttg agcccagaag ctcaaggctg 59041 ctgtgagtta taatcaggtc attgYactcc agcctgggtg acagagtgag accctgtcac 59101 tgaaagatag atgaataaaa gaaaggagca gaatcaccca cagagcttgt gtgtttcgga 59161 gccctgcagc cagggtttct gatgcagtag gtgtgagctg gggctcccag gcgatgctgg 59221 tgttgctgtt ccatgaagca cacttcgagc aacagaggga aggagcaatg gctcctgtgc 59281 tcagtgtgcg Rctggtattc aataataata ataacatgtt gcatagccac tctgtatcag 59341 gtccagcact aaagacctca tcctacttaa ttctcaaatt agccctgaag ttgatattcg 59401 ttttttttgt tttgttttgt tttatttttt ggcagagtct tgctctgtta ctaggctgga 59461 gtgcagtggt gcaatctcgg ctcactgcaa cctccacctc ccaggttcaa gtgattctcc 59521 tgcctcagcc tcccgagtag ctgggactac aggtgtgcac caccacgccc agctaatttt 59581 tgtattttta gtagaagatg gggtttcacc atgttagcca gggtggtctg gatctcttga 59641 ccttgtgagc tacccgcctc agcttcccaa agtgctggga ttacaggtgt gagccaccac 59701 gcccggccga tattcttaca tgccttggaa acacaaagcc atggaagctg agagaacaga 59761 gtgtggctgc aagggaaaga gaaggggggt cagccccagg gccaccctgg agcctScagc 59821 tccagaccca gcattcccaa gggctttgct gtgggccttc cttttaacag aagcaatgat 59881 tgaaaactta aaggcatgtg tgggactgca aagctggttt ccttcttgag gcatccaaat 59941 gtcacgagtt agcccatgtg tgccaagccc tcaaagtaga aaggtaagga ggtcccagct 60001 caggccttgc actgggtgtt tcagttatcc tgtgctgtgt aacaaaacac caggacatgg 60061 tggcctaaga caacagcgag aggtgttgct tctcacaatt ctatgactgg gtagttctgt 60121 ggatggtcag tcctgtggcc ccactctgtt gggagctcag ctggggctgg aagcctgaga 60181 tggcctcaaa cctgtaccca aRgccctagc actggccgtc agctaggccc cttgcctgat 60241 gtcctcttgt catccaatgg tctaaccagg gcttctatcc ccacgtggca ggggaagcag 60301 tgcaagcccc aacatgcaag ccctggtcaa gcctggtcaa gcctctgcag gcaggcgctc 60361 agtccagcct cgtctcccac aaaggacaag tgataggagg ctgtcagagt caaagcctcc 60421 aactacaggc ttatcgtgga ctatgggttc gtgtctccca gaattcRtaa gttgaaaccc 60481 taactctcaa caagggtgat attaggaggt ggggcttttg agggagggta attgggttgt 60541 gaaggcagag cccttatggg gagaggctgt aRgaggggag agggtgcctc ctacctcttt 60601 tccctccacc atgtgaaaac atgtggagaa ggccacctgc aagccaaggc cagccctcac 60661 cacacaccag acatgctggc tctttgatat tggaccacct ggcctccaga actgtgagga 60721 ctaaacgttg ctgtgtcatc cacccagcgc gtagcaacoc aaacagtaga cagggctaca 60781 gaYggcRaga gctggggaga acttagagac cagcctcctc atgggYtgtg accctgactc 60841 tgtgcagact tccagccatg ccagggaSct cacagctgga gtgagagcat ggttgccctg 60901 tggtgaactt gggtctgacc agggcctgcg tttaaccccc tgtacagaga agggaggatg 60961 gacagtgctt ggacctccac actcttcctt cagcagcctc acccgctgca tgtggtctga 61021 ggaccagcag cctcagcatc acgggggacc cggttagaaa tgcagaatcc cagacccatt 61081 ctcagatctg cagaaccaga tgctgcattt taacacaatc tgcaggtgat tcatgtgcat 61141 aagaaaaatt gagaagctct aagagatcat ggacctggtt cctccacaaa taaatttcaa 61201 aggaaaaaaa aaggggcggg aatctctggg ttaaaagaaa taaaacaggc caataacatg 61261 caacaggtgg acctggtttg gatgctgatt tgtatgaacc aatagtaaac actgatattt 61321 gatgctgagg actgttgatg gttaggtgtc tacgttacat taaaagcacc catcttttag 61381 aaatgcatac tgaaatgcct aatgacaaca ccataggatg cctgggatag gcttcaaaac 61441 aacccagtgt gcaggcagag ggagcacacg ggagggctgt atctcaattt tgaaaaaaca 61501 ccttgcatcc atcagctaga gatgagtata tgtgggccca ataaactatt ctttctgttg 61561 ttgtctggat tggaaattcc aataaataaa tgattattta atctcctggc tgtttttaaa 61621 taaataagca gatccctagg tgttactcag acttattgaa tctctgaaag tttagcccta 61681 ggaaggttat tgttgttgct tgtttgtttc aatcctttcc ttaggtaatc ttgatRcatt 61741 tggtaccagg gctgtggttt gggaatcacc aattgcattc aagtgttata tctagaaagc 61801 attaaatttc cagaaactca gccctgttct tgacagggca cgccagacag gcaggaactg 61861 gggtcaggat ggatgaggaa aacaaccata agtttctcaa agacagaagt aaatcggctt 61921 cttctgagca attgcttcag aacaccttct cctctgccct gagcaccctc ttRttaggtg 61981 caaaatctcg agggggcatt tgctcctagt tcttctgccc ctgctgactc tataatcttt 62041 gatgtggcca gatttgcaca gttacttaac tggcctgtcY tctgtgggca tttgtgtttg 62101 ccagaatcct gtatgacctt atgaaaaaca ttgttcagKg tacaatatct gtgctattcc 62161 tcccacagcc atttgcattt taaatgagaa cacttgttaa ctcaaaaaca atgactttct 62221 aatggctcaa ttttagagat ggtggccggg gcagagattt cgagctggct gtgctgcctg 62281 gagtatccta ggtcaggacc cttccttctg tgctgcgctg tggtcctggg caccacccaK 62341 cttgctggac ggaagctggc tacagcgtgc caggggctgt ttccctttca Yacactcctc 62401 acttaaaggc cttcaagtta ctaacaatga tattaataat gcacggtact taacaaccac 62461 aaaacRgaca gagctgctgg cctgttttct atcccccaga tacaaagagg tctaggttta 62521 tgcttctggt gagaaggtca agaaaacctt ctgcacctca gtttccccct ctgaacatag 62581 gggcaaaaca atcctggaat acaactgttt acttaaaaat cacacaattt atacatttgg 62641 aaaggaaacc atatttctta taaagggttc tgaccacagc cggaaggtag tcttcctgca 62701 ggctgggaag cacagcttct ggcaaagacc aaagtcaagc actttKaaga aaaataggtg 62761 gggggaggag ctttatgcca aatgagttgg ctaaacatgc atattcaaca ggttacagaa 62821 ggagctgtga atattcataa caaggatcct gatgcacaca tatagaacat gtatgtcaca 62881 tatgatccat gttcgccttg gggtggagac ttaacattta aatgcatgac tgttaggccc 62941 tatatatcaa aaggtctttt caggacacaa aggcgctcaa gtgtgaagcc tctgtaaacc 63001 atccagaacc agtccacagt tggtggtctc ttctctggag aaagttaccg aaatcagcct 63061 gttgttcaat caaagctgta gtcacagttt gtgaaacctg gggtcaatgt ccagtggagc 63121 tgcaattgtt tcaacattgc ttatcccaaa gccaatgctt gttcagctgc tagagaaaaa 63181 gaaaaacctc atgacagaac atggtttatt cttacagtgt aggggtgagt gatttaaccc 63241 ttgactctca tggccttagg ccctgtt'tat acttcagcaa tttattgcca cacagagtca 63301 gtcccttcag tcttatgatc tctattttaa cattcgtgct ggtcagttgt ttctaaacca 63361 caagagggag gggagaaatg aagggtgtct gacctcctgc cctgtcatgg ctgggaactc 63421 agtttttatg tttttttctg ggatcctttg gccaagagag ggtctgttca gttggtgaga 63481 agtctaggac tttattttta gtttacacaa caaagggtga ttggagaccc aagtgagaca 63541 gtgtttggga aactacaaNa aggggtaaga gagaatgctt ttctcatttc tgtcttaatt 63601 cagttttgtc ttcttaaata tctaaattct attatcatct tgaatattaa tcatcccaac 63661 tccttWaaaa agtgcatctc aacttctgct ttcctgtcta gcaRgtaaRg agtttgcaag 63721 tcattccttc atcctagaaa caaacaaaca aaaaaagctg aacaaaccaa aaaatcaaca 63781 actcttttta gattcatcag agaatYgagg tcacagtgaa acgggaaagg ttcccttgtc 63841 cccctcacag ggcatgcaac agggagagtg gctcgcttct tcagtgcccc actgctcaaa 63901 cctctagggg agcatagaga cgggcaggct gtggggctct gaccccacgg cagtgtctag 63961 gggtggatgt ttacagctcY tgaagcccca gtgggtgtgt attacagagt gttcttttag 64021 tttgccatct ataggtggct tgtgttaacc agctcaatta gacccgcttc catatcacaa 64081 ggacagaggg atttctgtat tccaggttct tgccctggta taccagaaga atcagatcac 64141 acatgggctt ggagaatgag tgcaaagttt tactgactgg aagtagctct cagcagatgg 64201 gggagccaca agggagacgg ttttcccctg gagttgggct gctcagtggc ccaggctcgc 64261 tttcaactgc cccagccaaa ctccacttca tcccacagtc gagatatggc agagatgtta 64321 gaattaccag acgttgaatt agaacagcta tgattaatat actaagggct gtaatggaca 64381 aagcagacag cgtgtacgaa cagaggtgca gtgtaagcag agagatggga attctaagaa 64441 acatccccca aaaaggctgc agatcaaaaa cactgtcact gaagtgaaga gtgcctttta 64501 tgggcttatt aRgagactgg acatagctga ggaaagaatc tctgagcttg aggatatctc 64561 aacagaaact tctaaaacta aaacacaaat aaaaaaagac tgaaaaaaga cctgtgggac 64621 aactagaaac aacacaRtat acatgtgacg ggaatagtag agggagaaga aagaaaaaaa 64681 gaaacaaaat aaatatttaa aacaataRtg cctaagaatt tccccaaatg tcagacacca 64741 aaYcatagat tcaggaagct cagagaatat accaagcagg ataaatcccc ccaaaaagtt 64801 gcacccaggc atgccacatt caaatgagga aaatgaaaaa taaagaaaca ataattaaag 64861 aagccagagg aaaaagaatc ttatctatag agaaataaaa ataaaaattt catccagctt 64921 atcctcagac accatgcaaa caagaagaga atgKagtgaa gtatttaaag tgttgagagg 64981 ggaaaaaaaa aacaaataac aaaaaaccag caacaaccaa caattYtgta ccctaagaaa 65041 ttattcttca gaaatgaagc agaaacagtc tttttcagaa aaacaaaaat tgaggaaatt 65101 tgttgccagY aatcYtgact tgcaaaaaaa tattaaaaga agttcttcag agaaaaagaa 65161 aaggatacag cctagaaact cagatttaca taaaggaaga gcattggaga aggaataagc 65221 aaagataaaa acttttagtt tttattctta attgatctaa cagataacaa tccattcaaa 65281 ataataacaa tatatttgag tatgtatgtt tacatatgta tatgtattat atattataca 65341 tgtgcttatg tgtaagtgaa atgaatgacg acaatgacac aaaggatgag aagggggaat 65401 taggattatt ttgctattat atggtacttg cactacctgt gaaatggtat agtgttattt 65461 gaaagtggac ctggactata ttgcaaactc tagggcaacc actaaaaaac agttttaaaa 65521 attataactg gcaggatgcg gtggctcaag cctgtaaccc aacactttgg gaggccaaga 65581 caggcagata acgaggtcag gagtttgaga ccagcctgac caacatggtg aaacccatct 65641 ctactaaaaa tacaaaaatt aaccgggcat ggtggtggat gcctgtagtc ccggctactc 65701 aggaggctaa ggcaggagaa tagcttgaac ccaggaggcg gaggttgcag tgagtcgaga 65761 tcacaccact gcactccagc ttgggtatca gagcaagact ccatctcaaa aaaataataa 65821 taacaactga tatgacaaaa agaagagtaa ataaaatgat atgaaatact caaatgaaac 65881 aacaaaaggc agaaagacta gaatgcaaaa gtaggaataa ataacaaggg cagtgaatag 65941 caaacaagta acaagcatgc tagatattat tccaactatg tgaataacta ctttaaatgt 66001 caatagtcta catacaccaa ttaaaagatg aagagtgtca gagtggatca aaaaacaaca 66061 cccaattata cattctctaa aaaaaactcg tttggataaa aagatacata taggttaaag 66121 ttacatcgat agagaaagat ataccatgct aacactaata aaatgaaagt tggattagtt 66181 atattaattt tagacagggc agacttcaga gcaaagaaag ttattaRgaa tacaaaggtg 66241 cattatataa tgataaagga gtcaattctt ccagaagaca atgtaatatt taatgtgtac 66301 gtccctaatg acagagcatc aacatacatg aRgcaaaaac tgacagaaat gaaatgaaaa 66361 atagaagaac tcactcttat agttggatac atcaacacct ctctatcagc aatggacaga 66421 tacagcaRgc agaacattag tgaggaaata attgaactca tcagcaccat caatcaactg 66481 gatataattg acatcaatct acttcattca acaatgacag aagacacctt cttctcaagc 66541 tcacatggaa cattaaccaa aagagaccat attctggggc ataggacaca cattaacaga 66601 cttacaatag aactcacaca atgtcttttc tcagaacaca atggaattaa aattagaaat 66661 cgataacaga aggggagctg gaaaaatccc caaacatata gatattaaac aacacatttc 66721 taaataacac atgaatcaaa gagtaaatct taagagattt ttaaaaatat tttgaaaatg 66781 aaaatacaac tgatcaaatt ttgtgggatg cagtgaaagc aatgcataga gagaaattta 66841 tagcattgaa tgcacctatt agaaaagaaa aaagggctaa aatcaataac ttaagcttcc 66901 accttaggaa actaaaataa gaagagcaaa ttaaatccaa agtaaacaga aaaagtaaat 66961 aataaaaatt agagtagaaa tcaatgaaat taaaacaaaa aatcaatatc aagaaaatca 67021 acaaaataaa aatttggttt tttgaaaagc tcaataaaat tgataagcct ctagccagga 67081 ttaactaaag aaaaaaagaa gacacaaatt tctaacatca gaaatgaagg agggcacaac 67141 actacagatc tcatagacat taaaatggat aatacagaac tattatgaaa agctctagtc 67201 atcaaacctc ataacgtgga tgaaatggaa caattcctgc aaggaaacaa tctgttgaaa 67261 cttacatgag gagaaacaga gaatttgaat ggagctatat ctattaaaga aattgaatca 67321 ataatgaaca accttgcaaa accaaaagca ccagacccag gtaaattata ccaagcattt 67381 aaggaagaaa ttgtacaatc tcttttagaa catagaagtc agaattacct taataccgga 67441 actgcacaat taccttaata ccggaaatgc acataattac cttaataccg gaactgcaca 67501 taattacctt aataccagaa ctgcataatt accttaatac cggaactgca catagaattc 67561 tgtctatgaa gtcagaatta ccttaatacc ggaactgoac aaatacttct cgagaaaact 67621 acagaccaac atctctcatg aatataaatg caaaaatgct caaaaaaaaa taacaaatcc 67681 aatccaacaa tgtatgaaaa Kaattctata ctatgaccaa taggatttat ttcaggtatg 67741 caaggctgat tcaacaatga aacatcaatt aaagtaattc taattcatca tatcaacagg 67801 ctaaagaaga aaaaaatcac atgattatat taacagatgc agaaaagcat tttataaaaa 67861 tccaacacct attcatgata aaaagtctca gcaaacttgt aatatggtga acttcctgaa 67921 ctgcatgaag aacatttaca aaaatcctac agctaacata ataWctaatg gtgaagaact 67981 caaaagtttt cctctaacat caggaaaaag gcaggatccc ccctctcacc actgtttttc 68041 aacattgtac tagaagtcct agctaatgca ataagacaag aaaatgagta gccaggcctg 68101 gtggtacatt cctgtagtcc tagctactca ataggctgag gcaggaagat cccttgagcc 68161 caggagtttg aggctgcagt gagctctgcc tgccccactt cactccagcc tgggtgacac 68221 agcaagaccc tgtctaaaaa taaaaaagaa ataaaagata caaagattaa gaagaaaaga 68281 taaaactgtc tttgtttgca aatgacaaaa ttgtttttta gaaaatctaa aataattgac 68341 ccaaaaaacc tcctggaact aataagcaat tacagcaagg ttgcaggata taaggttaat 68401 atacagaagt caatcacttt cctatatacc agcaatgaac aagtggaatt taaattaaaa 68461 acacaacagc acttacatta gcaccaaatg aaataaaata cttagataca aatccaataa 68521 catacacaca tgatctgtaa gaggaaaact ataaaattct gacaaaagaa atcaaatgta 68581 tcactctagt gtgggatgtt gataatgggg aaggttgggg gagcacaggt tatatgggaa 68641 atttctgtac cttctgatga atttttctgt gatcctgaaa ctactctaaa aaataaaatc 68701 tctttcttaa atcaaatctt taaaaaatgc atctctggac tgattcagca tgagacatct 68761 gcttgtattt caggatcaca tggtgcccag caaacctgct cagttatttc caccaagatc 68821 aacacagagg tgtgggtgtt gtgtaRgtgt ctgcactgat attcagtcct gctgggagct 68881 ctctgtgcac tccagccctg ttaRgacagg tatgggtaag tcagataaga ctgtgagctg 68941 cccagggcac acaactggag gtcaatgagg cccaggccag ccctgaaaac catttctcac 69001 tttgcatccc acagccgcaa cagtggcacc ttggcccctc tttgtgaaga gcatcttggc 69061 ctcctctgtg aatctttact tgaatccccc ttgcctagac tgtcagctgc aggagggcgg 69121 gggtagcctg tctggtttag ctgcttctcc agtgcctagc acagcacaga ctcaacagcc 69181 ttgtcgccag ctcaggtgct gcctctgaca gagcttatga ggatgcctca tgggagggag 69241 gcagaagcct gtgtcagggc ttctgccctg tgtgtggacc tccagaggag catccaagtt 69301 tcaggaaaag gctccaccag cctgtgcact cacacacgca tgctgtcata caacattagc 69361 ctttctttct ggacccctac accaagcgtg acatctgcca gcgccctagt gaaggagttc 69421 tgaaggtatg tgctgcagag gcYtgtgcct ggtattcagc aaRagtgcRa cacatgcgtg 69481 ctaaattcag tggggaagtg gtcttctcaa tatctcttgg actgcagcaa aactgaacat 69541 tcttcttctg tgtgtgtgtg tgtgtgtgtg tatgtatata ttcatattta ctataacaac 69601 taaagtgtgt ttgcactata catactgtaa atgcgRgact gaaataaatg tagattggca 69661 tgagaagtat ttgcataata tgtgtgtata aatagataga tatagataca gatagaataa 69721 aaacttagtt attgtaagaa ggaaagatag atgggagggg gcatgctggc tgcagacccc 69781 atgctcaaca aaaaggtgac acacacatag tttcaggtct actttcaagg acgtgcaacc 69841 ctgctgtgta tttccaagaa ggtccaactt acatcttcac tcacagtaag acgctgctgt 69901 ccatgggaac tcaggtctcc cctgttcctc cattgtcccc caactgccta agccccatga 69961 agctccttcc cttgggccct cccctgctgt gtatacatgt gggagggtcc ccctgccttg 70021 ccaactggcc cactccccag gacctctcca gacctccaat ggcggtctct gcatggccct 70081 gcctagggga agcctctatg cagaagatcc ctgatgcYcc aaggggacat gagggtggct 70141 ggcaggtgct cactgccttg aaaagccagt aagtctcctg cctggaagac agcaaatccc 70201 atgttctgcc ccaagacttt tccagaaagc aaggaaagca gcttctgagc cacaggagaa 70261 aacacggaac tccttgatca tcactgccct tgcccatcct cacccaagca gccctgaact 70321 tggtgccaaa tattctggga tcgtcccctc aaacccactc tacatgtagg tgagacagcc 70381 agctctctca gtgtggtccc cagaggcaaa ccctgggcac ggatcccagg caagaggctg 70441 agctgggaga agaggtgtgc aacctggcag aggaggggaa ggtgggctgg ggaaggggaa 70501 gggagtgagg actgacccta caYggagctt tgggagctgg cagccccatc tgggctttcc 70561 cccagacagg gaagctgggg cacttgggaa cccccccagc cctggttgag ggctgttccc 70621 tctggatggc caggggggat ccagcccacc cagccctgcc tggccccagc cagaaagagc 70681 cttggtagag tctcaggccc ttggcagctg gatctcagac gacagttaca tgtggctggc 70741 tctgaaggca gcatctatag cagagcttgg ggacatttaa gtgacagcaa atctctaggg 70801 ttcccttgag ccatgtggga acctaagtct gccagccttg gactcagacc tgagcatgcc 70861 ccagcagctt ctcacttcaa gtgagaagtg tcggcaccgc ccacacagca aaagcagcac 70921 taagagaaag aattgcaaac caccσcaaaa acactgctcc cttcagctgc gaggctccta 70981 ctcctccacg ctgctggtgg ttggagaaag gaccaggagt gggaaggcct ccgaaatgcg 71041 ggcctccaac agcagcagct tcctccccac attcggagcc aaggtcacag cccgcagaaa 71101 accgtagctg gaaggNgggg cctccagtgc acgtcccgcg cctggggtgc tggtggtcag 71161 ggagcaagta cagcagtcaa gaacatcaag ccaaaagaat ttttctttga aaagcaaacc 71221 tcagacatca aacgtctggc caggtctcgc tggttcaaac gacggagtga aggaaacaoc 71281 tggggcatgc actgcttccc tgtcgccctt actgaccacg ggaatgggaa gccgcccagc 71341 acacgctcgt ggtgggattg gagaagcgct caccgggttg atcgtaaaac agggacgtgc 71401 ctagatggcc ctccctgcag aattcacccc cgaggcccct tgattgactt ccagatgacc 71461 ctgaggtgga ggctgccttc ccattttata gagaaactgg agactcacca agggcagact 71521 gggtgggtgg gcccagggca cattgcagac acaactggca cccaagactt tgcttgggaa 71581 agatgacttg gggaccaaag tcaRgtgcgg ggtggaggac agcagcacca ggccatggca 71641 gccgagcagc gggatctgct ctggcctcca gggaggcttc ctcatttggc ggctgcaaag 71701 aagacagcct gggcttcccg gcacatWcct gagatggacg ccgctagatc cccaacctgc 71761 accccttccc ttgcctgttt gacaccaacc cagagtgagc agcttcaacc accccacctg 71821 tgctcccatc ttgcgatgct gtagtcgaca atggctcatt gggcagctcc agcctgtggg 71881 cttggaggtc aggcgggctc ggggctggct tgtctctgct ctgcactgtg tgccatcccc 71941 cagcagcccc actaggcttg ccaccacgac agcRggactc tagagtaagc agaaggacac 72001 ccctgttttt ctgaaagaca caagagtttt ttcttggtgg gcagcgaccc ggcctccaga 72061 cttccctgtg atgctctgga ctttcttcca ggactctcat cccccactca ctacatccac 72121 Ytcattcaat tttccgctcc caggagcact gcccagagca gcagcctctt gtctccttca 72181 ttagccacag tgcccatcac ccRctcagag ccctggactc tcctgatgac aaaggacaca 72241 aatgatgaca ggtaccatgt cccttcccca tcacttgYtt tagacgtggt tttaatgctg 72301 agtgctactt acatgagagg ctga^'cagYtc cctcagcctt ctctgaaacg atgctggaat 72361 cactggctga gcaccacgga ctcagcatgt gacctgctga aattctgggc cagggtaggc 72421 agctgtgtgt catctccatc tccagggtgg ccaagccctg ggagggaaag gatgtgattc 72481 cggaacaaag ctcctgacac cgatgggcct catgatgccg aaRggcataa gggaggtggc 72541 cgacggccgg gctgtgtgtc cacaggctac cacccctcct gcccaggcca gtcttgcctc 72601 ctctccacag accttgttgt gtaacctgga aggaggaatg aagaggaaaa agctaacRtt 72661 aaattttaac acagacacag gagaacacac acacacacac acacacatgc acacacaagg 72721 acacaagccc actgctgttc aaatctcagt cgccccagcc tactcctcat ttggaaaaat 72781 cacatccatc cttgtcttgt ggcatgcctt ctgggtttgg tcatatttat ttgtctgtca 72841 caagttcttc ttggaggatt aggaagaaac cctatgtgga aataattgca gccagtcaac 72901 tgccccgaga tgccctgaag ttctgtatct gctcccggag cgttcagtcc atgattcctg 72961 ctgggaccct cgtctacctc cacacattct gattttgcag gtgtagggat ctgtgcctgc 73021 ctagctcccc tgggactctg catctgagtc ctcaagcacc ctggtgggct cggcagcagc 73081 cctggcttgc tgttggctgt tttcatgttt gaatcggtca acactagctc aggttggaaa 73141 gccctgcatg ggaggcccag ccagtcccac gtggctggga ctcacagagc accaactctg 73201 cacaagtgct gggctggggc tcggggagag atccaggctc caccaccggt agagtgtttt 73261 ctgcagccat ctagtctttg gctgccaacc ccagactctg ttgacaagca gagaagtagg 73321 gatgttggaa ggggctcagg aggttaggac cagggactga gggactcgga agtccagatc 73381 actctgaatg gcccggtgag accccactgc ctccaYcgct ggctgccatt gccattagta 73441 ttcccaggtc tgccaagctc tgctcacagg cccacacctg tgccagatgc taggttgggg 73501 agatggtgtc cctggccagc tttgaccatt gtcaggcttc cccaaaatag aaagggggcc 73561 tagcatcaga aaagtgatac atgcccccta aacacattct ggggcttgtc acctcgtttc 73621 cctggacctc agatcccctg catcaaacaa aagaRgtgag gaatcaatag ttgcaaagca 73681 cagtcagtaa agcaaaggct ggtttaaaga tacaaacagg aattgaggaa atatgcttga 73741 atgctctttt gtatgccaac aaacacagca cacaaagctt ttaccacctc agtgatcagt 73801 ttaaggacag gcccatgacc cagctgaagc cacacgggga cagtgagact tgattctagg 73861 gcttgctttg agatctcagg ggcatactct ctcctctggt ttggaggtgg ccacaaggtg 73921 aggctagaat tgtgggagac ctccctgttg agcttgagaa tgaaccagca gggtggaagt 73981 gatggagaaa agccaagtct aagaagatta agagttgcct gctttttctc ctcctccctc 74041 cttgtacaaa ttctacaatc atagggtcat ctcaccgtcc aaaatggctg ctccagctcc 74101 agccatctca tctgcttcta gccagcaRaa gagaggaact gacagaggtt aaaaggcagt 74161 tatcttctaa gaaaggcatc tgaagctgcc atatgagaca cagtgactta tgccccatgg 74221 acttgaattt agtcctgtga ccacacctgg ttataaagca gtctgagaag catcgtcttt 74281 acacctgRtg gccttctcaa atcagactgc agtgtgggtg ctggattgtg gaagaatgca 74341 gatgaggagc tacctgcttc ctggccctgt cattgagtcg gccgggggcc caggaggggc 74401 ctcctctggg cctgaggccc agcaggtgtg cactcaccct ggactgggag acccacacMc 74461 tgataggtgc tttcagaaaa cctgtgtctc atgctttccc agagctgaag tcagtctgtg 74521 actcatcttg gaatcctgga gacaagacac ttgcaggtag agggctgctt ccagccactc 74581 gggctcatgc ctcagtctac atggctgact gctgggccag tcactgaaat ttatccttgg 74641 ccacaggcac cgtggccccc agtcaaaaag actgaatctg agtgcatgca cccaggctgc 74701 agaaccccaa acagcctctt gagccaccat cgctgggaga aggtagaacc catagcattt 74761 ggcagcacta gccaaaacaa tggctgttat ccagattcca gaggaaattt tcatctggat 74821 ttttgtcttt tggtattgag agtaagtggc aaagccaggt ggcagggtgc tcagcaggag 74881 gggagtctgg ccactcctct gcccacagct gggacagctt gatcccWtgc agactgagtt 74941 cctctgggtt ctggagccca tcaggaagaa tgggataaaa gggttcttgc ccaaaacata 75001 gcaacccggg tccctgtcca gggagtcaca tgatgtaggW cagctttcac tgtggagact 75061 ccaggagtYc agggtcagca atgacaaaat tccagggcag gggggccctg gcttccoagt 75121 ccctgctgca gccaagctct gtgtggactg tgtcatccgt gggttctgcc cagctttcat 75181 ggtgtcaagg agatggcatc agctagacct aagtccacaa ccgatccttt cRctcatctg 75241 ccgagggccc ctgcacaagt ccttctcgcc ctgcatccca gggcttgtgt gagggtcaca 75301 cacaggcaga gatgcataag tactggcaaa gtcacaggcc atgtccttgt ggctctgaca 75361 actggctttg gtgtcactgc caatgctggt gcctgtcagt gcctgcctcc ctgtgagccc 75421 ccccaccaac tgccacagtt cctgatgacc tcccaggaga gaagaggaat aactgggtgc 75481 cctaggcctg ctggtggcca tccctcatgt tgcctgatgg cctgaagtct tggtggtatc 75541 cagccacagg accacccatt tccattctag gtttacttcc tgtggggact cctcctgcca 75601 ctttgtgcag atcccccaga acagtcacYt ctgacagttg cccctcaccc cacctggact 75661 tgcctccatg ggagcagccc acctgaccct ggtgctggag gctgctccca tgctgccaag 75721 tagYcccgtc cRgagaagtg gaaggcccaa aaagcagaga atcacaggga ccaccctgca 75781 agccacagat ggtaggtggc agaagcctcc caccagcaag cacaagttcc cccttcccac 75841 tcaacaatgt gtgtcagcat gaatagctcc cagcaggatt ccaggaagcc tgcatttgca 75901 ctgtacttct tgttaaacct gcaagagagg ccccttatct ccaagccagt cgctcaacct 75961 ctgagtaatg actccaggct ggatccagtg cagcagagag aatggaacca agcaaggagt 76021 gcaatagYaa tcagcaaaca gcaggcagtc ccgtttccta tctgcctccg ccttcccttc 76081 tttctctctt cccaaaggca aaaatatttc ccaagtccct cYttggagaa cttcttaaca 76141 tataattagc aaagtcttaa ggggtcgttt atggaatttt tgtttggaga cYtagtgttt 76201 ccacYtaagt cactgcattt cccacagatg ggaaattcaa atcaattacc ttggatagaa 76261 attctaatta tcaggagtat atgcacttag aacaagacga atatgaatct ttcaggatgc 76321 acttattcca cccaggaacc acaggctgca cagctggctg ttctgtgtaa tacacggcat 76381 gtccagtgtg gctcttctgc tttcctctcc aattgtgtat ctcctcttcc ctctcccagc 76441 atMtggtSca tgtgagtgag aatggcatta gacatcccta ttaatttcat Mtgggatgta 76501 gataagcaat cccacccacY cagaacacag cagaatgtaa ggacgtcttt cttcctggca 76561 cccagtgaaa tggcagagtt gtcagtgYaS aagccagaac cctgaaacag tggaaaatgc 76621 aggccagctc atgagctggg ttcagtaaag catgaagaat tccaggcccc tccgcaaaca 76681 gctgccccga cagacactcc ccacaccacc aagctgRcca catgtgggaa gtgacgtggt 76741 gtggcatctg gggctgtttt ggagctgcag tttcttggca gtgatggggg gtcccctctt 76801 gcctctggga cccaggacac tcaatcctct gattaagccc agccctctgt gagttcaagc 76861 tgtgagcccc atctccgcca caggcttccc tctcactgtt gggttaagct ctgaaaccac 76921 gtccaggggg ccacagtatc cctgttgcac tgaagaagta actaaagccc agagaggttc 76981 tgtgccaggg cccctctcat gagcactgca aggccgatct acaatgcctg ccctcccctg 77041 cacagctact gccagattcc gggtgccagc tcYatgctga agctctttgg cagcaaggag 77101 ccagtggtcc taaccagaat gttccagaat ggtcaccatc agggcctcag actcctgtgg 77161 ttgtgaggac agaggttcaa gatggggctc cttaRgtgag ggcagagcag cacctgagcc 77221 cctccccaaa ttcccccttc cttcaggggt tttctccact ctcgtctgct gctgccggac 77281 ctgcccccag ggagcaggtc tgcaaagaac ctgacatgca ggcccaaggg cctccactgg 77341 caccaggcaa catggtcacg ccccaccact ggccaggtgg ccgcccccac cccagcatgg 77401 tagagctcgg tctccttgag caggggctga gggtggtcac tgtcggccat ggctggggct 77461 ttggccagca cttgctgggg actggggtgc cagtaccagt gggaaataag gggaacctct 77521 gctaggaggc cctgactgag aagccaacag ggagccattg agggctcYtg agcagagggg 77581 ggcatgcccc acgcagagtt tggccaagac agaWctgctc gcagtgcacg gRgatgccag 77641 aggagagaga cggggctggg aaacctcttg gagggccaca atcctagcac gggccagaga 77701 cctgcaggac agcgagcagg gtgtggtgcc ggaatagcta gggaagtgcg cgccaaggtg 77761 agacaggagg cagacagagt tggtccccag ccctgcattg ctcagactgg gaagcaggag 77821 ggagaatgtg acccttttcc caggcacaga cagggagact ggacaaatcc ccctcgttgt 77881 aggaatggtg agtttaaggc agaccccggg ccttcctaRt ggacacttcc agcagcaggg 77941 gagatgtgga gccaggtggc ttcggtcagc ttcccacaag gcctcctcag ccgagtcaca 78001 tttttattcc actcccttca cttctacaga gagtttaagc aaaaaatgcc acgggacttt 78061 ctttgtgcct cagcagcaag ccYtccKggg cagctaagtc catgatgctg tccgcatccc 78121 cagcacaggc cgttgggtga attccccagc gcttcccctc cctcaagggc taccccatgg 78181 gcaccatcag ggaggatgcg tgtggggaga agtgctggga ttggggcatt gccctcacac 78241 taggacgccc atgggaggat tcagcgtctc ctgctgtgac cgcccagagc ccggccttgg 78301 cggtatttcc tcccccttcc ttctccatgg cagacaaggg gcttccattt ccacacggat 78361 ggtgtaattc tgtctcaggt cttttggaag caggctgagc acccatggga gattctctgg 78421 ttccttgttg cttgagtgag gaggctgcaa tcccagccca gcggggccct ggctgtgctg 78481 ctcaacttca tgcccactga ctctgggaaa catggccatg gtgaagggcg gggtgccagg 78541 gaaccccgac ttaggaaagt acatttagaa aacaggttgt ctcttggaag aacacatatt 78601 ctttttagaa atttcctgaa cagtgtactt tcRtgtttaa tcttggtgca ttctagtgct 78661 atggaggaca atggtgattc atatctatgg ggtacttgac agctttccga gcaggtttcc 78721 ttctcagttg atcacctcga catctctctg aggcagcctc tgcaggtgtc atttccccat 78781 tttataggca tggaggagta aagtggccta gctgcagtca tgggtaaaag gcaaccgaac 78841 tcgaccctca atctctatgc agctgcactg cctctctgac tccctgtggc ttcatatgct 78901 ttgtttccac aaatttggaa gtattagcaa agggatgaag aaagcagaat ttggggcaga 78961 gaagcctctt tcatgtctca gttctgcagt ggatgacatg tgtgaccatg agtgagctaa 79021 ttaacMtttc tgagcctggg tgtactaatc agtaaaacag aaatgaaggc gttccccgcc 79081 agatgataat tctgaggcat tgcccatgcc tgcacatagg aaatgatggc ttcctgcaag 79141 gagaagggag agcggccccg gcagggtgag caggagcaac tcctccagat ctgcagatct 79201 cggcacttgc acacccaggc tgctccaagc ccaggagcag aggggacacc cagggctaca 79261 gtgaggcaag tcctgtcccc aagattataa ggatgtggtt ttcagcctgt cttgcattca 79321 ctttcacoaa gtaagatgcc aagagccagg aagaggctgc cagaggtgca ggaaggaaaa 79381 gcagagccag caggaaggag ctccggctgg ccggaatgga gctggaggct ggaggcggca 79441 gcagccctac ctgggcactc gaaagctggc cctgctcctg ggaccagaca gtgcccctca 79501 gggcagggca agggggaggt gaagcaagga ggggatggga ttttgcctga aatatttcaa 79561 aacttctatg taggacctag attactatct ccaggtctga tgtgtgtgtg tgtgtgtgtg 79621 tgtgtctgtt ggtgtctctg tgtgtgtctg tgtgtttctc tgtgcctatg tgtgtctctg 79681 tgtgtgtgtc cgtgtgtgtg tgtgtgtgtg tgtctgtgtg tttctctgtg cctatgtgtg 79741 tctctgtgtg tgtgtccatg tgtgcctgtg tgtgttcaca gtaacacacc ttgacctcat 79801 tagctctcct tgaaggtcca catctgtgtc tttatctacg tctccgtcta tgtatctgat 79861 ccaactacac cacacatata atgcagaacg gatctaaagt ctgctgcaat tcttcaaggc 79921 aaagaaaagc aacctttggg tgaccttcca agagaaggag cctgaaagca tctgatgtga 79981 aatgttcaga gcaggcacgt gttctaggtg ggaaacgctc tctgccacca cacctcgccc 80041 cccaaccgcc ccccagccac tgctccttca tcccacgaag acatgataat agcaataata 80101 ataatagtag tgacactgat gcggtgcttg ctgtgagcct gacactgttg gaagcactta 80161 gtgcacacta gaaagtacac aatgcaacca aataagtgtg aaccctgacR agggctcaca 80221 gacatgtggg cagggcggcg ctgaccttca gcagcaggtc agggatgtcg tcatccctga 80281 tgacagatga ggagggccaa ggacacagac aaccagagga catgccRtgc tgagagaaga 80341 aagggcaggt gccaaggccc tgaggcagga gccaggtggc tgttcaaaga cgcgaagatg 80401 ctctatggct gggggcctKg ggggaagaca cgcactcctc attcatcaag aaaaggctca 80461 tttcggcttt tttctccaag ttgctttcag tgatttccaa cgggagaatg gagaaatgcc 80521 tcctatatgt acccaggaat gcaaggaatt ggaatgcaca gtgtccatga tgtgccagag 80581 agagcccagt acttttcctg taataactcg ctaaatttac acttcagttc tgtgaggaac 80641 tgttatccta atttcacaca ggaggcaatg gggctggagc caggtgcttc agcaagttca 80701 caaagccagg ggaggacccc aaggatccac actgcgctgt gctgctgagt gagtgggtga 80761 ctgtgcactg ttgctttttc tatgaaattg cttggacagg ctttctctag cgacttggaa 80821 aagtttcaga actcctatcc aggaaaatcc caatcaggtt ctctccaaga caatccccca 80881 accacagaca ttgtattgct tggaggaaag ttgtttccac tcttccggga gcatatttta 80941 accctggtgc agttaggaag ccagacctgt ggctcatttg ggaccaccag cccaattcca 81001 gcgatcacca cagaaaccat tctctaggtt accctggaag ggatagcctt ggtggttctg 81061 ggctcaattc ttgctcagaa ccaaaagtag aactaacttc ataatgtgag caaaacccca 81121 cagtccagct ttgagcacct ccttgaatat gagcttgtgc ttttccatcc agacataaga 81181 aagatgggga aaggctgaca gatttgtaat tcacttcaac cccaccagct tagagcatga 81241 aaaccctttt taaaaaatga gtcacaagta tctgctggtg aaacatgact cacctcctca 81301 aaagagagaa taaacattga atcagctttt taaggggctt tcagacacca catcaccctt 81361 ggacgactag accacaacct gtcttaggca aatgcctaga aacagatggg ttacattttg 81421 ctgaaatgca gacactcagc aWcccctggc ctcacactgg ggccgagtct gacatgacac 81481 cgtggtgttc attataaacc tgtgctgacc agcttgaggg gtcagtagca gacaggggtc 81541 acctggctac ctgtcaacag cctgcagatc catcttggta ggcactgaag ccccaaaccc 81601 tgcatggtgg tggtgaccag tagctctggc cagggtccca ggttgagcca gagtcactgg 81661 gaatgttcac ccatcttcag catctccagc ctgataatga tcatatttgc agcttcctcc 81721 aggaggctgc ttctgggtcc actcctagat ccaattgtct ccctggcagc aacaattggg 81781 aaataacagc atcattctct cttgcaatca ttaaggagag aaacatcaag aagctgcttt 81841 cattgtttaa caaagatgac aaactttgga gaatgtaaag aacatgaggc cattgaagtc 81901 aatatttcac ccagagggag ctgcacagtt gggcagggag gtgaagggca tttctgaagc 81961 accatcatat gaataaaggt catgagtttt gatgggcagg agatggggac actgcacagt 82021 gcatgctttt ggggaagggg gaagaggtga aaaggacgag acgaagaaaa caacagagaa 82081 aaacgctagc atgtgaaaaa gccatattca ctcattgttt taaaaagtga gccgccacac 82141 ttgaaaaaaa tatttaccca gaagactcat cctgtgtagt ggaggccaaa tgccatcctg 82201 aagaagttca gcacggggtg aggtatgagg Ygcaggctcc cgacagagcc tctgagcatg 82261 gggtggtgMc tgcagtcact catcctccaa ggagtcaagc aggacaggga taagaatggc 82321 aagggtggag ggttttgata ttttgattaa gagggccaag ggagctccag taaaaagaca 82381 gcatttaagc caaactagaa ggggtaaaga agtgagaact cctcataggt atttgagaaa 82441 aaagcataac agaccctgta gggaaatggg gggatatctg agaagcacca aggaagccaa 82501 tctataaaac cattcagatg Yttattcaaa cagataggtc gagaaatagg aaatagaaaa 82561 acaKgcagtt aatctccRgc ataaaattga gatgtgaaat agaaatgcca cttggggatt 82621 ttcatagtcc cacagtggag aggttgaaag aatacagcct ttggtgttgg agaaatctga 82681 gttcaaaaac tgtctttgcc acttgttccc aaaaagggaa agaatggagg aggaaggaac 82741 aaaactaata aaatatgtaa aatatgattt ggtggcaaaa ataagctcaa acacatcaat 82801 agtcacaatg aaRgtaaatg gattaaaaac tctttactta agatacaaat atggtcagtc 82861 tggattagaa gcaaaatctc attatatgct gttataaaga gatatgtcca aaactttaaa 82921 atatacaccc cataaagaaa ataatagaaa aaagatatac caggcaatta ttaatcacaa 82981 aaactactgc agctataKca atagacttta gggcaaaaaa catcatatgg gagaaaaaga 83041 tcactacata ggaagatata gtgtttctaa acttgtgcgc aactaataac ttctaaatat 83101 gtaaagcaaa gatttgcagg attgcaataa gaggttgata aagccaccat caotgatagg 83161 tcaagaagac aaaaatggtt agcaaggaca taaatgacac aactaacaaa tgtgaactga 83221 caggtatgtg cagaacacgc acccattaat tggtgggatt tatttcttat acgatcacag 83281 acaacattta caaatattgc ttatgcattg gactaaatag caagtctcaa aagattgcaa 83341 aacttagtac tgtacaccat attttctaaa cgcaatacaa ttaagtgaaa aatcaatgat 83401 taaaagattt ttaaMatata tttggaaaag agagtgccca catataaaat caccagttaa 83461 catcagactt tgataagtga ggaatgcagg ctgtaaatgc taggctgtat caaagaatac 83521 agaagtcatR acctctaaaa caggaaaaag gaggtaacaa tgactcacca agtatttcta 83581 aataatttat aaataacagt acctaatatt gaataatcat taagagtacc tgtcacaacc 83641 tgtagaatac aacaaaaagg ttctaagagt ggttacatga tattagggct gttttagaaa 83701 agcaggaagt ctgagaatga atgaacttaa gaaaacatat tcttttaaaa cagaataaac 83761 cttaggaaaa tagaatgcac aagataataa agacagaagc agaaatacat gaaattgMta 83821 aagctatgct ggatgtctgc tgaagaatgc tgccatttgt caRttttatt tgaactgaga 83881 agatgcaaca aacccaaatc cacacatcat gctccatYtg agccaaagcc gggcagacac. 83941 tgctgagtgc tcaRgatatt ggggagcaaa accggcaaca actcacaaac aacaacagaa 84001 cagaagagta aacaacttgt atgttacacg actgtaagtg ttatgggaag gaaagaaagc 84061 agagtcagat acatgggtcc tgagtgtggg ctggagaggg gaggctctgc agtgttgggt 84121 gtgccaaaga gaaggtgcca aggacattgg ccaagcagat gactgggtga agagtgctcc 84181 aggcaaaccg cacatccaaa ggccctgagg catggctgtg cctgggtgct gaagggacag 84241 cgaggaggtc aggctggact ggcgagagga aagcagagag tggacagaag tgagactgga 84301 aggtcaaggc aggtcctgct ggctcttgga gcccttgggg gccactgcag ggatggtgga 84361 tcccactgca ggctctgagc aagagtgtac caggactcac tgtgggaaaa gagtgtgagg 84421 gcaaagggga gaaccaggac gccctgtcgg gacacacagc acatttccca gagaaagaag 84481 caagtgctcc ttactctccc agactctgtc cccagcctgg agggtgtcac ctcggccaag 84541 ggaggatgct gtcttcacac ccaYctgccc tgggaatctt ttctgacaaa caccccaggc 84601 acaaagcaac tgcacagtca tgtggcataa taatggcaca gcccatgggc aaaggagcca 84661 caggaMctga ctatggggMt ggaaggtgac acacctgcct cgaccccaga ggctctgagg 84721 ggctggtcat atgctctcct gagtgggtag tcctggatgc tcaRgtccca tcgtgcttcc 84781 attcttggat tcagaagatg aaactgcacc tggtcaatac aacatgagaa gtaacattaa 84841 aatacaaaag aatgtgacat gttagaggca aacatagaac caacattgtt tccatggaat 84901 catgtttcta cagaatcatg tctttaagct ctttaagccc catacataga gggtctttaa 84961 atagcttgtc tttagtctgg cacagaaatt aacagtccta caattattaa gcaaaatgtt 85021 tgagttccca ctatgtgcta aatttccaag agactggaca taaaaatagg ctacacggag 85081 aactgtgact atctgactca ggtttctgag agaattggtg cataaaggga tttcagcact 85141 gaatttccaa gagacttgtt ctaatgtaag gccttgtagc tcattgattt ttgaagagtt 85201 ggYgagacgc accacctgat atagaactga attccaaaca agtgctacac ttgcagaggg 85261 gattggatgg ttctctgcca cctgtcctcc tggagaaaat ggaagctctc agacacagco 85321 acggggtagg tgcaaaggag gcagYgtcca tctgttcttg tgggattcca ccccctcccc 85381 aagcctaaaa ctatcYctag aagcagggag aaagacaccc atgagtcatc attcatatgt 85441 ggatcctgga agatgccacg gggacagcct gaggactcag gagaggaggg gaaccttctg 85501 gcaaatgcag gggtgacact gaatgcctgc ctgccatgag ctaggatctg cccaccccac 85561 accccagctc ccaggagatc cctgtcaaca caggcaaagt tcccagcccc ttcctcaagc 85621 aaacatggaa gaggggcccc ttcagacaaa ttgagggact caggagaacc ctctgtaggt 85681 tctcttccag ctttacatgt cgctggctgc ctggcttccc ctcacattaa gcaaccattc 85741 attctctcct ctgtgcattc YgtccatctR tgtgtgcaag gttctggggc aggggaaSaa 85801 agacagggca ggacagatgc tgcctggagc atggcctaga gatcagggga gagagagaga 85861 gagagagaga gagggaggga gggagggagg gaggggtaga gagagagaga gagagagaga 85921 gagagagaga gagagagagc tgggaactga agctccttgg agccaggaca taaactggcc 85981 gaattccctg gaccaaagtc gccttccttc taggggctca gcatgctggg tgcctcatca 86041 ctgcttccca cacactgcca ggccagggca gggcaccagc gctgggcaca ggaagcctgc 86101 caggtggaga cagcatctgc atcagccttc ctattgggcc ggtgaggctt gaagccaggt 86161 tttcctctcc atgcgYccac ctttcagaaa ggctccgagg ctcccagatt gtcctccagg 86221 gtcagggtag gagggcctgc tgacagcagg tgcatgagga cgcccagatg aagacggcag 86281 tgctgccctg accacagtgg ctgccgcctg ccggcttctc ggaatcagca gagcacctcg 86341 ggactggcgc cagccagaaa cacctgtgca ccggaaccat gggaaggaaa agcgggacta 86401 gactgccaat gacagagctg gaccggggcc agaagtccaa gctcagctcc agaaggcagg 86461 atctaaccac cccttcacgc cacacccaag aaYctttcct cgggtccaca gcacctcctg 86521 cttccagtgt cctacccaga cagaccttca tctgattatt tatctaggtg cagaattaat 86581 tacaggccct aacYgtgcat ctagttacca ttttctcagt tgggaacaca actgttactc 86641 tggtcttggc tgggatgcag ctgtttcctc tgaacacagc gcttggtgcc cagagctctg 86701 ctcgctgtgc ctcctgcacc tcataagggc ctcaagctcc agggccacct ctcctggcat 86761 ttcctctgtg gaaatataac catcctaagt actgcggccc cagagattcc ttgttctttg 86821 gcccttccct ctcctgtgct tggatgagag cccagtgagg ggtggatgtc tgggcccaKc 86881 aagacaccga ggtgcaaaca atgacagaaa gccagaaggg ctgggccagc caagcYtgct 86941 ttccagcatg agacccacag cttccRttcc acacctttgc aggagaaaaa gcaacaactc 87001 tatcttatta aatagatgca caagtatgag ctgcatgcga t.tcccaatca agcaaagtgc 87061 aggatggaag agggtctgga ttttcctgga gggaatgagg catgtccgcY ttgcaggcac 87121 cagaaagaaa ccatagatgg gaaagtgggg tctgcagagc cagaacaaat cagaaggaac 87181 aggatggtcc catggagtca cagagtggct gaatttggca gtccacatac aaggccatcc 87241 tgggatctga atggaccgca gagataggca cgaggcacca ggtcacccca tggggaggac 87301 ctctgttcct ccccttcctc agaatcttcc ttggagtcYt gaatgacacc ccctgggagg 87361 actggagagc- tagcttcagg gtttactttg ggtttttgga gttccaaacc catgtgtgat 87421 ttgagctgcc accaatgctg cagcgaaggc cgaggaagga agcacctggg cccccatctg 87481 agctggaccc catggcatga ccactagcag ccttcagtgt ggctgtgtgt catgaggcat 87541 cagggcgtct gagcagaagg gagaacaggt gagcatggag agccccatgt ccccagggaa 87601 acctgtccgg tcttcatact ctgcagggct tctgaggcco ctctccaaga ccacccccct 87661 ccagggcttc ctggccctga cacagctgcc acctggcctt ctgcacatca tggtcatgtg 87721 ctggcttctc tgccccagaa gttcaagctt gctccagctc ccaattcttt ctggcaaggc 87781 ttttacctgc catatgtaat ttgacgtagt gttttactgg ctttgtcttc ttaaagggca 87841 ttttcaatta ttctggtctc ctgccaaacc ctaaattcat ctcctacttt- tattagacct 87901 gtttatgcat cagaatgagt ttttccagct cctggcaccc ctcagctatg tctactgtgt 87961 ctccctgagc cagtcttgaa cctggctcct gKcagaggcc ctacgagact gaagcagctc 88021 tagaaatcct ggctgtgcat ccatgcagcc tgcagcataa gcccagcctt tgccctaatc 88081 gggtgcttag gcccaagctt gtccttccca gaatgtgcat tgctgaaatc gcacatcacc 88141 taaggcagga oaacttaatc agtcaacaag aacccacccc atctcctccc aggcaaggca 88201 ggtgggcccc acccgtgctg ggggaagaac ttctgtttcc ttagccctgg gctaaccact 88261 goagcaggtg ttttccgctg gtgaggatga caaccgccag ggctggccag gaagaggggc 88321 cacaggcaga ggcagaaggg gatgtgtggc tctccccggg actggctccc agctcactcc 88381 caaagcagca ctgcccccag agggcaagaa acgagaccct gcatcoccac aatgggggtt 88441 tccaagtcca cctgtccatc cctccaaggt ctctccaagg tcaagcttca accatcccac 88501 aactctgctt acttatttag gagtggactc catcagtagc tgtgtaaccc agcaagcgct 88561 ccctgagtag tcagYgtgtg gatgcactgg tgagttacct gattctctct ccctgccttc 88621 agtcctcctc cctcacctca ccccttggct tgcagcctca ctgtacactg gaagcccttc 88681 agataaacca gtgaatgaat gaatgaatgg atgagtgagg tataggaaag aagactccat 88741 gggactcgtg tggagggagc tgacttggag ccgcttcaca gcctccttct cccacaaagt 88801 cccgcaaggg agtgagtgga aagaaagctc tgagaacatc cctggctcct gagcctgggc 88861 agcagcagag ctctctgcct tgctttgccR aactctgaca ctgggtgccc aaaactaact 88921 acagataatt tccactataa taaactaaat ggttcgagga ggttgtacag acaagctgtt 88981 gttaaaggga ctccgggtgc cctctactgg gtagcagtgg atgagccctg tggggagggc 89041 ggctaagagg gcagggYtgg gggctgtgca gagtccaggt ccagcaaggg caagcgggat 89101 tggaggcccc cagaccgctc tggtgctggc ctggctctga gacagctgcc ctggctgact 89161 tgcccaccag ctgtttccat agaaataaat agaaagcagg ttgacatggt tgtgttgtcc 89221 ttttcaaagc actattccca tttcttgtga ttttgcctca aactaagact gtgagctaaa 89281 gagcatccac cctcattaca caggtgagga aagagacttg aggctttgag cgactatgtc 89341 caaatgaaag tcctaattac tcgcaaatgt ggaggaaaat gggttctgat gtcctggatc 89401 gtggctacat cctctctcaa caaaagggta agagtgaatt gaaatgcatc ggctgtctcc 89461 atctaatagg gagacagctc ccgatgtccc caccccactc tcagcctttc ctttcctcac 89521 ccctcccaca tcccagcaca ccttcttcct ccatctttaa aaaaaaaaat cattaacatg 89581 gcttctgagc cacaccagac tgtacagcaa aatggtcatt cttccaaaag ccaggtgtcc 89641 tgccaaacca atgagcagga ggccaagaga atcttcaaga aaaagacaaa ttcaccatta 89701 aacaatgcct gaaatataaa attaataaaa gagaaaagaa agcggaaagg agcaggcatt 89761 tctgtgcagc actgccaacg tcggcagcac ggtgcatgtc tttctaccaa gccctagtct 89821 ggtccctttc ccaggctgcc gtctctcctc ctgcagcctc tataaacgct gcgtgtgact 89881 ttgggcagcc tctaacagag tctgcctcat cctgttgcca gggtccatca gtccccctct 89941 tttggtccct cggagcaacc tgatcaaagg ctcgctgctg gctcagacac atgagcatct 90001 ttttttttgg tccgcgtttg tttattttcc cagaaatgtt ttgctctgct tcagatcagg 90061 aggctgggcc actcatgttc cattgcttgg caaagtcaaa gggaaaaact ctatctcccc 90121 ttggctttaa tggattgaaa tgaagttcac ctacaatcgc agctctattt tagtgtcctg 90181 aaaggactcc cctcccctgc ctctcagccc atctcacgct tgattc^'tggg ctagcctttc 90241 taggagaggc cagggttcct ggagaagagg ctggcctggg ctgtaacagg gcatggggca 90301 gtgtcccctc agtggccaca gggcctcccc aaggaccagg gacagtcctg gagacagtaa 90361 ctggaccaca tcaccccctg gtgggtgctc cagccctgac gcttgactca caccaggtgg 90421 ggcctcccta ggctgcggag Rtcaggatga gaccagggcc aggctgtgag ctcagcaggg 90481 ctccctccta atgcagccga gacactcttt ttcctctacY cagaacatcc tgctccctct 90541 taaaggccac agcaatcaca tgatcctacg tggtttggag tgcacttagg gagccctccc 90601 tccttccccc tgcccaggtg gagagctcct tcctcttctg gcccaccgct caggcctccc 90661 gcccctRgtg tactacagtt gctggttctt gcatctgtct cgactactga ggtctaagcc 90721 atgggcacga agacccgcat tttactcgct gctgcccatg ctgtctcctg gcactgagtg 90781 gtttctctaa aactgtctag tgaattactc caaattctac cacttctgac taatgatggg 90841 tgacgcttaa gacagagaaa atcttaagag cccaaagaat ggattatggt taatgaaatc 90901 tctggtgcca agagaaacag agtaaaatgc acttaaggca tatagccaac tccagcccca 90961 gcagctgact tcccgccatc caYacaggcc acctctggca gaaggaccag cctgaacaaa 91021 atcccactac tgagtctggt tccccctagc cctccagttc tctcagcctc acacctcctt 91081 tcccaaggag ctcagaaatg ctaaggactg ccaggattct tcatgtacct gttcattgac 91141 tccttgcact ccctttaatt gaacaccatc ttagttatct atagcagcac aagtcaccac 91201 aagcttagca gctgagaaca acgcacaYgg tcaccacaca gtttctgcaY gttaggagtc 91261 tggcccgggc tcacctgcac cctctgctca gggtctcacc aggcagcagc ccagcagtgg 91321 ccagggctgc agtctcatca gaggctggac tgggaaagga tccacttcca agctccctcg 91381 gggtgtcagc agaatgcatt tcattgcatc tgtaagactg aggggcctgg cttcatgcta 91441 tcagctggag gccactgtca ggccctagag gctgtctgca gtcccctgcc aggcagcccc 91501 ctctctatag gccttctcac ctcgtggcag gttgcttccc caaatccagc aactRagaag 91561 agagcaagtc tgctagcaag acagtcttaa ataaataatg taacataatc acaggagtga 91621 catgccatca cttttgtgta ttctagttag aagcaaggca caggtctcat ccgctttcag 91681 gggagaggac cacacacaga cgtgaccacc aggaggaggt cctgagccat cttaacgtct 91741 gttcagcaca cacacctacc ttgccaggcc ctctgaaagc cacctgtgcc tcctgctcca 91801 gtgccccaca aaccagctct gcctcttctg ctttgcctct cctcagatcg gggcagtagt 91861 gccttctctt taaggctgtt gatggaaata tgggaatgca atactgggca cagagtcagt 91921 gctcaataaa caacagctat taacactagg attgggttga actcaagtgg aagaccactc 91981 ccagctaatc taacaagaga gcagatgctc aggtgacacc ctgactctct agttgtgcct 92041 taagtcagtg aaataagcac agtgactggt tatgctggag gtctcaggac aatgttcccc 92101 accacacagc ctgaaatgcc caKctgggca ctacatgctc ttcctggtgc caacatctgc 92161 ttgaccattt ccttatttta gagtctttgt attagaatgg tgtgtttgag ttctggtttc 92221 ctgactagct ttgacacatc cggtattttg tatcaggagc gggtttctaa tccacacaga 92281 tgtggcctgg agaatcatgt gatggcagct tctctcactt gttaccctct gcaacaattt 92341 tttttttttt ttgcttccca ttgWcacagc tttaagctca gctgttttgg aggtcttagc 92401 tccccaggga agaatgttcc accaagaaac ccaacaatag tttcactgaa ttggatattg 92461 agactgccac ctagtaatct gtgctccttg tacactgacc caacagtttc acataagaat 92521 aacatggaaa ttccaatgtg gctgaagaga gagaaggaca gatgtggaca cagagaaggt 92581 caagacatgg gacaacctca agggaaaagg agatctaaag actgaggggc tagtcctcag 92641 acatgatggt gcoagtagca ggtggggtgt tactgagcag actcctccag ccgtcccagt 92701 gcaggcRcaa gaaatggctc tggcagtgac tgccggggaa gtggggaagg ctggggcctg 92761 agagtgggcc ctctgttcgg ccacagccac tccctcacct cagggctata tcccagtgaa 92821 gttgacatct cactcatgac cctgacctca tgtcataggg atgtggggca tgtcctccag 92881 tacctactac cccccaggcc accccctcac accacagaca gcctcagctt agatccacgg 92941 agagaatagc accagcgtcc aacacagcaa acaactctca aattgcttct ctctgactct 93001 gtgacatcct gtctcatttg gtctaatgtg aaaattcatc tgcacttcct ggatattaac 93061 catctgctgc tgggaggcac atggagttgc aggcaggttg gccagggctt gggaccagcg 93121 ttccacacac attccttctc aattcctcat gagaaggaga ggacgggcac tggaatcacc 93181 agaatgccta agcgcccctc ccacgtggag tcctcatcag gcttcaaaag ccagacttga 93241 ggtacccact cacccaaggg cacagggatc agtggaggga atgggcccag gctctgacac 93301 gtctttctcc ttttgaacct ggcctccacc ctctgtcagc cagaggcagc tgattgcaca 93361 aaagcacttc taggaaatcc tcttcccttc tcattttaaa ggcagaggcg caggcagctt 93421 ctgcagtcac tccttgctct tcctcactca tggagggtcc agaaattgat tgcaggacaa 93481 ctggctcttt agttccagcc cagaggagac agtaacaacc caagattggc atctgtggag 93541 cacccatgcc ccgggtgctg tctggtgttg tcccctcagc agcccggtga ggggagcagt 93601 tatcagaggt gacatggctg cccacactgc agggctagca agagacagga tcaggacagc 93661 gcactcccct gccctccagg gagaagaacc accgaagcag aggagggaaa gtgagccacg 93721 gggccgatgg ggccgcccca aggaccagat gctggtgggc atccggcagc cagcacctcc 93781 tctctctgcc caggggcttt ctctgaaacc tggaacctgc tctgcccgca gacaaggcag 93841 ccacaaacat ccctgggagt gggcctgacc cagggtagac aggagtagcg ctccctcatg 93901 cctcccccag ggcctccccg tcccccgagg ccccagcagg attcaatccc agtgaccaca 93961 gagctaggtg gctgactccc accctcactc gccatcactg ccccttcctc cctcactgcc 94021 cccttctcca gctgcttcct gagacccctt ccagaccaat gcttcatccc aaagcctgtc 94081 ttggggtctg ccctgggcaa atgcagcctg agacaccccc tttctggtgg gctggccaga 94141 ccatctgcct tcactgtggg ctcacagccc actcacagga cagccctggg cccaccgtcc 94201 tcccgcatct ccatgagaag caggtctcct ccaggcccct gactgacccc acagagctgc 94261 tcagagagca ctcggggcat gagggcctga cagcggcatg ctcaggaccc agcggctgct 94321 gtgtgctcca tgacctttcc cgggagtccc ctgcaggaac ctcaccctat atgggttgcc 94381 cccgcccagc ctcttYtccc cacctcttcc tgtgcttcct gggatcacct tccacataaa 94441 ctgctgtgcc caaagtcttg caccagggcc tgcttctggg gaacacggtt gtgttagggt 94501 ggagggtccc ctggcactgg ctgtgaagtc tctgcggttc aagctggaac tgaatatcaa 94561 aacccccaga agtgaggtgc tgctgccggc cgtgtaagcc tgcttatccc tctgcttcca 94621 tgatcaagtc aaggctgata ccctctcatg cctccacagg agccccaaag cagggagtgc 94681 tgccccaggc caccacccag tgcccctctc agggacatcg ccgccgggct ggtggatgga 94741 ggccatgacc gctcttgata aagccgttgc atggtgggca gtctgtagga gctgacttac 94801 cctgggagag cagcagcccc cacagcagtg ggcccacgcc ccatgacatc cagagtcctt 94861 ctttgcacat atgaccacac attcctcccc atacattcgc ccccacctcc agcccttctt 94921 cccctccctg acacaagcat cacctttaag gtctttcctg tgtctctttc tctccaatgc 94981 aggaggactc cctccctcca tgtctccgtt tcactggtca agaggaaaca gacactattt 95041 ctagagttaa gcatgtgtgc accaggctcc ggaatcctgc ttcaatagcc ctgggtgatg 95101 ggtatttgtg ttgccttatt tcagagttgc agtaactgag gcttgagaag tttctgtacc 95161 tcacaccagg gcacatggct ggacttaaat gcaggtcRgc ctgacccctg aacccagagt 95221 gttcagtagg acaccatgtc acgtggtgtt agttacatgc agagcagagg ctacaggagc 95281 ccgggcccca aagggagtga tgtctgatgg agagctagtt ccattcatgg ccagggagaa 95341 ccttcgcctt tttgtgccag agactcctct gcgggtcagg tgaagcctac cgagcccttc 95401 tcagaaggat gctcctaaca cattacccaa catgcgtcgc cttacaatgt caaccaacta 95461 tactgaagtg gttatcaaca ctgttttaat aRcttttgcg gtacaggtgg ttttggttac 95521 atggatgaat tgtacagtgg tgaagtcagg tttcagtgca tctgtcacct gcgtagtgta 95581 cattgtaccc aatatgtagt ttttcattcc tcatcccccc ccagcctccc ccttctgagt 95641 ctccgatgtt cattatacca ctctgtgtcc tttgcatacc cattacccat agcttagctc 95701 ccacttataa gtgagaacat gtggtatttg gttttccgtt cctgagttac- tctacttaga 95761 ataatggcct ccagctccat ccaagttgct acaaaagaca ttatttcact ctttttaatg 95821 gcctgttagt attccatggt acatacatcc cacattttct ttatccactc attggtcgat 95881 gggcacttag gtgggttcta tatctttgca attgtgaatt gtgctgcaat caacatcctc 95941 gtgcaggtgt ctttgtgatg taagacttct tttcctttgg gtagatactc agtagcggga 96001 ttgaaacaat tcgtgactaa gactccaaaa gcaaatgtaa ataaaacaaa aataaataaa 96061 tgggacctaa ttaaaccttc tgtacagcaa aaaataataa taatcagagc aaacggacaa 96121 cctacagaat ggtagaaaat atttgcaagt catcaacatg ttttttttgt tttgtttttg 96181 agaccaggct ggagtgcagt ggcacgatct caKcccacta caaccttcac ctgccaggtt 96241 caagtgattc tcctgcctca gcctcccgag tagctgggat tacaggcatg catcatcaca 96301 ccaggctaac ttttgtattt ttgtagagat ggggtatcac catgttggcc agcctggtct 96361 cgaactcctg acttcaagtg atccacctgc ctcggccccc caaagtactg ggattacagg 96421 cgtgagccac tgcgcccagc cactcaaaat gtttttaaat acatgtgtga tgtgttaata 96481 tatgtgctcc tttactaaca tcttaagcag caagttcact ggaggatcta agaattacta 96541 aaatttcaaa gtcccaagat gcctgcaacc accatccatc cacgataaaa aaaaccctct 96601 gcaatgtcYg tgggaaaagt caccatggtg gaactcaatt cagaatcaaa agtaaYgcaa 96661 aatctgagtt tgaagctagt agaaataaag atgaaatttg ttttccttcc aagttcacag 96721 tcatctgaat tttaYgccca gcccctcagg aatccatgaa cccctggtta acatttcccc 96781 agacatggga tccctacccc agctcctgcc cagggtttaa gtcgtcccct cccttcgacc 96841 accatggtta gatttcctct ttccagtggt gcagaaaaca gcatagccat ggggatctgt 96901 tgcaatcctc tgagtccotg gaagtctccc cacaccccct gccctctgYt tcagctcctt 96961 cctgtgcctt gcataagaat tccgggcaca gccaggcagg gcatggaggg aaagcctgtg 97021 cattaaaaac Rtaggtttgc aggccagctg catcacctgg agatctgtgt aaggcccagg 97081 aatctgcatt taaacaagcc cacaggtgag tgcattgcat agcctagggg ccgtattttg 97141 gggaacactc ctgcaaattc agtgacttcc tcccagtccc Magccctctc ctccaacgtc 97201 ataccttaac cccttcaRgc aggagacccc ctgctgcccc caggagcctc agccccagag 97261 attctgcagt gtctaagttt tccacagtcg ccaatctcca cRgcatgaaa tgccttgact 97321 gtgcccctca ^'"caagcagtcc cagagccctc cctgcaaRag gagatccagg cagtgacttg 97381 gatggcagag gatggctggc tgtttcctcc RgagacaaRg ctaagcccag gagagcacta 97441 cccaacggca caggctcaga ccgcattcac cctgcaggga ggctgagctt ggcaagggag 97501 agggcatcag agcctggcaR gaagccacag gttctgctgt gctcagcaag gagccatcgg 97561 ggtggggaca agcaggtgac ccaggggcct gccagggagg ctgacagagc tccgtggaag 97621 atgtagagac tttcttcttt gttaagccaa gcctggaRgt agagcactga tgggtggggg 97681 aggaggagtg aggggaggag tgagggggag gagaggagga ggagtcagaa gaaggaatgt 97741 cctcccagca gctaccattt tctgagYctt ccaccccctg actgtgcacc tactgcagac 97801 tttatataca ttttcctYac ttcaccctca aaatacaNNt gttacagaaa cctaaggaat 97861 caaagggtta atccttggcc caaggcccac agtgtttcag gtgcagaccc agacattgag 97921 cccgggactg tggctccact tgtgcaggaa gcagtagagg cttagcggga attcggggtg 97981 catgcgaggg ggaccttaga ttYtcaagtc ccaYgcagaa oaacactgga tcattatgag 98041 cccccagaac ccctctgaga accatcctgc ccgagccctt tagggagctc agatccctga 98101 gtcccaggac agaatgacac tggatcatca tgagccctca gaacccctct gagaaccatg 98161 agccctgcag ggatcttata tccttgcatc ccaggcagag cgacactgga tcactttgag 98221 ctcccagaac ccctgagagc tgttctgcct gagccctgag cgcaggtgcc accttgccct 98281 gctctgagca gcagcgWgga agggctcYga aaaggaagct gtagttggtc tgaagctgcc 98341 cctccgtgcc cagtggaStc agctgaccag cgctgagttc tggtgcagaa ctcgcagcac 98401 tttcctgctg tgggatctgt agtgcatgYc ttacagcctc tgaaccgcct tgcagagatg 98461 atgaggcttc ctgcggggct gtaggccgta ggccacccct ccgccaagct ctggcccagc 98521 atcacagaga gagaaggtcg cagccagggg gacccagagg ccaacgtggc tccctttcca 98581 ctccatctcc Yggttagaaa gttttttaaa gagtcagttc aaaggttttt ggtttttgtt 98641 ttttgttttt tttcttgttg ttatcctgac agaattttca tggactcttt tgatccacat 98701 aaagcaaatt gaaaagtgaa taacctRgtt tggcctcata tttatgaaag gaggaaacag 98761 ccagctttct ctaaagcctg cacttgacct gatgtaaagg aataagaaaa aaataaagga 98821 ggggatgagg ggagagaggg aggagcatgc tttgaagttg agaggccaaa agggatgtgt 98881 gattagctgg gccctgagca cgttaaagaa aattaatcgt tcagtctata tttaaggctg 98941 gatcataatt ttgctcttcc acaatgaaaa gagctcacac tctttagctg ttggcctaaa 99001 ttactcaaga gaccaagacc tggaaacaac tctccagctc atctcagagc cagagacaga 99061 gacccctgct ccagccacag atggtgagtt tgataaccac ccaggattct aagaaaggga 99121 aactatcatg ctcatctgga aagtaattgc caaagagtgt cccctgagtg tcctgtcctc 99181 ctcctgcccc aaccactagg caggcagatt ctgggggaaa gtgagagaag aagcataaag 99241 cagtacaaag aaaatagaga aggacattcc tgYRccgaaa gaagagaggt ggttttctgg 99301 aaagcgtcgt aagaataaaa agcagcttct ggctgtgcgt gctggccgtg ataaatggtg 99361 tgcacatgcc agtcgtggat ttgcgtgcct aaaaaagtgt cattgcccaa acatttcttc 99421 tcaaagtgtt gtctccactg gtaaagcaag gctgcctcat ggcatctagc tgcacttaag 99481 ttggtgggat gggaggagag

[0285] FollowingisagenomicnucleotidesequenceofaEIFG4G2region(SEQDDNO:2).

>11:10767651-10866750

1 cttggctcac tgcaacctcc acctaactgg gttcaagcca ttctcctgcc tcagcctccc

61 gagtagctgg gattacaggc gctggtcacc atacctggct aatttctgta tttttagtag

121 agacagggtt tctccatgca ggccaggccg gttttgaact cctgacctca ggcgatccgc

181 ccagctcggc ctcacaaagt gccgggattg cagacgtgag ccaccgtgcc cagccMaaat

241 gattttaaat acagtgtctc tacctcaact gcatttttaa cttgaggtgt ttctagtaat

301 tgaaaatctt gtctgctatt ttaagcctaa tttcttatag atacagatat atttgcttac

361 gaaatatatt tatttgggcc aggtgtggtg gctcgtgcca gtaatcctag cactttggga

421 ggctgaggta ggaggattac tcgaggccag gggttcaaga ccagcctggg caatagagtg

481 agaccctgtc tcattaaaaa aaaaaaattt ttttttttga gacttagttt tactcttgtt

541 gcccaggctg gagtgcaatg gcgctatctc ggctcaccgc aacctccctc tcccgggttc

601 aagtgattct cctgcctcag cttcccaaat agctgggatt acaggcatgt gccaccactc

661 ctggctaatt ttgtattttt agtagagaca gggtttctcc atgttggtca ggttggtctc

721 gaactcccga cctcaggtga tccgcctgcc tcggcctccc aaagtgctgg gattacaggc

781 gtgagccacc gcacccagca aaaacaattt aaaaaatttg ttttaaggaa gtatatttat

841 ttggctcttg tcttttgctg ctttttgttt tgttttgttt tgttttgttt ttgtttttgt

901 ttttgttttt ttgagacaga gtctcgctct gtcgcccagg ctggagtgca gtggcacgat

961 cttggctcac caacctccac ctcccgggtt aaagtgattc tcctgccgca gcctcctgag

1021 tagctgggac tacaggcaca tgccaccatg cccagctgat ttttgtgttt ttagtagaga

1081 cgggatttca ccatgttgac caagctggtc ttgaactcct gacctcatgt aatccacctg

1141 tctcggcctc ccatagtgct gggattacag acgtgagcca ctatgcccat ccccttttgc

1201 tgttctttat tctgctttat ggcagaggta ttttgataac attttttcat ttttaaaaca

1261 gtgagttttg gaaaatatct caatttttgt gcatatgcct tgatatagct gatcaattct

1321 ggattgccac tactctaaca ctctgagggc aagtatattt gttcatgaag tccacagcta

1381 aatagtgaag agaacactta ttagcaaggc atgtggggct ggcttttcag gtatcttctg

1441 cagaagtcac tcaagttgtg aatttacctt ctttttaatt ctgtctccta aacagacctc

1501 gatccagtgg gttccccaga gtgttttcca ggacatgcta gttccaaaag atactcctta

1561 aaaaagagtt cgatagtcaa gtaagttatg aaaatgctat agcaattagg aagttttggt

1621 gacaattcac agaaaactct gtttcaaact gatttagcaa gaaggaaaga ctgggcacag

1681 tggctcacgc ctgtaatccc agcactttgg gaggctgaag caggtggatc acctgatctc

1741 aggagttcga gaccagcctg gccaacatgg tgaaactcca tctctactaa aaatacaaaa

1801 attagcaggg cgtggtggca cacccctgta atcccagcta ctcgggaggc tgaggcatga 1861 gaatcacttg aacccagggg acaggttgca atgagccgag attgcaccac tgttctctac 1921 cctgggcaac agagtgagat tctgtctcaa aaaaaaaaaa aaaaaggaaa gataattgta 1981 tcctataact ggacatctgg ggggattgcc gaaaggaagc tacagttcaa tcagaagttt 2041 cagtattatg aaagactcag ttttattcat tctttttatc atgcatatag aagagtatat 2101 gatgtgataa atacaaaYta atacctctat atcccttcta gagccctttc ctgtgtgcct 2161 cttgtgtgcc ctttcccagt tgcacccctc tcctttccoa tatatgctat gttcgagcaa 2221 agtgtttaaa cctgtctggg agtttagccc cttctgagga tgtaggtcat aatttgaaca 2281 ttgctatcat tgtgctttac cgtagaaagt gaggtgtcag gctccttgcc tctgccctgc 2341 gtgacccctt agtgttgatt gaaatgatct atttatcccc accagaccat gaacttgagg 2401 acagagctta tagtgtttcc atctatttcc aggggccaat cataaagcct ggcaagaagt 2461 agatgctaat ttatattttg aatataaatt taaaactgaa ttaactaaac atggaggttg 2521 tggcaaggat Kggactctgc tctgaggcct ctgcagctcc atcctgctct tctagaatgt 2581 gttttagcaa atgcattttg tgggagtcag gtttccactt gaactcagtg gtagcatgtg 2641 gcataagtcc aggtcccctt cacaaacgca gccacagcag atgcactgcc agactctcca 2701 cgtggctgga aatggtcagg ctgctgtttc ttacaaactg tccttatgcc caccagcttt 2761 tcttctcata ttgacaattg tgaaggcatt gaatgtccgt caaactactc aaagatcact 2821 actcttgaSc ataatctcaa taaatgaaca tgtaggtttg tctttagtcc cagacagggt 2881 ggaatgtctg tgatattatc ttctccagag ggggatcaat gccaaaacct ttgttctctt 2941 ctgaactgct ttgttctttg aaacaatact gttttgatct cccatgggag ctgctgctcc 3001 gatttcctta actgaaaaga agtggcgact tcaattcctg ccttagcccg ctgcggattg 3061 tcctggtctg cgtgtgtgtg cctgtgccta ggtgcagaca cgctccttac ttatctcact 3121 tcctgctgct tccagcttgg agtggcagct aaagcaatta ggccaaggag gtgggagaag 3181 ggagcatcaa tatattcctt ggccagaagc aactgtgagg ggcaaacgct ggggctagtt 3241 tcatggattt aaaaccttgc ttccacagcc tgcaaccttc ttgttggttc tagctgaact 3301 ctggcatggg aaccatgcac ctccttcttt ttcatggttt atagaaattt cagaactcgg 3361 gttcccaccc ttttgatcct ccaggaagcc tcgggaccct cccttctgga atctcacatt 3421 gcaaacagct gatcttgttc taaaccccta ttcaaggcag ctcggaagtt ctcagtagtc 3481 acatgagctg acggtgtgct ccccttgaca gctgtggtgt ggctggtagg tccttgtccc 3541 tgtggcaggg atgacaaatg ccttatagtt atttgactct aggcaatggg gttggagcat 3601 gaggaaaggg ttggcctttg caaagagctg agtcccttca tccacaaaaa aggaaatcat 3661 gtgtcagtgc aattattagc aagtcagtag cttagatggt aggaagattt aggggatgga 3721 gttgcttctc aatgaggtag aagotgaggc ccagagtcac cgtggctggg aaggcagtac 3781 agtccttggt ggtcagcaat ggggcctggg cggattaggg tggatatcag ggctcatcag 3841 attttaatgg gctaatcacc tacagattct gattcagtgg gtcaggagtg agaccagaca 3901 ttctgcagtt ctaaccggct ttcaggtgaa acgaatccaa agactacact ttgagcccgg 3961 gaggttgtat agcattacaa atgtgccctt tctgggagaa caccctcaac ttttctttcc 4021 Ytgaggctta aaagcctgac aaagcaattt cagcaggtag gggtggggtg tggagaagcg 4081 gatattacca ggggcaggag gaatgagtga gaggaggctc agggaggaga cgatgtgaaa 4141 cagctcttgt gaagagtggg caggtgagca caccggggag gtggtgaggt ccgacggcac 4201 aaattttaaa ggacctgggc cttcagaaga aagaggtgga cagaaagcag agtggacact 4261 ggccacRcca aggccactgg gcatgagacg caaggcagca ggggaagtga tgatgtcaca 4321 ggacagccag gtttccttta gagcaagaag atgacagaac tgtccagaga agatattgag 4381 gatgtgggaa atttgctgct gatagaccgt gaggcccaga gggtgtggag gaagggttgg 4441 ggagcgggga gaggggagga gagggaggga gaattggggg cacattagca ggtgtatgga 4501 gaagttcagc gtgaggtcca ggtccatact ggggcccttg gacttcccgt gggcgaggca 4561 gggctgaagc aggctgggaa aacaggtaac cagttccaac tgcacagagt agggcctttg 4621 gggatgctct ttcctgcact cgggtgatgc actgatcctg tttttggagg catgagggag 4681 gggcagtaga acttcaggag aggcgtcact cctgggacag gaagctgggg tgccccactc 4741 cagggcccag gtgtctcagc catggagtgg aagcoccatg cacgcgacct tgtctctcca 4801 gggcatgttg ttatggatgc tgccttttta gagcaatgtg gtcagacaat gctgtcccca 4861 cgcactggtg acttggtggt tacagctcag catttccaaa gataaagcaa tagttgtggg 4921 tttttttKtt tgtttgtttt ttgagacRga gtctcactct gttgcccagg ctggagtgca 4981 atggcatgct cttggctcac tcaacctctg cctcctgggt tcaagcgatc ctcctgcctc 5041 agcctcctga gtagctggga ttacaggcac acgccacaat gcccagctaa ttttttgtat 5101 ttttagtaga aacgggattt caccatgttg gccaggctag tctcagactc ctgacctcag 5161 gtgatccacc tgcctcggcc tcccaaagtg ctgggattac aggtgtgagc caccacgcct 5221 ggccaatagc tgtgtcttga gcttcaaata tcatagatgc ctgagtataa ggtgtcctga 5281 atataacgtg accccatgcc cactgtaaag gttctctgtc tgcccaaaag atttttcact 5341 aacttaaact tacaaacttt ggggatgtag atgaaatagt tcaatgtcta ctaataatac 5401 ttattaaatt taaaatgtgt ttaaatcaca cattcataaa atgttgagaa caagtgcttt 5461 cctccattca tattccatac aataatttca ctcaaattta tcacagaatc tttgtccatt 5521 gtacttgagc cactttcgga atcatctaac agttttcagg agaacgttgc cttcccaccc 5581 atcgtgttgt ttgaggtcca ggcttgagag tccatggccc tgtggctgaa tgtgttgtcc 5641 tgagctgcca gcactcctct gcatcgcatt agaacaacaa ctggccttcc catttgtccc 5701 gtaggtggct tttcccatct tcatttgatg tactgctctt tcttttttgt gtgagagagg 5761 ttctcgctct gtcagccagg ctggggtgca atagtcagat cattgcttac tgcagcttcg 5821 acctcctggg ctcaagcaat cctcctgcct cocctcccta ccagctagga ctacaggaat 5881 acagcattgt gcctggctaa tttttaaaat ttttggagag acagggtctc accgtgttgc 5941 ccaggctggt ctcaaacccc tggcttcaag tgatctcctg cctcagcctc ccaaagcagt 6001 gagatttcag gcttgagcca ctgtgcccag gctaatgtac cactttttaa agcaatcttt 6061 aaaatgcttg tttataactt ttgcaaactc ttgagatttt acaaccgtgt ccccaggaat 6121 aacaattaag tctgtattca atttctttga caccaagcct ctcgaaggcc tccataaaca 6181 tcaaaaacta gctattgatt gggatcactt caggttaatg tgtcatcccc aaactgtaga 6241 ttattgtcca aacaaatgta attgacaggg cctcatgtaa ttggaaattg tcaggcaatt 6301 atcgtgtgtc aattaaaagt aataaaagta aaaaacataa acaaaactaa caacacatgt 6361 ataagatatg tattctaaaa attacacaat gatgaaaaca atatcaaaga agactcaggc 6421 tgggcacagt ggctcacacc tgtaatccca gcattttggg aggtcgaggt gggaggatcg 6481 cttgagctca ggagttcaag accagcctgg gtaacatggc gaaatcccat ctctacaaag 6541 aatacaaaaa gttagccaga tgtggtggcg tgtgcctgta gtcccagcta cttgggggct 6601 gaggcaggag gatcacttga gcctgggaag cagaggttgc ggtgagctga gatggcacca 6661 ctgcactaca gcctgggtga caaagtgaga ccctgtctca aaaaaaaaaa aaaaaaagaa 6721 agtcttaaat taagagatat atcatgttca tggactggaa gactcaacat agtgaagatg 6781 tttctctaca aaaaaaaaaa agaagaagaa aaaattgtta gagcgaaaat gtcaggcttt 6841 ttttcaagag gataaaaact gcaggtattg gctaggcaca gtgaaacacg cctctaatcc 6901 cagcactttg ggaatctgag ggaggtggat cacttgagcc caggagttcc agaccaccct 6961 aggcaacatg gtgaaaccct gtctctacaa aaaattagcc gggcatggtg gcccacctgt 7021 agtcccagca acttgagagg ctgaggtagg agaatcattt gaccccaaga ggttgaggct 7081 tcagtaagct gagattgtgc cactgctctc cagcctgagc gacagaatga gaccctgtct 7141 tcaaacaaaa caaaagcaaa acaaaacaaa acctgcaggt atttatagtt tgccacattt 7201 tgttttattt tccccatctt tggaaatcag ctccaatttt gactgccgtg taatagaaaa 7261 catgcggact ttagagttat tcgaactcta aatcctagct cttcctctga caaatgatgt 7321 gactttgaac aatggctcca tccccctcag cttcaatttc ctactgttta aRttgggata 7381 acaatgtcta catcccagga ctattctgag aataatatag tcagagttca aaaaggttag 7441 tctttttttc ccactgattt tttaaagagc tttttgtggt taacccttga ttgtgcacat 7501 gcaaatattt taatttatcc tttataacat tttgggacag attaataggc aaatctgtca 7561 acatttccct tcatcgtttc tggatatgta tatttttttc acaaagagat agatgttcca 7621 tgaagttaaa gcttaggcat cagggtccct cacttgcctg ggcctcttcc aaggctgcac 7681 ctaatttttc atttgtgatt ttgttttctt tttcctaaag agacctccac cacccctgcc 7741 aaattatgta aacttcaggc cctacagaat ctggaacttt cccgagtaac gtgcttagaa 7801 aagtcacgtc accctaggcc gggcacggtg actcacgcct gtaatcccag cactttggga 7861 ggctgaggcg ggcagatcac ctgaggtcag gagttcaaga ccagcctgac caacatggca 7921 aaaccctgtc tctactaaaa aatacaaaaa ttggccgggc gttgtggcag gcgcctgtaa 7981 tcccagctac tcgggaggct gaggcaggga gaattgcttg aacccgggag gtggaggttg 8041 cagtgagccg agatcatgcc attgcactcc agcctagaag aaagagggag actctaaaaa 8101 aaaaaaaaaa aaaaaaaaaa aaaaaaagaa gcaaagcaaa gaaaagaaaa gtcacctcac 8161 cccaaattat gaaaaatttt aataggctta gctttatatc ttttcttttg gcttattttc 8221 taatttttta gtactaaagt agattactaa ttttcttcaa agaatttttc tcagaacaaa 8281 atagagctcc actgctcatt cattcactca ttttatttac tggttcgtcc aagctcttcc 8341 ctcacctttc tgtacctagc tgagttgtga agcagctggt gggttcaggg gaggagagag 8401 gaagggacag agctagaggg cacggtggcc ctggatggaa gtgatggtac tggggttggg 8461 ggcaatgtat tagtttctag gactaccgta atgaagtagc acaaacaggg tgtcttgaac 8521 aacaaaaaca tattctctca ttgttctgga gactagaagt ccaaaatcaa ggtgtcagca 8581 gggcatggga aggctctaga gataatctgt ccatgtctct ctcctagctg ctagcattgc 8641 tggcaaacct tcgcagtcct tggcttgtag agacgtcact ccaatctctg cccctgtcat 8701 caaatggcac tcaccctgca tgtctgtgtg ccacttctct tattataagg acaccattat 8761 atcagattag ggcctcctct aatgacttgc ttacatctgc aaagacccta tttccaaata 8821 ggaagatcac attcactggt acctggagtt aggacatcag catatatctt tgggggctgg 8881 ggacataatt caacccatga cagaaggatt agggggctga ttcttcctca cctccggtcc 8941 tacaccccaa ccctcagaag cacctgcccc tccctacact cattccgccc tggttacact 9001 tccaagcatg aggagctcat tgcctctgca aagggtcctt tactttctct cttcagtttc 9061 tgtcccctac cccaacatgc attttggtgt atctggtatg agcaccggct cctgagttac 9121 agtgtagggc ttgaatcacc accccatgac ttaatagatg tgtggcccag tacttcaaaa 9181 gagcatgcat gatatgatgt ggctctgtgt cctcacccaa atctcatgtc atctcaaatt 9241 gtaatcccca taatccccat gtgtcaaggg agggacctgg tgggaggtga ttcgatcttg 9301 ggggcggtct cccccatgct gttctcatga tagtgaggga gttctcacaa ggagatctga 9361 tggttttata agtgcttgac agttcctcct tcacactctc tctctcgttg ccttgtgagg 9421 aaggcgccta cttgcccttc actttctccc gtgattgcaa gtttcctgaa ttctccccaa 9481 acatgtggaa ctgtaagtca attaaacctc tttttttttt ttaataaatt accaagtctc 9541 aggtatttct ttatagcagt gtgaaaacag cctaatacaa tgcagaaaag gcgttcatag 9601 ctacttgcca aatacatgaa agatcttggg caggtgcttt gcttctctga gcctcagttt 9661 ggggctcaga catggggata gtgaaggggg atagtgaagc acctgcctca aggatgttgg 9721 gatgattaca agggatgact accttgatgc atttggtcca gcctggcata tgctaactcc 9781 tcggcaaaca ttagctacaa taatcataat atgtcctagc agagctcRgg atgcagtgca

9841 ggcactgcac tggtcttaat gagggattga tattaacaaa tgataaaaag caatcctcca

9901 aaggcagccc atctcactca gcataaaagc caaagtcctt actgggtctg actagttctc

9961 tgcactggcc ggcgcccttc tcctcagcct caaaccccct tgccctctgc ttggccagat

10021 tgttcctcag acaggccagg tgcgttccca atctcagggc ctccagcttg gcctcccctc

10081 tgccaggaat gctgttcctc cagatggctg^'1 tggagttcac cccctggcat ctcttagatc

10141 tttgctcaaa ggccacctcc tcctgaggcc atcccagaac cccctctttc aagcagcact

10201 cactccactc cctagccctt actSgcatcc ctgcatacag cactttttac tgcctggcac

10261 tgtacgtttg tKgatttact gtctctctgc tatcacccag aacgttgctt ccagaagaag

10321 actgtctcat tactgttaca tctctggccc tggagtagcc cctggcaaat atgtactcag

10381 tacatgtttg cgagacgcat ggacttgtag aacagttcca cagctgtcca tcactgatgt

10441 tccataccta gcgatgcggc ccctcgaaac gcactggaga gctgggcaga ccaaggataa

10501 tttcacaggt aagtcagata gagcctgggg aggtgcagcg attggcctag gctccgagac

10561 tgatgacccg ggaagctggg gcctgcgctc tgctctgtgg ctcggcatgc tgtgcagctg

10621 acctgagcag ctcttgagga gtcactgctc atttaccagt cacatcgtcg tgtcatgcac

10681 cgttgacagg agaccaagcc cagggcaaca ttctcacttc cccctctcca tgagcgtgac

10741 cagtgggtct cggtcttgcc tccgcgtggg ccgtRcagga caagggccag agccttgcaa

10801 cccgacccac ctgccagggg tggtctccca gcatcccggc agagggcgct gtgggacagc

10861 gttgctgatc ggtcggggac ctgggtccag ctcagcctcc tgcgctcccc ctgggtcagg

10921 acgggcaagg gcagggctgc ggggcggggc agggcaggct gtgggacttg aatgtcctgt

10981 gtccgctact ctctgccctg tgctcaggtg tctcctcgtc cagggctctt gcatattctt

11041 gtaggacttt gcttggaaaa ttgtctagtg agaaagtgat tcgtttttgg tttgcatgag

11101 gctatggttg cagagttaga aagggaggga gtgttggttt gcggcaaaaa gtttagggat

11161 gaatattgag tttgaagtgc tgtggcacat tcagaaatat gtccaggggc tggttggatg

11221 tgcgagttag acattctgga aaggggtttg gactcaagat acagatgtca tcagcagata

11281 gctggtaatc ggatccacag aagtgagtga cagtgttgaa ggagggaggc aaaacagcaa

11341 cattcagggg ccaggtgaaa aaagagggct tttaaaggag actgaggaga agctgggaga

11401 aaaacaaagt gggaaagagg aaagtcaact ggcaagtgot tttgattgat caaataagac

11461 tgagctatac cctttagtta tatctagcca atgatcttgt tagttcagaa gatggaagca

11521 gttctcctgg ggaggaatct tagaaaggag ggtgacattc atatctattg ggctgctatg

11581 tgggatgctY tccctagtga cttttacata ttagcttgtt tagctctcat gacaatcctt

11641 aagtattaac cctgttttct ttctttcttt tttttttttt ttttaaattt ttgagacagg

11701 gtcttgctct gtctcccagg ccggagtgca gtggcacgat catagttcac tgcagcctca

11761 aactcttggg ctcaagcaat cctcccacct cagccttcag agtagctgga actacagctg

11821 cacgttagcc acattttcat tcattcattc gagacagggt ctcactctgt tgcccaggct

11881 ggagtgcagt gacgtgatca tggctcactg cagcctcgac ctcctcggct oaggtgatcc

11941 tcccacctca gcctcctgag tagctgagac tacaggtgtg catcatcaca ctcagcaaat

12001 ttttctactt tttttttttt ttttttgtag acacagggtt tccccacgtt gcccaagcta

12061 aattttctaa aataatttct aaaataatca agactcagat aaaaaatatc ttacctaaga

12121 tcaccctRct tgtgttagag attaacccta gatcgatcta caactcgagt ctgaggtctt

12181 cccactactt ccttcctcta tgtccacatc ctgccatgta gggtaatttt attaattcat

12241 gatttggttg aacaaatatt tgagtttacc gggcactggg cactgttcta gatgctggga

12301 atacagcagt gaaaaaaact gtcaaatact tcatgctctt cacattctag caggaatcag

12361 atataaccat gcagtatgtc atgtaatgag acatggagat acaaaaagga aagagggatg

12421 aggatgtgtt tagagttttt aaatatatat atgaatttct ttcctgcccc ttaagatctg

12481 caggaggtta tcagaattga caatgaggac tttactaata aaagtgacat ttgaagctgg

12541 gcgcggtagc tcacgcctgt aattccagca ctttgggagg ccgaggaggg cggatcacga

12601 ggtcaggaga tcgagaccat cctggctaac acggtgaaac cccgtgtcta ctaaaaatac

12661 aaaaagttag ccgggcatgg tggcgggcgc ctgtagtccc agctactcag gaggctgagg

12721 caggagaatg gcgtgaaccc agtaggtgga gcttgcagtg agccaagatc gcgccactgc

12781 actctagcct gggcaacaaa gcgagactcc gtctcaaaaa aaaaaaaaaa aaaaaaaaaa

12841 aaagtgacat ttgagccaag acctgaggag ggggagaaag coagtcatcc agttatccag

12901 aagaaaggag gaacataaaa cctccaaagt aagaagatgc ttggcatgtc ccaggagcag

12961 caaatccagt gtggtgggag cagaaggatt aagtgccagc agtaggaaat tagatcagag

13021 aaacaggttg tggggcaagg atggggagag ggctaagaaa atcagatgtg gggtgatgta

13081 gaccaaatta agtattttga cataaaaatc ccactaggtg ggaagccatt tggcgggttt

13141 tgagccaagt ggtgctgtgt tgagacgaca aaatggagat gagggctagg cagggaggcc

13201 agttaaggct actgtggtac ctaggtaaga aatgagggtg gtggttgaag aaatgagttc

13261 ttcaatttct aaaatgtttg gaatgcaatc aacatgattt gatgctagaa tggatgcaga

13321 gtatgacaac aactgaaaaa gtgttgagat caggcatctc ccattggaaa ctgagaagaa

13381 aaagatgtcc tgggaacaag ttaacacttt caaggaatga gtaacttgtc aaatgctgcc

13441 tacaggagga tcaaaaccta ctggatatag cattggagtt actggtgacc ctaagaaagt

13501 tttggtgtgg ggaaccaggg gagtgaagcc ctactgaggc ttSagaatgg ggaaaattag

13561 acaactcttt caattttgca gtaaaggaaa aaaaaattgg gggcagtaaa gacatgcaat

13621 cttattttga agtcaccatg aagtgaatga agattagtca ctacatgctg atactaaaga

13681 aattggcaat catgcaaggt acatcccagt tatacccaga tactgccatt ccacagtatg 13741 gtagattata aagtacactg ttaggtgtct ttagaacaag gtagcagcag tattatacat 13801 tctctatggg ttgaatattt tgagtagctc ttgacatgtt tggggtggga agattaaagc 13861 atgattctgt aagcaatgac aaaccactgc gtaccgggtt tagttcattt tttattgaga 13921 cggagtttcg ctcttgttgc ctaggctgga gtgcaatggt gccatctcgg ctcactgcaa 13981 cctccgcctc ccaggttcaa gccattctcc tgcctcagcc tcccgagtca ctgggattgt 14041 agacatgcac caccacactc agctttgtat ttttctagaa gaaaataggg tttctccatg 14101 ttggtcagcc tggtcttgaa ctccgacctc aggtgatccg cccgccttag gcctcccaaa 14161 gtgctgggat tacaggcgtg agccactgca cccaggccca ggtttagttc taaaacttcc 14221 tttagcctga taccctggct gaattaggca aattctggca ataagaattg actagctgat 14281 ccacctaacc agttgctcct tttgctaggt taaaaattag tttcctcccc ttcgtgggga 14341 gggttgggca gagaaacaat ttacagcccc tttaaaattt aggtaggttc atacaaatct 14401 gtttagcttt aaattttgct gtactcaaag tacccaaaag cttatgactt gttaaaactt 14461 caggggaaga tgagtgccat aatgcaagat ttagcttccc tggcccaaat aagacagaca 14521 caaaaacatt gattggttct gcctcccacc cactggagca tgtgcaggca gcctcttctg 14581 acttcaaggt tctaatgggt tcggcagtat gatagtctgc cttgagggtc tccccaatca 14641 ccaagaacag gttcttaggt gttgacatca accaggactc cagtagcaca cttcaagagt 14701 ccccatccat gccaatgtta gaagtaatcc taggattgtc agaatgttcc agggctggag 14761 acaaatcctt cgtgtgtgtt tttggaaaac atgcagaggt ttagttgaat gaagtcaatt 14821 ttactgggac actggaattt ttccagagga agcagggatc ttcctggaca tttggggcag 14881 ctactgggaa tgatgcttgc aggacagcta agcttatcca gagatcacca tgtatttcag 14941 tctgacaaaa gataaattgt caccaaattt tagttgctat gtgtagctat gttcctccaa 15001 attcataaga cttgtgatct ttgatcataa aaatcgttta tattggttag tttcagtaac 15061 tcaaaggaaa taaacacctt aaatcttgtg tctcatcttg aagagNNtaa aaattccttc 15121 tggaacccag gcttgtacag cagaaaaaca aaaattggga agtccttaag tcaaactaag 15181 gtgggtctcc tatacctcaa aaacaaagct gacaattctc ccagactatg gatgccattt 15241 acagccacac atcactacat caagtatcac aatgtttatt gatagataca agtatataaa 15301 atcagggcat gaacatgact tgataaatta agtagactta atttcaatac tataatagga 15361 gggaccaatt caaattctca ccatttgttt cacacccaca aaaaccactt caagggcatt 15421 aacgatctct caaaactgat cagttttgtg caagtaaacc atgtttcttt taaaaagact 15481 tgtgcacttg cccaggctca aggatattaa aatctagcac ataaagccca ttactagagg 15541 tagaaataca ggcaatatac tattacggca acaaccatca attacagtta agaatttttc 15601 tgtaacaacc aaatggataa tcaaatattg caacaactca agtattactg agcaaagtgc 15661 atttctacag tattcagtgt tgctattcag ttttctaact taaaacagcc tatgataact 15721 ggcagcaaag aaggtccttg caatagactg cctctgcttg agaacttatg atgtaattat 15781 tgcatgctgc taatatacta tctaaacatt aaagatactc ctaaaatatt tgatggtaga 15841 ctatgattaa gacattacac tacaaaaaaa ccttatgcag aaggaaatcc taactgacgt 15901 gcttctgctt taaatattgt gaaaacatta cagcggaatg aattttcgca gtggttaggt 15961 caaatgcagt tacatcatag caacagtatg ttttgcacaa tttaaggctt tggctggttc 16021 tttagtcagc ttcttcctct gattcttctt cttcagcagt ttctaaccag gttagccact 16081 gattcaccta taaattaaga tttgtaaatt aaaatagttc atgatataaa cagaaatcca 16141 tccaaaaagt tttaggtggt actacacagt tttagaatat gaaacaagga tatccctacc 16201 aacaatttgt atattaagtt aacgaacagt ggtatattat ccagatttgg gacaacacag 16261 agctaaagat ttaatcctgc aaggatgatc ctcgtgaatc ttgtttatca tcagcaataa 16321 aaaggtagga agatgctgca ggaccaatgt ttctcaagcc tgggccccct ggaaaactag 16381 tagcatgaga aagaatcacc tggattttgt accacagacc tactaaacca gaatctctag 16441 gaataggcct ggaacctgct ttttaaactg ctcttcaggt gatttgagag aatgccctga 16501 tgttcttccc ctagggctac aaSttcattc aataagaaaa aatcaaattg tgagaaatca 16561 gaaacatctc ctctttttag aaaaatatat agtatttaaa ctttttttct ttttttgaga 16621 cacagtctca ctctgttgcc cagactagag tgcagtggtg tgatctcagc tcactgcaac 16681 ctctgcctcc tgggctcaag acatcctccc gagtagctgg gaccaggacc acagaacatg 16741 tcaccacgtc tggctaattt tttgtatttt ttagagacag ggtttcacta tgctgcccag 16801 gctggtcttg aactcctgag ctcaagtgat cctcccacct cagcctctta aagtgctagg 16861 attacaggca tgagccacgt gcccagctac aatttcctct ttactgatgt ttttaaaaaa 16921 gcttaaatcg aaacttgtac agtcactccc atgtatataa gtagctatac tccttgaaaa 16981 gttagctacc tctaacatct tatacaccac tagaattgat tcattgtgta gctttactta 17041 atMatagctt caaatagtgc agaatgaaat gtacaggtga agacaaacta ctaactagga 17101 ctaccttgcc tgtatttcag ttgaaaaagg ctcttaactt gaagttaata ccaagcaaac 17161 tgaagtaagc agaccaaatt tttaacaaaa gacttacctg gaacaaagcc ttgccttttc 17221 ccggaaactc ttgggttata tcttctttcc aagccaagaa agcttcttct tcaataattt 17281 ccatgtcata gaagtgcaca aaaaagcgaa gtaacatgcc ttaaaaaaaa aaaaaaaaag 17341 aaaaaagtaa taagcccatt atttagtgtt ctgtttaaga acttcctcac gccgttcttc 17401 tgatacaagt cctctcacct tttgggaagt tgctgttata gcagtgcacc tggagagcat 17461 acagggcact gacttgtaga tcaacgtgat catgaagaaa tttctgcatt actggcttga 17521 aagatagtag tagttgtttt tcctgctcta actgttcttt ggaaggagca gaggatgaat 17581 ctgtttcatc gctggggggg tttacttcac tagaaatgta ctgtaagaag ctggacagaa 17641 agaggtcttg ttagaaccca acagtgagtt ttcttgctca agagacaact cttagtctcc 17701 tacgcttctt ttcYagtaca tgaaacatta ccatatgcag aaaaccattc gtcttaccta 17761 gtcattaaga tgttcacaaa tcctttatct acatgaagtt tgggagagat gttatcttta 17821 atccatttat atatggtttg aggggatgga tccaacttta tttgcttcaa cagttccttc 17881 tccaatttga ggagtgggaa taagaaactc agtccctttc cttccaaaat ctccaacatg 17941 cggtccttat tctgatcaat ttctgaagag acaaagccac ctgcatcatc taatagttca 18001 ttttaccaag ttgtcctgtc cagagagcag agcttcacaa atgatgtccc caagtatgta 18061 agatccatgt agcagaatag agaaccaacc cagcaaatga aaaaaactca acatacggat 18121 caaatgaaag tagttaaatt ataaatctct ctttataggt gagatctgtg gtaatgttta 18181 tcattatctg agcaggacaa tcagactgtc tgacctacat aaatccactc aaggtacctg 18241 aaatctctag atataatatt aaaaaaacaa aacaaacaag tcagcattct cttacctggg 18301 agcattttct gcatattgac cttgctttgt tgaaaaagtt ctgttaacca ttctcgatct 18361 tgtaatttag ctaactgctg aagacaaagt aggaagagag gaaaatgggt gccactttct 18421 agtggttgag ctagttctga aatgctcacc agctctgaaa tgatggcacg agctgcaaac 18481 tgtgctaaat aggatttcac caaagggatg tcaacctcca gtttgggaca ctggtccaat 18541 acattcagga aagccttgaa agaaatatac aacagtttat cagttttcga atttgagtgg 18601 taagagttct taccacacaa tcagtaaagt gtcctacctg catgaagttg tcacttgtgg 18661 ctatcccttc ctgtttgagt aaactgatca aagaacttgc tttttcttta tcttcatcgc 18721 ttctatctag tgacaggatg attactttgc ttaacatctc aggaagaaag tgtttaggag 18781 ccctcatttc tcttacacca ttgacagcct catttgcatt tccactattt agatattcag 18841 tcacaacagt ttcctgtgaa Raacacaagt atctttaatg tattctctat ctcaaataca 18901 ggctaattac actaaaatgg gatatttgaa acttacagtt agtttaagga gttcttcctt 18961 tgacggtggt ggctttttgc tggtcttggc aggcttttcc tggataagcg gtggattagt 19021 tttgagacca agctgaggtg tctaaaaaac aagcaatgac agactttttt taaaaagagg 19081 actatgaaat tagggggaag aacacactaa atttagaaaa aagtcttcag atatctttag 19141 aaaatgctgt cctactatgg tctgtacctg tcccagaggt ggtgtttgag tgcgtggtgg 19201 ttgtgcacta ggaggaatca tagttatctg gggctgaagc tttggcactt gatttttatt 19261 cattaggaac gactgagcag gcctcaggct aatctggaat tgaaaacaaa atatatctaa 19321 attaacaaca tgcagttggc gaacatatta aatacaacat tctaaaatcc tatacagtga 19381 cagaatctag ggaaacatta agctttttga. aaaactaaag aaggtactcc acattaacag 19441 gtttaatttt tggcaaaaaa tttaaagatc tgatgcatac agtagtaaga tactattata 19501 aatcttacat tctcttagaa ttagcatgac taaaatattc aaataaaaaa ctgcaaattt 19561 aactacagtt tagaaaatgc cctgttttat ccttagttaa atcaccctta caaagaaaga 19621 aaccacaata ttttgacaac cagttttctt gctctaacag actttaggag acttgccctc 19681 atatctcata atcttcRctc acaggacgct ggacattcaa agaaagaaaa agaagtatag 19741 aaaagagaga aaaaogtcaa gaactccagc ataaagtcct cttaataacg cgtcttttta 19801 taatcatcgg gcaataaatt tctgaatgga caaactatgg tatataagta acataggcaa 19861 atgtacctca tctgcattaa gctgtccttt cttagaaaac cgaggtggca tatccttcga 19921 ctgtccttgc agctgggata agagtccctg actctggtta tggtagagct ggcttagccc 19981 ctatttcaga aaaggagaaa gaaagtctag ataaaaaggg gtccacaaat tatggtaatc 20041 aagtaccaaa gggatgagcc aagccataaa gttagtttaa ctgaatttgc ccagagaaag 20101 taaaagatga aacagggaag aataaaaatc taacctatca aataaagtga tgtgatttta 20161 ctaatacttt actaatctta aggataaaca tttcagtttg aaataaatgt tgcagataag 20221 gtttagaaaa catgcacact caaatattac ttacctggct tttcataaac ttgcctccca 20281 tctctccaaa ctgcgattgt gtgggaggca tgatgtgtcc cccatggcca ttgaagagtt 20341 gatttgaaog atgacgtccc atggtgggtg aaaatctatc ctggataact cctggaccag 20401 taccaattcc gctaccttaa aatacatWta cggacaactc tcaaaactaa agttaactga 20461 tttttcagct taacgcaacc attgtttttt caaaattacc tggcatttgt ccaaacatat 20521 cagcaagtcc tccaagtggg tccctatcca ttttcatcct gggtggcatg aacggtccct 20581 ccagaaagaa gtcacttctc atcccttgag ccataggagc aggaataaac acccctagat 20641 cctttagaaa tgaagtgaat atgcactttt tgtctctgga cactatttca cttaaaacta 20701 aaattcttgc aactaggggg ggaaacctag aatattaaac cataatttat gttatttctg 20761 taaataactt cttccaaaaa tggcagacaa ggctgggcat gatggctcac atctgtaatc 20821 ccccgacttt gggaggccca agccttggtt tgcatgaggt caggagttca agacaagcct 20881 ggccaacatg gtggaaccct gtctctacta aaaatacaaa aaattagcgg ggtgtggtgg 20941 cgcacgccta tagtcccagc tactggggag gctgaagcag gagaatcact tgaacctggg 21001 aggcagaggc tgcagtgaat cgagaatgcg ccactgcact ccagcctggg tgacagtgcg 21061 aaactccgtc tcaaaaaata aaaaaataaa agtggaagac gagacactaa aaacattaag 21121 ctccaccact aagatgagac agacccctca agcgtttggg gtgggtgagg aggaaaccca 21181 ttctattcta cacacacaga gtctatgtga caaacaaaac aaaacccaat cttactttta 21241 ctgcatcttg acgaatttga ttgatcgtct ttggtccatt gtcaagaaaa gccttgcgag 21301 gaacccaatg gtgttctcgc aactctacgg tatcctttaa ttgaaaaata attttatttt 21361 aatattccta aaccaaaaac tcagcttacY aacaaattta aagaaaccag tattacctgc 21421 agcaggaaac gaatccttgc tggcaattcc ttacttaaca tcaaggagca cattcgggca 21481 aagtactgat ccattaagga ctgataagag aagaatacat tcattggaag agctaaagca 21541 aatgtgttca atttacagct ttaagacttc taaaattata acccagttaa tggctaaata 21601 tggcaatccc ttatgatgtc acaaaaatca atagcttgat ttaaagacaa actacttgta 21661 ctactttcat cagctacaca cgtaccttgg ctcgttcatg gtctaatcta ggtcccactg 21721 tcctcattat ctgacagagg cactccaaat cctctcccat atctttgagt tggactctct 21781 tcttcttttc caaaagctac aagaataaaa ggccatggtg acaaagtttt agttactctg 21841 gtttaggcgt agtactttct ttccctttat gtttgcactg actcattcac agttcctaca 21901 gaatctagta tagggctttc taccagtctg gttgatcagt tctaactcta ctttgtcaaa 21961 cacaccacgt atttcaaatt attctgttta gtaaattttg ttgcacatct gtatttaact 22021 agtcaacctc cctcttagat gaataattga ctcatttcct ccaaacgact gactacattc 22081 gcctaacttc cctgtcacac ttactgtttt gatgcaetta tgaaggatag attcgtgaat 22141 aagatcaagc ttgccaagct ctccaatgaa tttgatgttt cccaacatct tgatcttagc 22201 aatggctctc tgttcctcct cctcggggag gaggggattt tcacgcttat catagactga 22261 aaaagatacc aatgaagtaa gccaacattc agaattaagc tgaaaatata cagtagtact 22321 tattatcagc tataagtctt accatcaaca tttctagttc ggttttcaaa ttcatcttgt 22381 aatttggaaa ttaggaggcg tctgaatgtc tggaaaagaa gacattgtca tgctttatta 22441 aggaaatttt tcaagtcaac tttaaaacaa gcaaacaaaa actaccactt acggtgcttt 22501 gcttctgtcc tggttgaccc tctgctgctg ggccatcaaa gtttggtgca tcttctgcca 22561 atcgcagaca tagctgagca tacagtgagc tatactttgg ctcttctagg gctttgtcca 22621 caatctacag aaaatgtcat tgcttaaact aaatatgaaa acttctccaa gaacccttcc 22681 tttaggaaaa atacaaccac ctaaatgtta gctattacag tctaccaaaa atgtccagtt 22741 atacagattt catctagtca catccatctc ctgggagtca gaaaatgcca tggatatcaa 22801 aactttcaag tctacataaa ctgtcataca atgcatttcc aagacctaaa tacggtgttt 22861 tccacaaaag aaaaagaaca gcttgctaag cactcccatt tacctcttca accaYaccat 22921 gaacttaaca tttacctctt caatctaatg ctactaaagt cagtggttct ttttaatcac 22981 catcagtatt caaaaatacR tacctatcta actcacacct aagggtttta agtagtaatc 23041 caagtgtaaa aaaacacaac ttgagtttgt taaacagttc cctctccctt ttgagttaag 23101 ccaatattta aaacttacca gcagtatgac ccctttaagg atgagtttag actctacacc 23161 cacattgagg agctcaaggc atagcttgtc aaacttttca ggagtaagct tatttagtat 23221 gctggagaaa aaggaattac attttaagtg ttagctaata cacagaattt gaattgaaaa 23281 actgctttta aattatactg atttttcttc taacttgctc cctttaaaaa atcaagacat 23341 gttttcttac tcatctaaaa ccaaagggat gctgaaataa acctgttatt ttaattacaa 23401 tgatttgaat tggactgggg ggtccccagc tgtttgacaa gaatcctttc tcactttctc 23461 aaggttagag cgcaaagatc tcattatcaa ggctagacca tgaactaaga ccattatatt 23521 ccctgcctca ctggcttaaa taacatagca cttcccttag tcaagggaaa tgctagcaYg 23581 acaggattat ggattgcaat ccaatggctg aaagcaacgg gaagccccaa aatatgacgt 23641 gctgttcttc agttcaagat acattttttt tttttgagac acagtcttgc tctgcaccca 23701 ggc±ggagtg cagtggcgtg atctcggctc actgcaacct ccacctgtgg ggtattcaag 23761 tgattctcct gcctcagcct ctctagtagc tgggactaca ggcgcctgcc actacgtccg 23821 gctaattttt gtatttttag tagagatggg gtttcaacat gttggccagg ctggtctcaa 23881 actcctgacc tcaagtgatc tgcccacctc ggcctcccaa agtgctggga ttacaggcgt 23941 gagccacagt gcctggccag ttcaagatat ttttaaaaat tgctaccatg aggattcatt 24O01 aaaacataca tactctgggc atgaaccttg ccttcttagt aatacagcac acacaccaaa 24061 cacagctaat ccacacttcc catcttttag taaaacagac cttgaaactt accctcttac 24121 tttcctgaag attgcatcat gtcgttcttt ttcgtttgcg gagttgtttg ctgcggagtt 24181 gtcatctcgt ctagtgcttc gtgcaggaat ccatttctga gcgttttgoc ctggggtttt 24241 ccccaggaac tcgctgatta ataaaaatca gcaaaaacac ttattgtcac acaccaaatg 24301 ttaaacatca taaattctct tacatagaaa aaagtaattt aggctttctc gacttcccct 24361 ccaagaaagc caactctgga aattagtgct tctggaacag tagtgtgcat cagaatcacc 24421 tgaagggctt gttaatacag attgctgggc ccacccagtt tctgctttca ctggtttggg 24481 gtggggccta agaatttgca tgtctagtaa atattcccag tatcaacgct gtggaaccac 24541 attttgaaaa ttaacatttt ttttaagaga tggggtcttg ctgtcttgcc caggctgatc 24601 tcaaactctt gggttcaagc gaccctccca cctttgcctc ccaaagttgt tgttgggatt 24661 acaggtgtga gccactgtac cggctgccaa taaacacttt ctaatgtttt attgaccatg 24721 ttgagtgcgt actactttac taataacaat cagtaggaat aatagctact gatttcagaa 24781 aaacacatta gtaaaaataa cccaaagaat aaggaaaaaa ataacagctt gagagtctca 24841 actcacttag aaaatttggc taaggaataa tcaggaactg atattctgta tttaggatac 24901 ccaacagaaa ccacgcccct taagattagg agtcttgatg gctattgcct taattatacc 24961 gtcacatggg aaagactttt aatctgttaa ataaagctca ctgttttttt acatgtttac 25021 cacacctgtt gccagcagtc ttgggatagt gctgaggtgc acccctactt cctcctccgc 25081 ccgaagaagc actatttaaa agaaaaaaat tgtttactgt atcccaacta tgtctcactc 25141 aaaaagaata agcatctatt ttgtgttttg ctttgcttgt agagatgggg gtctcgctat 25201 tttgcccaga ctggagccag gcctgtattt tagtgcttgt atattatgct acaaatgaag 25261 actgaactcg gacccaaagg aaaggcaaat aattgatttt atttattctt cagatggcag 25321 ttcttagaag gctgtcaatg aaaacttaag aacttttcaa atgaaaattg cagcccatta 25381 agtcggactt atttgctgtg ttaactactt tttgagactg gccttttcaa aaggattccc 25441 caaaataaat ctacaagtac ctgaaacgag aagcaccccc ttctgcaatc gcactctcca 25501 ctttggcggc ttgacaacga agaatcttca aaagaataat attaatagat ggggtgggga 25561 ggggagggga caggagaaat gaaatacctg gaacgagaaa gagcaccaaa attagacact 25621 gctaacatac agatctataa gccttcattc aattacaacg tatttcagat cotggcactg 25681 tcactgcatt gcagatctgt aagactaacc taaaatgtac tcaaaacact gacaattaca 25741 ttttgtttag ccacctggaa attccccggt gttcaaggat gcaaagagac ttcgtagaac 25801 acaagagcat tttaaacggc tcagaacgaa tcttttgaaa aagccacatt ctactatctt 25861 taaaactgag cactgagatc aatagaaaag tctaactaca gacacgagca acatcacgtg 25921 gaaaatgtct gccctaggaa tttttactgc cttgacgagg ccagcgacta gatgaggtct 25981 ctccgaaagc tcttcagcag ttttcccctg tccacccttt cgcctcctcc ccgtggagag 26041 ctcgtggaaa gacgcgcgag agggggccgg gtgtacagga ctagcacttg caggcggaag 26101 accagggcca caacatggca gcaggaacct ccgccccgtt tttcccttcc tgggaacaaa 26161 agagcggagc attcctccca cccaggcgca agttagggaa gtgcttccga caacctcccc 26221 gcgaggcccg ggtcgctcga cggggaggag cagctgaggc cacccccgcc agcccggcgc 26281 ccagctcttt gttctccaag caggaaggcg gcctcctgcc cacccgccgc ctccaagcgg 26341 gccccctcct gcaccataaa tccccccggg actgacaacc gcctcgccac ggcctcctct 26401 gctgacaaaa ggggcagaaa tcatcactct ctctttcctc cccgacgaag ggcagcccct 26461 gccgactcca ggtcctacac acctccccgc cgggaggcca ggctccggga cgcctgcggt 26521 tccctggtcc cgcgccaacg gcctggcctt ccctgccggc ccgcgtgcct cccgccacgg 26581 cgctagcggt ccgagccacg ctccctcgcc gtccgagcac agccgtgcot cggtccgcca 26641 cggcctcgtc cctgcaggcg tcggccatcc ggccatgacc gcacggcggc ctggccaaca 26701 ctgacgtttt ccttctactc cgtcagcaac aggaagagag aacaaaagcc aagactttcc 26761 aggtatctga agcgcagagg aaatgctaaa aaagggtcgc cccacccggc tccgcctgcg 26821 gccgccattt tgtaccactc gagaagaagc gaccagggac ggcggccatt ttagagcgct 26881 ccactcggcg gcggcagcgg ctcaactcac cttcaccgag aactcagcag ctgccaccgc 26941 agctgcctcc tcaggatccg gtcgtcgggg atagggaagg gaggggaaag gggaacggaa 27001 aacaaaaaaa agggggaggg aagggggagg aaggagtcgg ggacggcctc aaactcagct 27061 cagaggagtc gctgctgcag ccgccactcg gtacccgctg ccacctccat agagctccga 27121 ctcactgctg gcgctaaggc gtgtctgaag ccgaacttat cactcttggg gcagccgaac 27181 ccaccagagt ctccccgaat ggctccttcg ccgcccaatc agcggcccgg ttgccgtctg 27241 ccaccaatcc gcgcagggca gcgaggagga gccacagggc tgagctcggt tgcggcgcag 27301 ccccgccgca gtgcgcaaag ccatattcgc gaagtctctg aggctgagcY agtggcgtaa 27361 ggggcgccga gcgctgtcga gatgagggtt gcgtgcgtaa agccggagag cccttttgag 27421 tctgcgttgg cgtggctgct gcttcttgct ccagtccctt tgttcactga gtccatatgc 27481 catgctccag ttgtatcatc cccttttccc tcgacctcgt tttctcaccg ggaatatggg 27541 aagaaaacgc acccttacct cccccgaacc ctgtgcgtgg cgagtgagca ttgcttttct 27601 tggcgcccct tggagctgtg gctgccctcg cgtgcctggc ctctcccggg gctgRgccct 27661 tcgggttgag gcctggagcc cccgggcgca gcgccgggac actacccggc tccaggtect 27721 cggcttcggc agccttaggg aacccagaaa gtagtgggga ggaggcgaga cgtgcgcccg 27781 gatgccaaag gggagcttca ttcagctcct tattggccca ccccctgcag agtgaatgag 27841 aaagtgatga aaggaagggg ttgattttct tcgaaccgca cagaagaagc tgcttttocc 27901 ataggaatgt ccggctggcg gtcaccgagg aaaacaccct gtgtgtcaga cttccgcggg 27961 tgtttggagg atttcgaatt gctagctcct gttttttttt gtKttttgtt tgtttaagtg 28021 cacgttaaac attgtcagtt gtgtattttc attttattta aggttcacca taagaaatag 28081 gattaagctt ttcaaagccg gcaagttgaa ctatttatac ttaccaggta atgtattgat 28141 gagtacctta ttccatcgtt tgcgacattg tagctatact aaaatggagt catacttcca 28201 taaacttaaa caacaaaaat gtccccatct ccattttaac atgtagtact tttacagtgt 28261 atagtcaaag gcaagaatgt gtgtgtttta acatgaatga cttttaaagt gttcagtaag 28321 aggcaggatt ttcaaagacc caaacttaac ctttgatNtg tcaaaacagc tcttggtatt 28381 agagcacctg gtccttaata caattttccg gaaaattgca gtttttccta cgacatttaa 28441 atgtaataga aggctgtggt gtggctctga aggtttttaa cacaattcca acatctgtag 28501 atctttgcta tagaatagtc accattccct actttactgt tactacactt attgctatta 28561 catcaatttt acttgaactt taaaacttgg aagagatatt ctaaaaaaaa aaaaaaacta 28621 ttttggggtg gtggtggtgg tgcaagtttt gttttaaata caagaggttt cactttgtat 28681 ttctttggac ccttctagct tcatgataac acgagaataa tgtttcttta taatttctgt 28741 agggctttaa ggtttggaaa aatgcattag tatatgtgat atttttacat aactggttta 28801 cattccattt atctgataat gaacgaatac attagtttac taagaagagt agtattcaaa 28861 aactattgtc tagacttcaa agagaatatt cacctagccg taaaagtcgg atgttcttat 28921 aattaagaca cttaaaattc agtaattaaa aatttaaaaa aggttttact taatatttta 28981 tttaatcttt gctaattggg aacccttttg gtatgggctt tgcagatatg agtttatgtg 29041 agaaattgac ctggaaggga ataacctaag gtagaaaaag taaaaatatt gataaaacaa 29101 tctttcaatt acctttctct cacttaaata gaaagatttg aagttgaaat cgtacctgca 29161 aagcccattg cagaagggtt cacaattagc aaagattaaa taaaaacatt aagtaaaacc 29221 tttagaaaaa aaaatttttt tttgagacag agtctcactt tgtcactcag gctggagtgt 29281 agtggtgtga tctctgcaca ctgcagcctc cacctcctgg gttcaagcag ttctcgtgcc 29341 tcagcctcct gagtagctgg gattacaagc atgtgccacc acgcccagct aatttttgta 29401 tttctacttg agatggggtt tcaccatgtt gcccagactg gtctcaaact cctgacctca 29461 agtgatccac ccgtctgggc ctcccaaaat actgggatta caggtgtgag ccactgtgcc 29521 cagtgtaaaa aatttttaat tattgaattt taagtgtctt aattataaga acatctagct 29581 tttagggcta gatgaatata ctctttgaag tctagacaat agtttttttt caaatcgaaa 29641 tatatttaag tgagggaaat aaacattgaa actttctaaa tgtttccatc acgtcatgga 29701 tatatgaaaa ttcagcagca cttttggagg ccaagctggg aggattcttt gagcccagga 29761 gttggagacc aatctgggca acatagggag acccccccat ctctaaaatt aaaaattaat 29821 ccagatgtgg tgacatgcat ctgtagtccc agctacttgg gaggctgaca tgggcgaatc 29881 ccttaagccc aggactttga ggctgcacta agccatggtc acgccactgc actccagcca 29941 gggcagtaga gtgagatcct gtctcaaaaa aaataaaatg ctaggcatgg tggctgatgc 30001 ctRcaatccc agctcttttg gagactgaag caggtgggta gcttgagctc aggagtttga 30061 gactagcctg ggcaacgtgg tgaaaacctg tctctacaaa aaatacaaaa attagcctgt 30121 gtcccacatg cctgtagtac cagctacttg ggaggctgag gcagtaggat ggcttgagcc 30181 ctggaggtcg aggctgaagt gagccatgat catgtcactg cactccagcc tgggtaacag 30241 agcgaaatcc tatcttaaac acacacacac acacagagtc attgtctgga atttagcttt 30301 tagttcattg aaaattgaat tttaaatata cccacttaag tctgctagtt ttccactgct 30361 agttttatca gttttctcta agtcctgact aacttgttaa ctcatatatt tttgccttat 30421 tttaactaat catgtcaagt gctggttact attctaacac atactgtttt ggaagcatct 30481 accatcctct ctgtgcttat gaattcccta atcatttacc ttcagcccag atctctcact 30541 ttacatccag ttctgaattt ccaacagcct tttgctcaga gatgcaaact tgaagccata 30601 gtttgagcca cagtagtttt aaacacttga atttgatatt cacacaaatt tttgcataca 30661 aatccagatt tccatctttt catgaaaaat cttaaaatat ggcaatactg ggcctgaaat 30721 tctcataggg caacattcaa gcataactaa gtagaactac cttctctcga tgttttgatt 30781 tctccacagt tgcatctgac ttgattcact catttatgtt cccatctggc ctctatagcc 30841 attttgcttt tttgagttgt ttgctcaaat tcaacagatt ccatatgtaa actggtcatc 30901 ttcctatgag gaaaagtagt tagaccagtt gaggtcaaat gtcttctcta ccatttactg 30961 tgtaactttg ggcaaataat ttaattactc ttactcagtt tctaaaactg taaaatcgga 31021 atgatagtag tatttatatg gtggttgtaa agattaaatg agataatgta tgtaaggcac 31081 gtaggttaga ccccgactta gaatttaatg ttagtttcca tattctcaat aatattgatt 31141 aaccagctgt ttcacaacta ctttaatttt gttaaggagt ctattattct tctatgctag 31201 aaacttgacc atattttttt tccttttgct cagatttaac attcaatcac ttactgaatc 31261 ctggtgctcc ttctctccaa atgtttcttg cattcatctt cctccctaca acatcattgc 31321 atgtatgcta atccagccct tactaaactt ttctcctgga ttattgcaaa attctagttg 31381 atcttctgta gtctttccct actagtctgt atattcctgt tagtctttct taaaatacct 31441 tttttcagcc aggcgcggtg gctcatgcct gtaatcccag cactttggga ggctgaggca 31501 ggcagattac aaggtcagga gttatagacc accctggcca acatggtgaa accctgtctc 31561 tactaaaaat acaaaaaatt ggccagacgt tgtggtgcgc acctgtaatc ctagctactc 31621 gggaggctga ggcaggagaa tcgcttgaac ccaggaggtg gaggttgcag tgagttgaaa 31681 tcatgccatt gtactccagc ctgggcgaca gagcaagact ccgtcttgga aaaaacaaaa 31741 aaaacaaaaa aactaaacta aattttaaca tattattacc atgcttaaga atcttagtgc 31801 ttcactattt tctacatgag ttgatctcaa ccttggctgc acattagaat cacctggaga 31861 acttttaaat atctcagtgt ccaggctgca cctaagacca gataaatctg aatctttggt 31921 agtgagatct agccatcagt agcttttaaa gctctctagg tgattccagt gtgcagtcaa 31981 ggtttcagag ccactgtagc aggtcagagc attatagaaa attacaacat ttatagctga 32041 agcaaatccc aggaaaagga aactggggtt taaaaaagat aaggggagtt tctccaagta 32101 gggaaacagt tattagaacc caggcatccc agtttatatg cttttacctg gctttcaagc 32161 cctttatatt ctgtccctac cctacctttt ctgttggcct tattttttgc ctctcccaaa 32221 cacccagtct tctcttatgc agccagttag gctggtattg ctgtccctaa aaattcagtt 32281 ctaatacttc attgcttgca attttgaggg taccctcatt tatcccctct actgattcat 32341 tcctgaagta caaaatgaat atataagtgc cctactcaaa aacctcaata gctctcctct 32401 aacaataata tctgaacttc ttagtttggc ataaaaggac ctttatcatc tggcttcaga 32461 ctactttcct attcctaggt gtatc^'actcc ttcattccta cagttatccc taatctggtt 32521 ctatggtaot caaattttgc tccattgtta agatatattt tggagataaa gccattaaaa 32581 cttctgatgg attgaatatg gaaaatgaga gaagaatcaa gaatgattca tagattttgg 32641 ccttaagcaa ctggcaggta gtaaacaatg gaggaaaaac tattctgaat atattaaact 32701 tgaaatgcct attagatatt caaagggaca tttcaatagg caattcaaaa tagatgatat 32761 gcatctatag cttgcatggg aggaagggtg gatcagagat ggagatatga ccaataccag 32821 tgttctgtat tacatgtgac tacaatttgg aggtctttgt tcacttggca gaaaaagaaa 32881 taaagttatt gagtttatat gcataatacc tgtttccaag gatctcacaa tctagacaaa 32941 agataaatac accaattata taaaaggcag ggaagggtgg aatcagtgct aaaccaaaga 33001 taccataagc tttcataaag ggaataatag ggagatgagg ctgtggccat tcttccttaa 33061 gtgccagaat gatgatttgg gacttgacta cacagacaaa gttcttgaac tgatcagaac 33121 tctgatcagt tttagtgtaa agctgatcag ttttaattga tccatgtact gttttagaaa 33181 aactatcctt acagtttgtg tagaatggat tgaactgggg tgtggtggtt cacgcctgta 33241 atcccaacac tttgggagga cgaggtgtgt ggatttcttc agcccaggag ttcaagacca 33301 gcctggataa tatggtgaaa ccccgtttct ataaaaaaat acaaaaataa gtcagggtgt 33361 ggtggtgcac ctgtggtccc agccactcag aaggctgaga tgggaggatc gcttgagccc 33421 aggaggagga agttgcagtg agctgtgatt acgccactac actacagtct gggcaacaga 33481 gttacaccct gtctcaaaaa aaaaaaaaaa aaagaaaaga aaaggagggc aaacttggag 33541 atagggagat cattagttag aaggctaaat aatttattat ttttatgggc ttatttttat 33601 ctcccttcca aaatcataag gttcttgata tcaagtactt ctcttgtatt accaatagaa 33661 ttatttacat acacaagagc tgagaaaata tttgtgcata ttatcttgct gccattttat 33721 ttatttYttc tctagaattt cctactgcct ttaccaattc agctcagtct ttgctgggtt 33781 ctcctactct gtttgaccta taaatattga agtaccacca aggatttatt ctgggtcttt 33841 tcttccctct gaatactttt ctccgaggta attcatcaat cctatgactt taaatcccat 33901 ttatatgata aaaatttcca aattcatgtc tctatctctt atctaccttt ccccccatgc 33961 aagctataga tgtatatcRt ctgtattgaa ttgcctactg aaatttcccc ctgaatatct 34021 aataggcatt tcaagtttaa catgttcaga atagtttttc tccattgttc accacggtca 34081 gttactaagg tcaaaaacct atgaatcgtt tttgattctt ctgtcccttc tatattcaat 34141 ccatcagaag ttctgttggc tctatctcca aaatatatct taaactggtc cacttctctt 34201 gatctacatt tctatcactt taatctaacc accattctcc ctagcctgga ttactgcaat 34261 agcctcctag aattcatccc tcaacttcRt ctcttgctgt ccaatacatt ctctacccag 34321 aaccagtaat ctttaaaaaa tgtaaatcag ataatgccac ttccatgcct aaaaccctct 34381 aatcatggat ataYataata tccacaataa aatccaaact ccttagcgtg gcctatatga 34441 ccttacatga tctggccctt gactatcact ctgacttcaa ctcctactat gttccctttg 34501 atctctattc agtcacactg gcccctttct acaaatatgt taagctcatg caaagctttc 34561 tattcctcaa gtatgcaaaa actatggcta tttctttttt ttaagttcca ctgcccaaaa 34621 gctc'ttatcc caatttttta cagaatggct ttttgtgtgt gtataattta gatttcagct 34681 tgaatggcca cctctctaga aaagccttcc ctgatcatcc catgtaatgt tgtttcctct 34741 tctagatact ctattacatt tcccctctta gttttttttt gtttttgtct tttccatagt 34801 ccttcttact atctgaaatg attttttgca ttcattcttg tgtcttgtot gctcactgca 34861 ttaggatgtt aagctgaatg gcagcaggaa ctttatctgt catgttgtat tccacagatt 34921 ttttaaaaag atgactggct tctggcaggg cacagtagct catgcttgta atcccagcag 34981 tttgggaggc tgcggcaggt ggctcacttg agaccaggag tttgagacca gcttggccaa 35041 catggcaaaa ccccatctat actaaaaaat acaaaaatta gctgggtgtg gtggcacaca 35101 cctgtaatcc aagctacttg ggaggctgag gcatgagaat tgcttgagtg cgggaggtgg 35161 aggttgcagt gagccaaggt tgcacagctg cactccagtc tgggcaatag agcaaagctg 35221 tgtctcaaaa acaaaacaaa acaaaaacac acacaaaaaa cttcacatta aaaagatgac 35281 tagattctgg atagggaatg tattggacag caagagataa agagcttaga atagttccta 35341 gcatatacta ggcatcatta aatatttatt gaatacagga atatacatta tctcaattga 35401 ggctcactac aaactRtttg gaggaagtag agatgtatta tttcccccac tatatatatt 35461 gggaaatgga aagtttggtg acttttctaa tgcaattcgt taatatgtgg cagcatctca 35521 tactttccca ggtacatcaa gctcccccac cccacagcaa catgaatagc cataatggga 35581 atattccttt cttatcactt ttgcatgaat aaggtgcttg_. cattagtttc ctttggctgc 35641 cataacaaat tgccacaaac ttggtggctt aήaacaaccc aaattaattt tctcacagtt 35701 ctggaggtca gaagtcaaat caaggcattg gcaagggtgc actttctagg gaggcgctag 35761 gggagaatcc aactcttgcc tcttctagct tctggtggct gttggcatgc ttggcttgtg 35821 gccacatctc tctgctctgt cttcacattg cctttctgtg tgtgtgtgtg ttgtgtacat 35881 tccttggctg tggccacatc tctgctgtct tcacattgcc tttctctgtg tgtgtctgtg 35941 tgtgtgttgt gcatccccaa aacccctctg cctctctaag gatacatgtg attgtaccca 36001 gataatccaa gctaagcatc tcctcttaag acccttaatt taattacatt atttgccata 36061 taaagtagta ttcccacatt acagggatta tgacatgggc atatcttttc gggggtactc 36121 atcaattcaa cccactacag tgctcatact attttactgc agtactaaat tctcagaact 36181 ctatctaatg ggccagtctc tttactgttt tactgcagaa ctaaattctc agaactctgt 36241 ctaatggRcc agtctcttta tatggctcat cattcattca ttcatttaac aaatatttag 36301 tgagcaccta atacatgctg tgcactgcta gaaatagggt atatattgat aaacaatagt 36361 aagcacttta tgtgtggggt gaaagagggt gttactaata attacattgg gatagctgac 36421 ataaaccagg actataccag gcaaaccagS tcctgtgacc accttactta tgatgcatgt 36481 tgttaggcca ggataatgaa ctagaccaag accttgcctg ctagtatttc tccctttgcc 36541 atttttcttt tctaagtcaa acatagtgtt tagtttttaa agtttttaaa tgaatagcct 36601 gcatagtagc atgattgaag tgattttact ggacttcatc aatatgtaga tcagttttac 36661 ctttggatat tggact.tgta acctgggagt agaaggccca ttccagagca aaattttcta 36721 tactagatag gctagagaca cacttgagcc ttaagcaggg gaggacaact ggtgctttta 36781 gttcactgta cagttgactc ttgaacaaca tgggtttgaa ctgcatgagt acactaataa 36841 gtggattttc ttccacatct gctactcttg agacagctcc aatgaggtct ttgacagcaa 36901 aaccaacccc tcctcttctt tctccactgt agcctactca gtgtgatgac tacaaggata 36961 aagattttta tgatgatcca cttccactta gcaaacagta aatacatttc tcttatgact 37021 ttcttgttaa cattttctta aatttttttt tggctgggag cagtgactca cacctataat 37081 cctagcactt tggaaagcca aggcaggaag atcacttgag ctcaggaatt caagactagc 37141 ctgagtaaca tagtgagacc ctgtctctac gaaaaaaata aaataaaata aaaattagct 37201 gggtgtagtg gcgtgcatct gtagtcccag ctacttggga ggctgaggtg ggaggatcac 37261 ttgagtccag gaggttgagg ctgtggtgag ccatgtggtg agatcgtgcc actgtactcc 37321 agcctgggtg acagagcgag accttgtttc aaaaaaaaca aaaatttttt ttttaccttt 37381 tttttaagag acggactctt actattttgc ccaggctgtt ctcgaactcc tggcctaaag 37441 caatcctccc gccttagcct cccaaagtgt tggggtaaca ggtgtgagcc atcacactcg 37501 gcccatttcc ttttttcttg ctttattgtt aaaaaataca gcatataata catataacat 37561 acaaaatatg tgttaataga tggtttatca gtaaagtcaa cagtaggcta ttagtagtta 37621 agtgtttggg aagccaaaag ttatacgtgg atttttgact gtgcggtgag ggatgtgttg 37681 atgaccccta acctccacat tgttcaaggg Ycaactatat ttcataattc atttaattta 37741 gaaaaattaa agttagagaa tgggtgatgt tcatctgtaa cactcctgaa aggtgaccaa 37801 gattactggc agcaacttaa ctgagataaa caggcttcaa gttatgtgca atacccagtg 37861 ttccttgctt gctaaagtaa taaaagcata tatgaatgca aggtactgag aatattatta 37921 tagggataat attgcatcca ctctcattga ttgattgatt gattgagacg acgtcttgct 37981 ttgtcgccca gcctggagtg gagaggcgYg atcttggcac actgcaacct ctgcctcccg 38041 gtttcaagca atcctcctgt ctcagcctcc tgagtagctg agattacaga catacgccac 38101 cacgcccagc taattgtttt atatttttag tacagatggg gtttcattat gttggccagg 38161 ctgatctgga actcctgggc tcaagtgatc tgcccgcctc agcctcccaa agagctggga 38221 ttaaaggtgt gagccactgt gcctggccac tttaatttat taataaaatc atttgcaaat 38281 tttgtttatt cataattttt attagtgaca atatttattt ataatataac cccatggtgg 38341 ctcatcatac ctgtaatccc agcactttca gaggctgagg cggctggatc acttgaggtc 38401 aggagtttga gaccagcctg gccaacatgg tgaaaccctg tctctactag aaataaaaaa 38461 tgtgtagtcc agctactcag gaagctgagg cacaagaact gcttgaaccc aggaggtgga 38521 ggtttcagtg agccgagatc gcaccactgc actccagcct gggtaacaga gcgagaccct 38581 gtctcaaaat aataataata ataataataa taataattta taaacaaatg taatcaaaat 38641 gctaaaacaa cacagttaaa gaatcactSt tctagaaaat gcaaattatt tacctggaat 38701 agagaaatgt aagtgcaata aaccaagttt ttcatcttgt ttcaaggggc agaaagcaca 38761 tgtccagagc acaggtttaa ttcattaaca attgtttata gaatgatcaa gtttacattt 38821 taaaggatgc ttccatatgc aggggaaata tctttatttc cattttatga ctgaggtttg 38881 gagaaactaa cttacctcta tctttttctt tccctttttt tttttttttt tttttagaga 38941 caaggccttg ctctgttaca caggctggag tgcagtggtg tgatcatagc tcactacaac 39001 cttgaactcc tgggctcaaa gaatcctccg gcctcagcct cccaagtagc taggactaca 39061 ggcacatatt accatgcctg actactttta aaactttttt tttcctaaga gatagggtct 39121 agctatgttg cccaggttag tcttgaactc ctcacctcag cctcccaaag tgctgggatt 39181 acaggtgtaa tcccaccaca cccagcccca tatctgtttt ttaaactttt tttccagtga 39241 tctttccttg actttatact ttctctctta atagagcaca gagtgagcag aagtaaacaa 39301 aatagacact agaaaaacac agaaaagatc aatgaaacta agtggtggct tttataaaag 39361 ctaaaaaaat caataaacct ttaactagac tagcagagaa aaagagaaga cgtgaataaa 39421 atcagaaatg agaaaggaga cattacaatt gatacaacag aaatagaaaa gatcatgagg 39481 ctactctgaa caattataac caacaaattg gattaactag aagaaatgga taatttcctt 39541 gacacataaa acctaccaaa attgaattat ggagagaaag aaaatctgaa ttgaccaata 39601 acaggtagga gactgaatca gtagtaaaaa gtctctcatc aaagaaaagc ccaggaccac 39661 atggttgcac tggtgaatgc tacYaaacat ttagagaata ttccttgttt gaatattttt 39721 gattagtgat tcaaactgct tactcattat tggtctattc agattttcta tttttcatgg 39781 ttcagtcttc ctaggttgta tgtgtctagg aacttaacca tttcttctag gttatccagt 39841 ttgctggcat gtaattgttc atagtagtct cttaagatcc tttgtgtttc tgtggtaccc 39901 attgtaatgt ctcctctttc atttatagtt atttgagtct cctgtctttc ttagcctaga 39961 taatgctttg tcaattttcg ttttttaaaa aaaatttagt tcactgatct tttcttttgt 40021 ttttctagtc tctatttcac ttgtgctcta atctgtatta tttccttacc tctgcaaact 40081 tagtttgttc ttgtttatct agttccttca gatggaaagt tatttattta agatctttct 40141 ttttcttaat taggtattta ttgctgtcac tttccctctt gaactccttt tgctgcatct 40201 cataaatgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgWgatagat 40261 ctcactcttt tgcccaggct tgagtgcagt ggtgtgatct tggctcactg caacctccgc 40321 ctcccaggtt caagcaattc tcccacctca gcctcccaag tagctgggac tacaggtgcc 40381 tgccatcacg cccggctact ttttgtattt ttagtagaga tgggggtttc accatgttgg 40441 ccaggctagt cttgaactcc tgacctcgag tgatgtgcca gccttggcct cccaaaatgc 40501 tgagattaca ggcatgagcc actgcaccta gccacatccc ataaatttYg gtatgttgtg 40561 tttccatttt catttgtctt aagatatttc tgatttcttc tttgacccat tggttgttca 40621 ggagtgttaa ttccacatac ttgcaaattt tccaagtttt ctcctgttaa ttatttccag 40681 tttcatacca gtgtgtgaaa cctttccttg atgtagtaat agatataaat acacacatat 40741 gtataggttt ccatctatga ttcctggctc ataactccca gagtccttgt tacagtcttt 40801 tgttacaatg ttggtatgtt aggcctctct gactttctcc agtgttcctt tcacctgccc 40861 caaggcaggt ctgtaatctg attgtgggtc ataagaccac cattccagag agggtcccat 40921 cccataccct gggggaagga atgctaacgt cacgaagctt ctataaaaag ccaggatgac 40981 tggatttaga gagcttctgg atagctgaac acatgcaagt tcctggaggg cagctcgccc 41041 agggagggca tgggagttct gtgccccttc ccccatacct caccctgagc atctcttcat 41101 ctgtatcctt tgtaataaaa taaattggta aacatgtttc cctgagttct gtgagtcact 41161 atagccaatt aattgaaccc caagagggat tgtgggaacc ccaacttgaa gccagttgtc 41221 agaagttcca gaggccccag acctgtgact ggtgtctagc agtgttggga gagggaaaga 41281 ggacaatctt tggggggctg agcccttacc ctgtgggatc agacactatt tccaggtaga 41341 tagtgttgga attgaattgg aagacatcca gtcagtgttt gttgccaaac tgattgcttg 41401 cttgttgcta gggagaaatc cccacatagt ttggggtcac agaagtcttc tgtgctgatt 41461 gatggttctt gtgctggcat gagagcagag aaaaatcagt ttgagggttt ttccaaaaca 41521 cttggctata aaaacacact gttctggttg acagttacat tttattgtga ctgattagat 41581 aaaaggtgga gaaaaagaga acatttgtga accaacaagg aactcaaaac agaaagcaaa 41641 aatactacgg taaaacaatg tcacccaatg ctgtctcgga gactaatctt ggccctagag 41701 cactgcacat ctccattatc acatttctac agtggagcct agggcctcta actacttccc 41761 tcccttagaa gagaaagtgc ctgtcagaat atacaaatat acaaatatcc ctccattttg 41821 gggggagaat ggtaaaccaa acaaagaact gtcttttatt tttagttaat tcactgtatc 41881 tttttaaatt cttttttctg tctcaagcat catttttact agaacttcat gtttttttag 41941 atagtgttct tattcttttc tggacagaac attttaaaag tctgtgtctc ctttttgcat 42001 tctttcaccg tgatcacaag tcagatataa aatccagctg gatctggcta acaactgttg 42061 agaaacggac ttaaatgaag acatttcaat ggtaaattcg gtgatgtctt tctggttaca 42121 gctcaccttt ctacatttat gtgtagccca aaggcaaaca catatatact gacaaaccac 42181 caaaacaaaa ccagagtagg ggcagggggc aggggctcac gcctgtactc aaagggatac 42241 caagattgga ggaaggcttg agcccaggaa tttgaggcca gcctgggtaa catagcaaga 42301 ctccgtcttt acctatatat acacatgtat ttcatataaa agccggatgg gggtggaaca 42361 gagtcatcat ttcaaggtct gaagttatga tttctgagaa cttggagaac tgagaattta 42421 ggaaaaagat aaggtatgca ggaaaatagg aaaagatata attttgacaa tctgataagg 42481 gagacaaaga tgatcatgat tgatgtttac agcatgtgct tctgatcttt tgaagaagag 42541 agaatataag ataatattag aagtcaaagg gcaaatgttc tttcttgcat tcaagagtca 42601 atagaggcaa cagtaaagaa ctactttttt taagagatgg ggtctggcga tattgcccag 42661 cctggtcttg aactccaggg ctcaagcaat cccctcactt caacatccca aagtgctggg 42721 attacagacg tgagccacct catctggcct ataaatgatt atttaaataa aaagcYactc 42781 ctttgccatc attactatct ataaaccaaa tgttgctcat tgaagttagc attagttttt 42841 gcttcatctc tatgttcttc ccagcatagt gtgtgataca ttatggtcat tcaataaaca 42901 tttgttaaat tattagggtg gtagaagtga cgtgggtctc tctccaacaa gatcatgggt 42961 gaactcataa tcaataaaca ctaagtgctt accatctttt atacttttct aagtgtttta 43021 catgtataca ocaccacagg agatggttga tattactatt ctctctttac agacaaggaa 43081 gctgaggcac agagaaatga gtacatgaca gagttgggat ttgagactag gcagtatggg 43141 ttatagagcc tatatgctat actagcactc atacgatctc aagtcaatca gaaaaatgcc 43201 ccaggataac tccacaatac attaaaccag agctagatat ctgcccgacc caagaaccaa 43261 aaacaggaag tgtcacacta ggctggagag tcactataca cgtataaatt ggcagtgggc 43321 taatagtaag ccaggaatca ggtagggcct ctgctagcct gtagactggg gcaaactcac 43381 tcaccaatac ccaaagcttg tttagtggat atggtacagt agatttcaga agatcttaaa 43441 cccttcactg ggtgccttta tgctatgcaa aaattgcaga gagtgtaagc aagagcgaga 43501 ccaagaagag aaggaggaag agaaagatta aaagccaagg acaaaaatag gcatgggagg 43561 gagatggggg tgaggaacag atggatccag aaggccaagt tcagaaattg ataaatcaat 43621 tgtggtcacR ccatgcttca atcaagagaa ttttaaaact tccccctaac tccacccatc 43681 aaatcctgct cctaaaaagc ctgttccttt tgatcaaagg aataatataa atactgacaa 43741 gtaacaataa acgtggccta ttatttttat ttttcattta tcattttttt tagagacagc 43801 atctttctct gttgctcagg ttggagtgca atggcatgtt catagttcac tataccttca 43861 aactctcagg ctcaagggat cctccttcct cagccttctg agtagccagg gccacaggta 43921 cacgccacca cacccaaact gagaatatgc cttaaaaaaa acaaaaaaaa aaaccaaaaa 43981 aaacaagaaa aacacctctc tgttacggtc tgaaagcttg tgtctcccct aaattcatac 44041 gttgaaattc taacccccaa gctgactgta ttaagaaatg ggggccctta gtgggaggta 44101 attaaatcct gaggacagaa ccctcatcaa tgggattaat tatctcatga aagaggcccg 44161 aggtgcttgt ttgctccttc tgccatgtga gggtacatca agaaggcaca atttatgtat 44221 cagaacaagg gccctcatca gacactgaat ctgttggtgt tttttttttt ttttctttga 44281 gatggagtct cactctgtag cccaggctgg agtgcagtgg catgatcttg gctcactgca 44341 acctctacct cccaggttca agcgattctc ctgcttcagt ctcctgagca gctggcatta 44401 caggcgccca ccaccatgcc cagctaattt gttttgtatt ttttgtagag atggggtttc 44461 accatgttgg ccaggctggt ctcaactctt gacctcaagt gatccaccca cctcagcttc 44521 ccaaagtgct gggatatagg tgtgagccac acgcccagcc tgttggtgtt tttattttgg 44581 attttccagc ctccaaaact gccaaaacta aattactgca gcttaaaagc tacctgtttt 44641 atggtatttt gttatagcag cctgcacaga ctaatgcact ttcaaaccaa tcctttataa 44701 cagagactag actagcaggt ggagtgatat attgatatat gaaatttagc ttgactttaa 44761 ttaaaaattt ttaatttggc ataataatct ctccaaggga gattattagg aagaaatggt 44821 actgattaga caaaagtagt acacaatttt ttcctcactg actaaagatg cttgccattt 44881 tcactggtcc cactactaca gatagatgca cagaaagata aactgctaat aggcacaagg 44941 agaagagtaa gaacaacagt tcatccaaaa aaaaaaaaaa aaaaaaaaaa aaaggcccat 45001 catcccattc ctgtgcaatt tctcccagga cttacatacc tgagacctca gggaagaaag 45061 gggacaaggg aagagcacac taggtgagYg gcagcatcga gcaggatgtg gaacagacat 45121 catgagcctg ggcattaatc agtatgtgtc agaacagaaa gctatactga aaaaaataaa 45181 ttttattaaa taaatctgta tttttgaaat ttgaattttc ttttttgtag tttgtttaac 45241 ttccttttgg aatccataaY gttttaataa aactcacttt gaaaaaaatc tcaaatacac 45301 taacaaggga aatacatttt gttatttaca aatatgggcc agggagaaat gtgagacagt 45361 gtaacttggg gccaggcaca gagttattca tttattcaat aaatatttac tgaatgccta 45421 ctatgtgcca ggcattatgc taagatgctg gggatatacc tagtaatgaa gaaggaagaa 45481 attgtctctg cctacatgta actaaaagtc cttgggagaa gaaagatagt gaaaaataaa 45541 tccaaatgcg atgtgttatg aaagaggaag tataaagtgc catgagtatg agtggaaaga 45601 gcagttaaag gtgagcagag gagcagctct cagtggaaag aaatcaaaag ctaagataaa 45661 aaccagtaac actctggatg ggtgggaata gattgaaatc cataaagcca aagagatttg 45721 aattacttga cttcaaatag gttgaatatt tcagtaaggt aaggactcta ttctttttct 45781 ttctcggcct ttgtccagag agtgggaaaa gtttgaaaga tttggtctga atccaggttt 45841 taaaaattat ttttatggat tgattaatat tgttatRcac aacaggacta cagaatgtag 45901 gagatggggt aactgtcccc aaaagaggtc atagccttgt tggagagaca acatataaac 45961 atagaaaaaa ataaaagagg tctcttagga gactataaat gattaaagcc ttaatgaagg 46021 cagaggaaga agtttctatg ggcacaaata ataagtaatg atgtcttgct agagatgtcc 46081 taYtttagaa cttattggtg aattatgaca ttctaagata ggcctaagtg tacaagactt 46141 aggtctaaaa ttaggcatta gaaactgcct ccctgtttgg cctggctgat ggcagaggRa 46201 ggKtcagaaa tacaggRgag attcagtagc caaagatggg ttcatctata gctatgatga 46261 gataaacagt tKacaccaag attatacatt ctggtgtcta gaagggggat cttcgtgtat 46321 tcatccattc tcacactgct ataaagatac tacctgagac taagtaattt ataaagaaaa 46381 gaggttaatt gactcacagt tctacatggc tggcgagtct tcaggagact tacaatcatg 46441 gtggaaggtg aagaaaaaac aaggaccttc ttcacatggc aataagagag agaagggtga 46501 gcaggggaaa tgccagatgc ttatagaacc atcagatctt gtgagaactc attcactatc 46561 acaagaacag catcggggga acgaccccta tgatccactc acctcccacc aggtccctcc 46621 cttgacacat ggggattatg gggattacaa ttcaagatga gatttgggtg ggaacacaaa 46681 gcctccatat cattccgccc ctggcccctc ccaagtcttt ttctctcatt tcaaaacata 46741 atcatgcctt cccaacagta cctcaaagtc ttaactcatt ccagcattaa accaaaagtc 46801 caagttcaaa gtcccatctg agacaaggca tgccacttct gtctagtagc ctataaaatc 46861 aaaagcaagt taattacttc caagatacta tgggggtata ggcattggat aaatactccc 46921 attccaaatg gaagaaattg gccaaaacaa aggggataca ggccccacgc aagtctgaaa 46981 tccagcaggg cagtcattaa atctttaagc tccaaaagga tctcctgtga ctccatgtct 47041 catatccagg tcatgctgat gaaaaaggtg ggctcccatg gccttgggca gccctgcccc 47101 tgtggctttg cagggtatag cccccgccct ggctgctttc atggctggca ttgagtatct 47161 gcggcttttc caggctaatg Rtgcaacctg tttggaggat ggtggccctc ttctcatagc 47221 tccaattagg cagtgcccca gtggggactc tgcatgagaa atccaacttc acatttccct 47281 tccacactgc actagcagag gttctctgtg agagctctgc ccctgcagaa gacttctgcc 47341 tggacacctg ggcatttcca tgtatcctct gaaatctagg cagaggtgcc caaacctcac 47401 ttcttgtttt tctgtgcacc cgcaggccca acaccacatg gaagctgcca agacttgggg 47461 cttgcaYcct ctgaagccat gacccaagct gtaccttggM ccctttcagc cacagctagg 47521 atgaagggtg ccaagtccca aggctacaaa cagagcagca gcggggcctg gcccacaaaa 47581 ccattttttc ctactaggcc tccaggtctg tgatgggagg ggctgccatg aaggtctctg 47641 acatgccctg gagacatttg ccccatcgtc ctggctatta acgtttggct gctggttact 47701 catgcaaatt tctgcagctg gcttaaattc ctccccataa atggtttttt cttgtctact 47761 acatggtcag ctgcaaattt tccacatttt tacactctgt tgYccccccc cttttttttt 47821 tttgagatgg agtctcactc tgtcacccaa gctagagtgc agtggcgtga tctcagctca 47881 ctgcaacctc cgcctcccag gttcaagtga ttcttgcacc tcagcctcca gagtagtagc 47941 tgggattaca ggcacccacc accatgcctg gctaattttt gtatttttca tagagacaag 48001 gttttgccat gtaggccagg ctggtctcca acccctgacc tcaagtgacc cacctgcaat 48061 tggcctccca aagggctggg attacaggca tgagccactg cgcctgaccc ccttttaaaa 48121 ataagttcca atttcaaatt atctctttgt gaatgtataa gactgaacac tttcaaaatc 48181 aaccaggtca cctcttgaat gctttgctac ttagaaattt cttctgccag atgccttaaa 48241 tcatctctct caagttcaaa gtttcacaga tctctagggc agtggcaaaa tgccagcagt 48301 ctctttgcta aagcatagca agagtgaccc tttgctccag ttcccaagaa gttcctcatc 48361 tccatttgag accacctcag cctggactac attgtccaca tcattatcag cattttggtc 48421 aaaaccattc aacaagtctc taggaaggtt caaactttcc cacatcttcc tgtcttcttc 48481 tgagccctcc aaactgttcc aacatctgcc tgtcacccag tcccaaagtc gcttccaaat 48541 tttcaagtat ctttatagca gtgccccaaa ctcttggYgc caatttactg tattagtcca 48601 ttctctcaca ctgctattaa gaatattacc cggacgggca cgggggctca cRcctgtaat 48661 cccagcactt tgggaggccg aggtgggtgg atcacaaggt caggagatcg agaccatcct 48721 ggctaacacg atgaaacccc gtctctacta aaaatacaaa aattagctgg gcgtggcagc 48781 ttgcgcctat agtcccagct gctggggagg ctgaggcagg agaatggcgt gaacctgtga 48841 ggcggaggtt gcagtgagct gagattgtgc cactgcactc cagcccggga gacagagcca 48901 gactccgtct caaaaaaaaa aaaaaaaaaa aaaaaaggat attacccaag actgggtaat 48961 ttataaagga aaaagtttaa ttgactcaca gttccacatg gctggggagg cctcaggatt 49021 tacaatcaca gcggaaggtg aagagaaaac aaggaccttc ttcgcatggc agcaggagag 49081 agaagagtga gcaggggaaa ggccagatgt ttacaaaacc atcagatctc ttgagaactt 49141 cctcactatc acaagaacag catggggaaa attgccctca tgatccaatc acctcccatt 49201 gggttcctcc cttgacatgt ggggattatg gagattacag ttcaagatga gatttaggtg 49261 ggaacacaaa gcctaaccat atcacttgga ttccagaatg Ytgggatgaa aacttccctt 49321 tcagcagaag gcatatagga atgacttgtc cttgagacaa tgatcaagac aagaaagcta 49381 ttctgggcca gtggaacagg aaagatacac atttagtctc atgcaaggga agataagaaa 49441 atctcaaata agcttctatc agggatctga ggtgcaactg Ygtcaatata taggacatag 49501 tgtatcaaca tgtataggag atgagccaga taagctggag taggtagaaa caggagacRt 49561 gaagcttcac ctcctttggc tttcagctta ttagtattat gcagctggac tagataaact 49621 cttatgttct ttacaattcc aaaattatat ttatgaggtg gaggaagaca ttttaataat 49681 cgcataaagt gtctactatg tgccaggtac tttcatacac tatctcacat tatcctcaca 49741 actttgtgag gttaattatt actatcctaa tagtatagct aaggtttaga ggcattaata 49801 acttactcat gattatatag ctagcaagta gataagccaa aattcaaaca caaatttgtc 49861 tgatacccaa atccttaatc tttccaatca ccatggtatt ttctaagatg tgataagaaa 49921 tgatgtggag gaaatttcag tttcagccag gggttgagtg aaggcaacga gttgcatctg 49981 gcagaaaaag ggaatcatgc aaggatgagt ctttacttac atacataaag gttcttagta 50041 agtattaata caaattcata aaatagtatt gtgttggccg ggcgcggtgg ctcacgcctg 50101 taatcccagc actttgggag gccgaggcgg gcggatcaca aggtcaggag atcgagacca 50161 tcctggctaa cacggtgaaa ccccgtctct actaaaacta caaaaaatta gccaggcatg 50221 gtggcaggcg cctgtggtcc cagctactcg ggaggctgag gcaggagaat agcgtgaacc 50281 caggaggcag agcttgcagt gagccaagat catgccactg cactccagcc tgggtgacag 50341 agcaagattc tgtctcaaaa aaaaaaaaaa aaatagtatt ttgtttgtgg cattgcattt 50401 gagggaggca ctggtaaatg ctgggtattc taaatatgaa taaaatttta tctctgtttt 50461 aaaagaactc tcaatctgat agaatcaatt ctactaacca Mttctatagt acaatatttg 50521 atctgaacaa aatgttttga gagctatgga ctgatgctca atccatttct aatctgcaaa 50581 agctggaaag ctaacaagtg acatttacca gaatcccttt cagtgagcat tcctgccatg 50641 atttggttca gtacatcttg tgagaaatga attcagaacc gagtcatgtc aggagagagg 50701 aaagatgcat ggactctaat ttgccatgtg gattggcaga ggtgatttgt atgattctgg 50761 agcaagtagt ttcctataat agcagcagca gaagaggtaa taagttgtgt ggtgagcaaa 50821 aatggcagca gattcctaca gcaatggtgg catgagctat tcttttctct ctctttcttt 50881 caagacaggg tctcactctg tggctcaggc tggagtgcag tagcacaatc acagtgcact 50941 gtaacttcaa ccacccaggc tcaagtggtc cttacccctc agccactgga gtagctggga 51001 caacaggtgt gccccaacac tcctggcttt tttttttttt ttagagatgg gatttcacta 51061 tgttgcccag gctggtctca aactcctggg cccaagcggt cctcctgYct cagcctccca 51121 aagttttggg attacaggta taagccaccg tgctagtcca gtgggagctt ttctaatcat 51181 ggtagaaaga gttgtgagtg gtggaagttg tgagtagttg taagtggtgg aaggtgttcc 51241 aaggagttgg acctacagct ttgctcctct agtcctttca gtagttttgt acacattcaa 51301 ttccttgctt taaatccctt tatgcttaaa cttgaccaga ttctctgtta tgcaactgaa 51361 cacggattga tgcagaaata Wgaaaagttg taagcaataa actttccact tgtatctgaa 51421 ggcagtgagg agcttgttac tattagagaa aacttggctg ggtatggtgg ctcacacctg 51481 taatcccagc actttgggag gccaaggcag atggattgta tgaggtcagg agtttaagac 51541 cagcctggcc aacatggcaa aaccccatct ctactaaaaa tacaaaaatt agctgggcat 51601 ggtggcatgc gcctgtaatc ccagctgagg caggagaata gcttgaaacc gggatatgga 51661 ggttgcagtg agccgggatt gcaccattgc actccggcct gggcgacaag agcgaaactc 51721 catctcaaaa taaataaata aataaatata tattttttaa agaaaggatc atctctggtc 51781 atctggaatg aagtgtctat taaagtcaag gctttggggc tgggtgaagt ggttcatatc 51841 tgtagtccag ggctttggga agctgaggtg ggagaagtgc ttgaggccag acgtttgaga 51901 ccatcttggg caacatagtg agacccccat ctgcatgaaa aaataataat aggcctggtg 51961 tggtggctca tgcctgtaat cccagcactt tgggaggccg agacaggtgg actgcttgaa 52021 accaggagtt caagaccagc ctggccaaca tggtgaaacc ccgtctctac tgaaaataca 52081 aaaattagct gggcatggtg gcatgcacct gtaatcccag ctacttggga agctaaggca 52141 agagaattgc ttgaacccag gaggcggagg ctgcagtgag ctgagattgt gccactgtat 52201 tccagtctgg gcaacagagc aagactctgt ctcaaaacaa taataataaa attagccagg 52261 tgtggtggca tgtgcctgta gtcttagcta cttaggaggc tgaggtaaga gaatcgctta 52321 agcacaggag atggaggctg cagtgagcta tgaccacacc agtgctctcc agcctgggtg 52381 acagagcaag actRtatctg aaaaaaaaaa agaaaaaaaa attttttttt aatttgaaaa 52441 ggaaaaggca aggttttggt ggaccagctg gctgctggga gggactatta tggaaggtac 52501 aaggaatata agggcagggg ttgtgctggt tgcttctaac tatgctagaa acgttaaaga 52561 aaattatagg cccaagattt caaattttta actcagcact tcagaaaacc agggattttc 52621 catgattgcc ctaaaaaatc ccgtaaagcc acaagtctaa cacatcaaaa attagaagca 52681 gaatctgatt cagtagaatg ctgaattatg accaaagtag aattaatgat tttacttgat 52741 ctctgattgt ggaagttagg gcagcgactg aaaaagagta gggctataaa aatggtatcc 52801 tgtgctcccg aaatctactg aatgtcccat gcctacagaa gcagcctgtt tactcctctg 52861 atgaggctgg tcttgccttt gctgaaaact gtattagtcc attctcatgc tgctataaag 52921 acatacccga gactaggtaa tttattaaaa aaaaaaagag gtttaattga ctcacagttc 52981 tgcagggctg gggacacctc aggaaactta caatcatggt ggaagtggaa gcaaaMatgt 53041 ccttcttcac aggcagcagg agagagaaga atgagagcca agcgaagggg gaagcccctt 53101 ataaaaccat catgatctcg tgacaattta cttaccatca caagaacagc atgtaggaaa 53161 ctgcccccat gattcaatta tctccacctg gtccctacaa ttcaagatga gatatgggtg 53221 gggacacaga aaagccatat caaaaaccat attgtgatcc ttcagtaacc agtctccaag 53281 aaggccccag tgatctcYac tttctagtat taaatgacct tatgtagcct cctcccatac 53341 tcattagggt tgacctgtgt aacctataga atattgcaga catgatggtg tgtgacttct 53401 gaggctatag atatcataat aggtattgtc atttctgcct tacatctgga gaaagccaga 53461 tgccatattg taaagacact acagagaagt tcaaatggca tggaactgag gcctgctaca 53521 aagacccagc acaaacttgc caagtatgtg agtgaaccat attgaaagca gatccgccag 53581 ccccagtcaa gccccaaatg acatcttgac accaacgtta tgagataacc tgagccagaa 53641 tcacccccct aagccaattc tagattcctg acctaaagaa actgtgtgag ataatgcttg 53701 ttattttcag ttgctaaatt ttgggtaatg tgtcacacaa tacagataat aaaggtctca 53761 tcttgcacag ggatggcaat tttcctcttc tctatcctat ctcctataac taactccaga 53821 ttcatatatt gagtcagatc ctcacatgct gtaaggcaga ggtccccagc ctgttaggat 53881 caggctgcac agcaggaggt gaggggcagg tgagtgagtg aagcttcatc tgtatttata 53941 gccattcccc attgcttgca tgaccgcctg aactctgcct tctgtcagaa cagcagcagc 54001 attagattct cataggagca caaaccctat tgtggactgc acatgtgagg gatctaggtt 54061 gcatgctcct tatgagaatc taatgcctga tgatcttcac tgtctcccat tactcccaga 54121 tgagaccatc tagttgcaag aaaacaagct cagggcttcc actgattcta cattatggtg 54181 agttgcataa ttatttcatt acatattaca atgtaataat aatataaagt gtacaaaaaa 54241 tgtaatgagc ttgaatcatc ctacccctac ccctccccac caatccccca tactggtcca 54301 tggaaaaact gtcttccatg aaaccagtcc ctggaaaatg ttggggaccg ctgctctaaa 54361 ggaccaacaa taaagtaagt ttgggaagag aaagattaca tgtcagaaga atggtaagat 54421 tttgctaaac tgcattggca aaaagctgga gaatatatgt agaaatagac tcttgaagat 54481 gcaagatcaa ggaaaaagga acataatttt ggattgggct gaatgtattg atatgagaac 54541 atttgtctaa gattctggta ctagttcagg tagctttgag tgttctagtt atgctcggtt 54601 gattaattaa aaactagact caactggtga ctgaaaccaa ataggattgg gttggcaata 54661 attttttttt tttttttctt gagacagtct cactttgtca cccaggctgg cgtgcagggg 54721 ctggtctcag cttactgcaa cctctgcctc ttgggtttga gtgattctcc tgcctcgcct 54781 cccaagcagc tgggattata ggcatgcacc actaaactca gctaatttct gtatttttag 54841 tagagatggg gtttctccat gttggccaga ctggtctcaa actcccaacc tcaggtgatc 54901 tgcccacctc gacctcccaa aatgctggga ttacaggcat gagccactgc gcctggcatg 54961 ccccaaaatt ttgcttaact tttattttag atccaggggt acatgtgagg tttgttatat 55021 aggtacattc atgtcacggg tttgttgtgc agattatttt gtcacccagg tactaagcca 55081 aYagttattt tttctgctca tctccctcct cccaccttcc atcctcaagt aggccccagt 55141 gtctgttgtt cctctgtgtg tccatgtgtt ctcatcattt agctctcacc tgtaagtggg 55201 aacgtgcagt atttggtttt ctgttcctgc atgagtttac taagaataat ggccaccagc 55261 tccatctacg ttcctgcaaa agacatgatc tcgttctttt tcatggccac atagtattcc 55321 atggtgtata tgtaccacat tttctttatc cagtctgtca ctgatgggca tttaggttga 55381 ttocgtgtct ttgctattgt gaacagtgtt gcaRtgaaca tttgtgtgta tgtatcttta 55441 tggtagaatg atttatattc ttctgggtat ctacccagta atgggattgc tgggttgaat 55501 aaatgtcttg atataatgct gaagataagc tccaaagKct taggaagaaa gaagaaagca 55561 aactcaaagt gggttttttg ttttttacga cagagccttg ctctgttgct caggocgaag 55621 tgcagtggca caatcatagc tcactgcaac cttgaactct taggctcaag caatcctcct 55681 gcctaggcct ccccaaagct cttggattac aggtgtgagc cactgtgccc agcctgaaat 55741 gggttgttat ttgcattgga tcatcaaccc ccgtgtcccc caaaggacct agagcacatt 55801 atcttcacac catagcataa ataaatagac tggtgagtat agtgcaagtg cccctgaaca 55861 ttactataat ggctgtcctc tggggataaa ggttgcatat gttggcactg aaatggSctt 55921 cccccctccc cctttcttgt tcttttttct tttctttgaa atgggctttc cactttcagt 55981 gatggtgagg gatcctgagg tggtagaggc cagacaggag aacataactg ccatagtaac 56041 attatgcaca attaccaaga gtggtaattg aaaggtYtga cctacagaga tctttgaYgg 56101 ttgctaattg atcatagttt ttaatactga aacagatgtg tagctcacta aggacttaaa 56161 gatttgtgca aatgaacaaa ctctagatta ggaaaacaca ggcctgacta cagacaccac 56221 taaaagtcag agcccacatc tatttctatt cctgggaagt tcagagactc agaatacaga 56281 gtatactatg tacctttgag aaagaactgt gtgattacat caaaagtatc tttctctcag 56341 ccttcaatca aaaggacata tagctatttg ctagggtaaa attgtgcaca ggaggaaata 56401 tcttgacctt taagggatta tcagacacaa gtgttaatcc ttggtgaccc agaatactat 56461 gctcacagac tcactggtct tactgtacat tccatcatcc agaagcagct ggtcttcaga 56521 actcttgaac agctttttga agactcagtt ccagctgttc cattttgtga ctcaggtact 56581 aagccaacag ttattttttc tgctcatctc cctccttcca ccttccatcc tcaagtaggc 56641 accagtgtct gttgttcctc tctgtgtgtc catgtgttct caacatttag ctctcacctg 56701 taagtgggaa catgcagtat Ytggttttgt tcctgcatga gtttactaag aataatggcc 56761 accagctcca tccacgttcc tgcaaaagac atgatctcgt tcttttttat ggccatttag 56821 tattccatgg tgtatatgta ccacattttc tttacccagt ctgtcattga tgggcattta 56881 agttgattcc atgtctttgc tattgtgaac agtgctgcaa tgaacatttg tgtgtatgtg 56941 tcttttgttt cccagcaggg aaggaatgct ttgcaaagtt aggatgtcgc cctatagcag 57001 agattagcaa attatagtct gagggcaaat atgccctaaa tcctattttt ggacagattt 57061 taagaatttt ttttttacac tttttaaggg ttgtaacagt aacaacaaaa aagaatacat 57121 gacagatatc aatcatgtgt ggtctttaaa gcttggaata tttattatct ggtcctttac 57181 agaaaaaagc atgccaactc ctgtgctaca gcaatgtgct gtgaaccagc aaccaacata 57241 aagcgcggtt tttcccttat ctatatctgc tgggaaaocc aggcttgaga taaacacttc 57301 ccactaYgat acccactgat gcactcaaaa tgttttgctt tctattttca caactttgag 57361 ctttgcctat gtagaactct ttatctaagg gagacatgct ctaacccaga aaatccaaga 57421 atggttcctc ttaactggaa gtttattaac cagctgcaga tgctggcagt atgaagatgg 57481 aatagataat gaaggaagga tattctagtt tacgagacca gttgtagaaa taaagatgta 57541 gtagctaccc atctacttta ttctattttg tatgtatcta tataggttaa tcattcccat 57601 tgacttgttt tctctcctca tttatataag gtgtatttgt aatttagcta atggtattgt 57661 acttatgttt attaattttg ataattatgc tataattata taatacgttg atattagggg 57721 aagctatgtg aaggtattgg tactattttt gcaacttttc tgtaagtgta actttattta 57781 tttatttttg agatggagtt ttgctctgtc tcccaggctg gagtgcaatg gtgtgatctc 57841 ggctcactgc aacctctgcc tcccgggttc aagtgattct cctgcctcag cctcttgagt 57901 agcccgccac cacacctggc taatttttgt atttttagta gagatggggt tttgccatgt 57961 tggccagatt ggtctcaaac tcctgacctc aggtgatctg cccgcctcag cctcccaaag 58021 tgctaagatt acaggcatga gtcaccacac ccagccagtc taactttatt tcaaaataaa 58081 aagtttacgc tgggcatggt agctcacacc tataatcctg gcactttggg aggccaaggt 58141 gggagggctg cttgaagcca ggagttcaag actgaccagt cttgaacaca gtgagacccc 58201 atcatagtga gaccccatct ctattaaata tatatatata tatatatata taaagtttaa 58261 aaatgagcac aattatgcaa acataaatat atgatttaga aacacatgaa gtgatgaaat 58321 ttttgatgca atgtggaata aaaaataaga tgcactaaaa taatgtttgc tccttt'ttta 58381 gatgcaaatg acattaaata aatcttataa attacactaa agtaatgcca ggaatttttc 58441 tttataacat tttaaaaata catatatatt taaaaataga gacagggtct cactgtgttg 58501 cccaagctag tcttaaactc ctgggctcaa gcgatcctgc tgcctcagct tcccaaagtg 58561 ctgggattac aggtgtaaRc cgctgcaccc agacatggac ttttcttcta tcacttcttt 58621 aatatttcct ccgtaaaatt atttcatgtg tctctctttg gaactatgag ttactggaat 58681 ccctgcattt attttacatg tctctgaaat caccctccac cattatcttt gttcttttgg 58741 agtaactctt tagcttactg ttccagtttt gctagtttgc tcttcattga agaagtccat 58801 tcactgttta gtccaccttt taatttttaa aaattatatt gtattttatt tatttatttt 58861 ttggagacaa ggtctgggtc tatgcccagg ctggagtgca gtggcaccat ctcagctcac 58921 tgcaacatct gcctcctggg ctgaagccat cctcccacct cagcctcctg agtagctggg 58981 actacaggca tgcaccacta cccccagcta atttttgtat tttttgtaga gacgaggttt 59041 cgtcatgttt cccaggctgg tctcaaactc atgagctcaa gcaatccacc cacctcagcc 59101 tcccaaattg ttgggattac aggtgtgagc caccacacct cgcataattt tttaaaatgg 59161 taacaatcta tttaactggt tctttttcat cattacaata ttctctccta ttcctctggg 59221 gatattctgt atacaaacta Ratttaaaaa aaacatgtga ggtgcttaga agaatgcctg 59281 acaccacacc aggatgcact aattattaat aattatcatt tcacagatcc tcttctgttt 59341 actctgaaaa ctacttgctt tttgtttgtt gactgctgtc atgctttcat ggtactggtc 59401 ttcctccggc atttggttgt tcctaatttt gttctcatct tgttatttcc tgttctctgt 59461 gtatgaggcc atttctgttt atcatagttt gctctagtga ttgtgagggg ataaaatgta 59521 atcctggaca gggtatgcca gtagctaaca ttctgagtgt gaaatgaggc ttcctttcct 59581 ggacacagtg tagccactgg ggtactgcct ggcttattgg ccccaagttt ccaaagtcac 59641 tgtgctagct aggggcaaat accattctga ggtacccttg gctttgaaga atgaatgagg 59701 gaaggagcca acccaaccag aggtttcaaa ttccattccc caaaagttat cctttatagt 59761 tgctctagga cgctatgcca tccccacccc tgccttctac tcccctactc catctatctc 59821 ttttctttaa tctatcactt ctgagcctga attattacac tgccaatttg atcccatctc 59881 ccttctttca gagacttctc aaaattccaa gtctgctggt aatttggact ctgataatct 59941 ttaataatct tgaacagact gggcgtggtg gctcaagtct ataatcccag cattctagga 60001 ggccgaggca gaattccttg aggccaggaa tttgagacta gcctgggcaa aatagcaaga 60061 ccctatctct acaaaaagtt gaYaattagc tgagcatcgt gatgcacacc tatagtccta 60121 gttactcagg gggctgaggt gggaggatta cttgaggcca agagtttgag gtggcagtga 60181 gctatgaagg catcactgca ctccagcctg gagtgagatc ctgtctctta aaaaaaaggg 60241 agggctttaa aaaaaaaaaa acacagtgcc ttggccacct gataaattca gattcatggt 60301 tcaagactca aatacagcat ttatctctat gaatttgtct ttgactcata cttcatcata 60361 tttttctctg aacttaYata gatccttgta taaatcttta ttgttattta taaatgtctg 60421 tccctgtaMc ccattaaact gtgaataaat taacaaatga aaaaaatgct ctccacaggt 60481 ctattagtaa tactagcata tccaccagat tattttcctt agatggtctt gctgacaggt 60541 aacttctact ttgtgtgttt ttaaaaatat gaactaaaac ttggaattta ttatcacaga 60601 ccaagaatga aaaagattta actgtcccta tctattaaga aaattgatta ggatgaacaa 60661 tcctaaaaaa cattagaatg aaggtaactt attctatgac acaaaacaaa cttttttttg 60721 agagagtctt gctctgttgc ccaggctgga gtgcagtggt gtcatctctg ctcactgcaa 60781 cctctgcctc ccgggttcaa gcaattctcc tgcctcagcc tcctgagtag ctaggattac 60841 aggtgcgcag cactgcacct ggctaatttt tgtattttta gtagagacag agtttcacca 60901 tggtggtcag gctggtcttg aactcctgac ctcgtaatct gcctgtctcg gcctcccaaa 60961 gtgctgggat tacaagcatg tgccaccgtg cctggccaaa catttttaat gctttagaaa 61021 aattcatctc tagtcaagtt tatgctaacc ataaacataa tataaaaatt acataMaatt 61081 ctaYgtattc actgagagaa gagcaacaaa tggaaatact gtgtgctttg aagtcagaca 61141 gatgtaacct ggaatctcag gtttgttact cattagcttt gtaaaactgg ataaacaact 61201 tgagcaccct gatcctgagg gagacgcctt ctaaagtggc tcactgtgat ttcYgcctcc 61261 tggtattcac actcttgcat aataccttcc ccttgaatat gggctggacc tagtgacttg 61321 cttttaatga atagaacata acaaaaatga tgggatgtca cctccaaaac taggttacaa 61381 aaaattatga ttttggtctt actggtgctt tctcacttgt tcactttgat gaaacctgct 61441 ggaatgttgt gagctgccct gtagaggtcc atgtgtcaag gaacttccaa cagcctgcaa 61501 aaaactgaat cctgccaaca ggagtaagct tggaagtgga tccttcacta gtggagtctt 61561 tttttttttt ttttgagacg gagtctcgct ctgtcgccca ggctagagtg cagtggtgca 61621 atcacggctc actgcaagct ccgcctcctg ggttcatgcc attctcctgc ctcagcctcc 61681 caagtagctg ggactacagg tacctgccac catgcccggc taattttttg tatttttagt 61741 agagacgggg tttcaccgtg ttagccagga tggtctcgat ctactgaccc cgtgatcctc 61801 ccacctcagc ctctcaaagt gctgggatta caggcgtgag ccaccgcgcg cggctctagt 61861 ggagtcttga aatgactgca gctcttgcta acaccttcat ogcagccagt gagagactct 61921 gaagctaagc tccacctgat tcctgacgta tagcaactgt gaggtaataa atgttgatgt 61981 tttaagccac tatgttttgg agcaatttgt taagcaatag gtaactaaca catagccttt 62041 gtttcttcat ctctaaaatg ggattgatag cttacctcac agagttgtta tcatgattaa 62101 atgaaataca tatataaagc atctggcatc caatatgtga tcaaaaagaa caaaacaaaa 62161 aaggtaacta ttattaactc aagtctacta aaaatctcta ccaggtaata ttgtgttata 62221 acattgttag tattaaaata atgatatttg ataatgctat aacattttac atagggattt 62281 tacatgtatt acattatttg attctcagag cagggctgta aaacacagaa taaaatatta 62341 ttcctcttaa aagagaggaa gaaactgagg gtgagagaac ttaagtgact tgaacaaYgg 62401 tccagactag aaagtgtcaa agagttcaga gtcaaaccta gtccttttcc caccactaac 62461 atatcgatac taaacaccca tttaatgaac tattaggcat caggcattat tttaggccct 62521 gagaatacag aggtagataa gaaagtcaag gttcctgccc tcatagatct tacattccct 62581 gttctactct atagaattgg aaataacaat ttaaactttt cattaaacat ttctttagtc 62641 tgaattagca tgttttaaaa tattttatga cttggaaatg ctacactaac tttgtccaga 62701 ttcctaagtc catttcacta gcagtgatgt aatacaaggc agaggcatgg ttgtatgttt 62761 cagtgtttga ctggctaaat accaagtaaa tgctccatac atacaccaaa caattgttca 62821 ttgattttca caatagagtt tgtgtcttga acttcaagcc ttaacaaagg tttgataagc 62881 actattcatc tctcatcttc ttgcataaag tttagttggt gaaattctgc cttttttcct 62941 agagtacaaa attaagcaga aatagaatag gtagagttta gggtgctgca ctatttagga 63001 attgctggaa ttacttgatg catgcaggaa aaatgtgaga acttcataac tggtagtcta 63061 ttgtgaaaat attattgtag taggactcaa aacagactag agttctatat tatatttgac 63121 tggatactga agcctgagag cagcttattt tctaaaataa gtacacagta tgactgtcag 63181 aagtgtttSc ccctctccaa agtctttttc tgaaaaggaa tgttggctta gttcctgatg 63241 acagctgagt ggccaaatta tggtgcttta atagaccata aatattttaa aaagctgaga 63301 tgggtatttg caaagtgagt ttctgttaag gtacatgtat tctacagcca tcttcactcc 63361 tgcctttcaa aacaggcagt tggttgagga aaaaaaaaga tgcataaatg ttgctgaatg 63421 aacctgggaa aatctgtcaa gaattccaaa aactttgaga ctgacaatac accatttttt 63481 acatcttaga gtataagaag tgatgtctaa cctttgcatt tatacatcta agaatagcaa 63541 aaacactttg cactttaaag gcctcctata aagtcccaaa gtgcttccgg acggttaggt 63601 gattcttcca tagctataaa atggttgtta attgcctaac aactagcaag tgctctggaa 63661 atggacatcc agagtgatcc ttaaaatatt attttagtag cattgagaaa agccttgaaa 63721 aataaaatct tattctgtta ttccaagctt actcagtgct atattattca gatcagggtt 63781 ccccttacac actttgggca ggatgatagg ggctacttct ctatatgaag tcttgaaatc 63841 atatgattca aggtgattca aggtggaggg aatttaaaaa ttaaaaaaat aattccaaca 63901 gtgaaattcc taagggtgag tctttgctct tctacccact aagaattccg gcttcctctt 63961 cccaaaagaa cagaagagtg gggaaagatt tgtgacagcc aaaaggacat ggtgtagcaa 64021 gccaacttgg aagagttact ggagatggct tagcaaatat tcatgccttt actcaactaa 64081 aacaaaaaca aaacaagtca aatttgggca ttttttatag atcacaggct tttgtttgat 64141 caatgcacta catttcttta tgacaaaagg taacgacaat gattttgcat attcccaaat 64201 ttggatagtt gtccaattta acagtctcaa ggagcctaac atggtgctgt gtgggatg^'aa 64261 aagaggttca aagtatgatc cctgtcttaa aattaagata cagaatcttc caattaatat 64321 gtatattttc taaagtggag tccttaaact gctggatctc ctcagaagtc ttttgagggt 64381 cccaatatca tccaagcttt gagtttctca aaagaaagag tatatgatac taataggtct 64441 acaatactcR ttacaatagc tcttccctca attcccttat acatttStaa atactcccta 64501 aaggaggtaa cctaaccctc accccttccc cgtgtttaag aaccacagtg gcttcccaac 64561 acagttgaaa taaaatccaa accccttaca ctggcctgta agaccctSag tgccctgcct 64621 ccttcctacc tactgacaat ttctatgatg cattcctcag acacacctca ctctttcctg 64681 catcagggta tttgtacttg ctttctttcc ctctggaata ttctttcccc aatcttcatt 64741 tgattggctc cttcttatta ctgaggtctc agctcaaatg tcatttcctt ggaaatacct 64801 tcttagatca ctcgcagtaa ggaccctcct tcatttactc tcttttgaaa aaatttcctt 64861 gtagcactta ttattgtctg tctctcccac tagaatgtaa attctttgag agcaaacata 64921 acttttttgc ttcttggtgt tgctatagat ttagtctaag tttgatattt ctttcagcat 64981 gcctgaaatt ttagcaagtt agagacaaat gtaggcactc aggttaccat ataaggcctc 65041 tgccctcttt gttgtgttgt ggctttaacc actagctggg tagctagagt ggcattattc 65101 ttgctctcac atacacagga cacttatctc ttccttaaga gtgaggaagc atcttttttt 65161 aaagccccca tactattgcc cttgcttttc tctggtttgt attgagtcac atagtattcc 65221 tggaccaatt ctgtggtcag agtaatacca tacctccagt aggcttttat ccaggtttct 65281 caacaatttt tctaagggaa attgcattac actcatcagt gtctttcaaa cagtggtcca 65341 taacctgaga atgaattagg aaattaactc ttgggttata accattactt aaaaaattag 65401 actattaaat ttgaaactgc ataacatata tgacgagtta atactgtttt atgaaacttt 65461 ggtgtataca cacaaacaca cctggatcac catataaaat ctacttgtgg attggagtca 65521 aaaaaagctt gaaagctacc atcttggaca aaacaggttg actcctaaag ctggagtagg 65581 gtcagcttca gattatgtag ggaaagaatg gacacctgaa ataaaatcag ggtatgattt 65641 agaagaggaa aatacatgct gaggagatag ctaacaattt ccgctacagc ctgcttgata 65701 ctttagttac tgtattccaa tacagtcata accaaacatt ttcatttccc ctccaatgtc 65761 ttctaaattt caaagtattt atccattcca aaaaagcact tcattctttc catccaacaa 65821 gtatccatga tggggcaact cataaatttt atcatttggt tggtggaaag tgtacatctt 65881 atcaccctaa tctttactta tgtttaaatt ttgatcttat gtgataggaa ctttagaact 65941 cagcccattt atttatttat ttttttgaga cagggtctca ttcggtcacc caggctggag 66001 tgcagtgatg caatcacagc tcactgcatt ctctatctct tgggctcaag tgactctccc 66061 gcctcaMctc ctgagttgct agaaccacag gcatgcacca ccactcctgg ctaatttttt 66121 tatttttgta gagacaaggt ctcgccatgt tgcccaggct ggtcttgaac tcctgggctc 66181 aagcaatctt cctacctcag ccacctgaat agctaggaat acaggtgcaa gccaccatgc 66241 tcagctaatt atcMWttttt tttttagaga tggggtcttg ctatgttgcc caggctggtc 66301 ttgaatttct ggcctcaagg aatcctccca cctcagcctc ctgaatagct aggactacag 66361 gtgcaagcca ccatgctcaa ctaatgatca ttttttttgt agagatggga tcttgctatg 66421 ttgcccaggc tggtcttgaa ttatttttgg cctcaaagaa tcctcctttg gcctctcaaa 66481 gtgttgggat tacaggtgtg aacaaccacg ccaagccgag agctcattct agttcaacat 66541 ctttcactta agaaactaag gcctagaRag gggagtgaac ttacctaagg cagttaatta 66601 gtagcagaac acgtctcttg acacccactt aagaattctt tccattgtac taattaacag 66661 tatacttatg ccaactttta aaaataaagg taaacaaaca tgtaagttcc agaggcagct 66721 aggtttacat agctaacaaa ttctttcaag aattgtaggt gacttatatt tggggcagca 66781 aagctgcatt tttaaggcaa caggggaatt tattaaagaa atgctgctgg ctggtggctc 66841 atgcctgtaa tcccaacact ttgaaaggct gaggcRggag aatggcttga ggctaggagt 66901 tccaggccag tccaggtaac ataccaagac ccagtctctg caaaaataat aataaaaaag 66961 ctaggcatgg tggtccatac ctgcagtcct agctgctcag gaggttgagg tgggaggaca 67021 ccttgagccc aggagtgagg ttacagtgag ctatgattgt gccactgcac tgcagctggg 67081 ataagagatc ctgtctctaa aaaaagaaat attgcttttg aagtgtttga agggcaaaga 67141 ctagttactg ccttatctgt ttaagtgagg ttaaggcaac cagcatgcat caccacacac 67201 agctaatttt tgtatttttt tgtagagata ggacttcgcc atgttgcgca ggctggtctc 67261 gaacccgtga gctcaagtga tctgcccatg ttggcttccc aaaatgctga gattagaggc 67321 gtgagccact goactgggcc aaagttaatt ttcgtaatgt tacatatagt aggaattgtg 67381 ttttaMctta atacttcact ttttaagcta ggaaactcaa ttcRctgttt actttttata 67441 ttattagaaa tttaccaaga tttatgaatg acacatcata cccacaaaaa gcttatggtg 67501 tatttttgta tgtggggtgg tagggcaagt ctaacttatg aaataatcat aattaagaaa 67561 tcaaggcaat ttcaattatt gtaaatatag ggattaaaag tgggaaagtc cttttgcgtt 67621 ggacacaaga ggggcatttt actgttttat gcatgagttg gaagagtagc tatcatttga 67681 gggtgccatg agaatgtaat ttagtcccca aatagctctt ccatttatta aatggaatgc 67741 cattcatttc ttcctctaag agttgttctc tcttttatgt gaaagggttt gtcagaggtt 67801 tccctccagc tccagagagt gcttcattat tacagtctca gggacattac agtggcagaa 67861 gggtaaccaa agggctttgg aagtatggaa gaaagggagg ctggcagtgc ttgttacttg 67921 gtttcctttg gttttattta gagaaaaaaa agccaattct gaagggtagg tagggtttaa 67981 atacaaagga aaagaatctt cYctttggga ttcagtcacg gtaactacat ttaggttagg 68041 gtaatctaga actagttgct atctggaact cgacttgtct gttgtccacc agacccacct 68101 tcaSgtacta aaagtccatt ctcactagct gtgcatggta tccataattt agtcctgata 68161 cgttacagat gaggtgaaca gctggcatca agaaccaaaa tgggtaSggt cagcattaaa 68221 aaggtctagt agcagacagc agggtctcag ataatggact tggacttaag agcaggaatc 68281 tagtctccaa ggaggttagg ggaaaaggac tggaaaacaa gaatggtttt atattttaag 68341 aggctgacat cttggacaaa taatctaatg aagRgctcga actcagcaat cgcaggagtc 68401 tagttaccag gcttgaggta tatgctggac acagatatta aggaactgca catccttctc 68461 aaactagggt ataattctgg gactagtaaa taaaaagcat tgcatatata agaaattatg 68521 atacatcttc taaggaatta gtagttgaca gcaatttact ctatatttta catgaaaatt 68581 agtcatattt taaattagcc aatttcggtg aatttagaag taaacacaag acttcaaaga 68641 aatgtccaga ttctagtagg cagtttcagg ctgtacttcc aagtcactgt ttgtcttaga 68701 aaagttcaga aggcaatgat gggaaaaagc tctgtatttg ggaaagactt actttaaact 68761 aaatcctgct aattacctat gacctaggtc aagtccaaaa atgactgaat cccataagat 68821 tgttgtaaag attatagata aatacaaagc aactattaaa gtgcctgaca ggctgggcgc 68881 agtggctcac atcggtaatc ccagtgcttt gggaggccta ggtgggcgga tcacctgagg 68941 tcaggagttc aaggtcagcc tggccaacat ggtgaaaccc cgtctctact aaaaatacaa 69001 aaattaggcc agctgtggtg gctcatgcct gcaatcttag cactttgaga ggccgaggcR 69061 ggtggatcac ctgagatcaa gagttcggga ccagcctggc caacatgcag aaaccccgtc 69121 tctactaaaa atacaaaaat tagctgggtg tggtggcacg tgcctgtaat tccagctact 69181 cgggaggatg aggcaggaga atcgctgggg gatggggggc gggcgggggg tggggactga 69241 agttgcagtg aggtgagatc acgccacttt actccagcac aaacaaaatt agctgggggt 69301 ggtggtgcac acttgtaatc ccagctactt cggaggctga ggcatgagaa ttggttgaac 69361 ttgggaggca gaggttgcag tgagccaaga tcgcgccact gtaatccagc ctgggtgaca 69421 gagcaagact ctgtctcaaa aaataaataa ataaaataaa gttcctcaca gacaaataag 69481 tgcttaataa ggcaacaagg aggaaaaacc tgggctagaa gtatgtaatc ttgttgcctt 69541 ggatcaggaa atgtcccatg gtctagtaaa ctgttgagtc tccagagaat aaaaatccag 69601 attagaagtg tgaagtgtag actcaacttt aactggaaca tagttggata tggcagagaa 69661 ctaatatatg ctgtacacct actcctgatc atcaactgtt aggagcttta tatttataca 69721 ttcacattta atcttgataa caacccttca aaggaggcgt aattgtaatt ttatagatga 69781 aacaactgag gttcaagttc agattaccgt acattacaaa gtaaagtagg tacttgaacc 69841 Yagtcatttt accacattct gccttaatgg tggggggtgg tacctttact ccctaaaatg 69901 gaagtttcaa taaatgagat taaataatgg ttatctacag tagttcttga ctacaggagt 69961 aacaaatatt taacactgag ttggtgaact gtgttgcatg acgtgatgta ggaaaagtag 70021 cccagagaca ggaaattcag tcaggaaatt tttacagtat tataagaaca aactgatttc 70081 tggtctaagc atctctgact acagtaaagt ctcattaatt tatactgcat gtggaattta 70141 caataatcta tataggaact gagaaaaaaa caaagtatct gaaaatactc ttcacacttc 70201 atcccctctc cctcaatagt tcagcctgaa tcataaaact atgacattcc tcgatgacct 70261 ctgcataatg gccacactga actctagtta atagagtaag tgagccaaaa aacccaaagg 70321 gtagcagtgt gtacacctgc taccatacca atcaatgaat gtaggaaatc ccccattYca 70381 ttttttgttg gttcactttc accaacatgt ttttccttta ctgagcatct aatttagtaa 70441 agcctttttc cagattatgg agacacagat ttggataaga ctcaataaga ctctctaaga 70501 gcttagtctg aaaacattgg gaaccgtgag accatcaagg agttcacagt tgagacagac 70561 acaaacatta aatacaagtg tgaaacagca tcaaaatagg aagatacaga gaatgaaagt 70621 acctacaagt caaagtgttg aagcaaatag gagcctacca gaaagtaaga tggggacaga 70681 atcgcttttt gagacctgaa acgataaaac agtgtgatat gtttagggaa tggcaagaag 70741 ttccatggga ttggagagct gcagagtaga cacggaaaga ttggtaggga ttagatcctg 70801 aagagatatg ttaagggact gggactttat cttggggatc attatttccc agttatgatc 70861 atggaactct ttaaaattac aatgtaaaga aataccaata at^'aacacaat atgtttaaaa 70921 cgtttgattc tttagccttc ttaaaatcta aatagtataa aaaaatggaa tcattttatt 70981 taaatccccc aaataccaga gatgaagtaa atcatctttt attttcatct tacatttggt 71041 tatcatgaga catgcaaact cctccaattt taatgagaac agtgtttttg tgtcttttta 71101 tcacatatcc gcttaatatt aggtgtaata ttgctaagtc ggattcgcat atgaggtgca 71161 gcatcaagtc ttttcctata ttttgttttt gttgcagcRt aatatgaaaa ccccgtttca 71221 cacaggtgca ttgtagcaaa aggaagaagt acRcgcactg cacgccttgc aatgcttggg 71281 tattcctgaa ttaggctact ccaaaaatca tttagtgaaa gttcactaaa attttgcttc 71341 acttgagaat cagatgttaa atcaatcagg ctctcatagt cccgtgctac taatgaagct 71401 ggtttaacag taactgtaaa tggatttcta acccaagcat tattgtcatt tgttacagga 71461 aagtatttta acagagtagc gcgcaaaccc cttaggtgct gcacaatggc actgcaaata 71521 tctttatcaa ctgtagaatt aatttcagtc aaaaaatcac tgagWgtagg aaaacaatca 71581 aagttttctt cttctacaga tgaggcccaa aattccaatt ttcttaacaa tgaYgacatt 71641 ttatcaaata ctgtaaaaac ggtcacattt tttccttgca ttgacaaatt aacttcattt 71701 aatttagtaa aaatatctgc aagatatgca agtcttagca gccaagatga atttgttaaa 71761 caatcagata gtcgaaaagc agaatccatg aaaaccaaaa gttcacgacg aagttcaaaa 71821 agtcttacaa gaactttacc tcgagaaagc cacctcacYt ctgtatttag aagaagtgct 71881 gtgtgctgag cacccatttc ctcacataaa atttttaata gtcYggattg atgtggtcga 71941 gctttaatat aattgatgat ttgtactgcc tggtctagca cattttttag agatgtaggc 72001 attattttaa ctgccagtgc atgtctgtat aataggcagt gactactggt gctttcggga 72061 gccacatatt ttattaaggt gacagcttcR gcaattttcc catccactgc cctagaagca 72121 tcactacaaa catcaacaca tttttcccat tcaatttcat gtttctgcat aaaactgttg 72181 atacagttga atatttcttc accggtagca ttactttgca aagattcaca caggagtagg 72241 tcttcctcaa tagacttatt aaacctataa cgaacaaaca caagcagcac agcaagtcct 72301 gaaacatcag ctgattcatc tagttgcagt gaaaacccat cgcaaatttt cagtctacaR 72361 acaagctctt cttcaatgtc agcagctaga tccttaattc gacgtgcaac agtactgttt 724_,21 gatagctgta ctgcatctat ttttttacta tattgttcat caaacatccg catcactaca 72481 tcttttgcac aaggtttgat aagcaattct ccaatagtat gagcctctcc actcagcgct 72541 atatggtaac ttacattgta tgatgcttct gtagcacttt cattatctgt attcacaatt 72601 ttaggtgttg ggggtttatt attttcaggt gaatcgagat gttgcttgaa aaagcttatg 72661 tctttgtctt tatatgcagc atgtttagtt tccaaatgtc ttcgaagctt actaggggct 72721 aaagagctat ttgataaaat tttcttacat aatacacaYt gagcatgagg tgcatctcta 72781 tttccgaagt aagtaaatcc aaaagacaaa taactttcat catattttct tctttttggt 72841 tttttactaa atgttatttt gttggaattg gatataaatt tgaccctgga aagctcacct 72901 tctgattttt tagaaactga agRttgcaac tgcttatctt cactttgtaa tattccaacc 72961 ttctgatcat ttgattcaga cacaatctga taacagaaag attccacttc tYgtttaaga 73021 cttccttgtt tcagcaacag atccatgggc aatgagtttg tggtacaaaa catggttaat 73081 ttagaataga cattgagtat cRcaaatgtg ttgaaattat aagacaggat iacaaagaaga 73141 ggagcaatca tcaaagagat gatatacagc aacacatcag ttaatttgta aatgctgcct 73201 attYatcaat gcgcagaYgg aacatcatac gttcatgtat caggtgatct ctcatgcgac 73261 ttcctggtgc tctcaggtat ggtacacctt ttcttaaagg tagattatca cataaaaata 73321 aaagctatag aaatgagttt agcagtctta atctcatatt taaataaaca tattaaaatc 73381 aaccataaag aaaaaccaat attagcatca atcattttct caaaacattt attaacttag 73441 agaatattaa tattctataa aacataattt gggaatcact gagccaataa attattaaga 73501 gttgttatac atatttttaa gaaagggacc ctgaagaata tgtcccatgg caggggttgg 73561 caggcttttt ttggtcaagg gccatatagt ctctgttgca actactcaac tctgtagttg 73621 taacatgaca gcagccatag acaatacatg aaagaatgga cacaggtgtg ttccaataaa 73681 actttacgta caaaaccaga cagcatgggc cataatttat cagccctgtc tcatggtatg 73741 tagtattgtg aaatctcttt tagcttttga tgcctactgY cattagatgt attagttgtt 73801 gatactatta tatatctgaa gtcccttcag ggctagcaac aattctgaag aagtgaatta 73861 aacacacaca cagttccaag ttttgcgaga tacataattc tactgtatcc taaatgttat 73921 gcgttaacaa tgaagaataa attgtatatc aaaagttagg tactgtttct ctggacttaa 73981 attatataaa Ygtttatatt atccaaatta agactcaatg aaagtaatgt atatttttac 74041 agataactct gcattctatt tatacaacag gtgacgactt aaccaggacc taaaaaaaaa 74101 aaataaactc tcatttaaga ggtttatttc tcatataata aaacaaatca aaattaaaag 74161 gataatgcaa tctaaggatt gctaaagaat actattaact ctataaatca aggcatacaa 74221 attatgtctg tccaaatata gctacttttg atttaaactt tataacctgg ctatagagta 74281 agttttgtat tctcatgtta gatcttgagt caaaatggtt ctcctattaa ggggtagagg 74341 ataagatacc tgaaataagg tgttctcctt tctgtaatcc ctctctccac cttggcagct 74401 tgaaatgcac tcttcaaaag aataaaatta agggatgggg tgggaagggg agtaaccaaa 74461 agcctagaat gagaaaaatt aaaattagat acagtaacaa gcagaactaa ctataaaccc 74521 gtaagatggg tttattcttt ctggatctaa gcagtgaaaa tgattcttta ctgcaatgca 74581 gatcttggac tgaaagagaa gacgcctagc atagtaaaaa ttctaacatt ttcatcctgt 74641 tcaatatctt ggcaatttag atgctttgag atgttccccc acctactgac ttcatagaaa 74701 catgttaaaa caacaccacc accacacttt ctagaacttg aaactaagcc taatttttaa 74761 aagtacaacc tcatcaatgt ctctaaaact aggtcttgaa tctaaaatgg aattatacat 74821 agaactatta catgaagcag ttctttcact acaatcattt ttagcccccc agtgaccaat 74881 ctcctcaggt aaacaatgtc taatgactga tgattgttta ctgtatgcca attactgcta 74941 aatccctcat atagattatc tcatctatga agacacaagg attattaata accccacttt 75001 agagataaac agacacaggt taacacatct cgotaacacc tcttgtaagt gaaaaaccaa 75061 gttcagagcc caaaaagttt gactgcatag cccatgtgtc tagccattac ttgggtgttc 75121 ctgaatactt ttaattcccc aactactaaa aaatctcgtt actaggagtt gggttatgca 75181 gcgaaacgga tgaacaatgg attataactg ccagaaagtc gagggtctca tactagcaac 75241 agcataaagc cctgcttctt attgggagca aaaaagcaga ttctccttcc acagtctcct 75301 tttggatttt gcaacggaga actctgtgga gctgctggtt cacgtaaaag atcaggatcc 75361 ctctcgttgc cagaggacac agaagagtag gaagcttttg ttttcagaaa gaaggtcctc 75421 aaccccacct cttcgaaggt gtttccccga atttctcgag gacaaagaat ctggactcct 75481 ttgagagtaa agtttccttt ccactccctg aagagcgggg aaaacttccg tctttagtct 75541 ccttccggtt aaactgacaa gtatcacaat cctttctccc ctatcttcgg gcggttccgg 75601 ctgggaacaa taccctcagg gtcaggagga caggatctga gtgcaggcca gccaaaaagg 75661 tgggaacaga tgctccttcc aacacctaaa tgctttttta aacggtcacc tggatgtgca 75721 gccagggcca actatccctc agctcctccc tgtcacaggt gcgcgctgcc cacagattgc 75781 cacgactggg gggctcccta ccagtcgcag cccaccctcg cctcaggtct tctctcgcgt 75841 ccccgggcgg ccgcctgcgc taacgaccac atgaaaacgt ctcagcaccc aacaccatct 75901 ctctatttca tctccatcag cgatggagag aacggatttt gccgcggctg ggctgcacag 75961 cagcgccgcg gtccacagca gagcccgcga ccgccatctt aggcagttcc aggaagcggc 76021 catttcagag cgcaccgctt agccgcggcg gcggctctgc ttctcacctt caccgaggcc 76081 tgaacagggt caacagccag tcgtcgtgga ctggaggggg aggggagaga gggaggggaa 76141 tgaaaaacaa aacagagagg aaagaaggat tcggggacag ggtgatgctc tcagctcagg 76201 gatatcgcct aggccatMtc catagaSatc cgattcgcgg ctggcgcggt cgccggtctg 76261 aagataaatt tagcactcta gagcacccga accctacaat cttcacgagc gactctgccg 76321 ccgoccaatc agcgccagat ttgcgtcccg ccRccaatcc gcgctgagca gcggggcggg 76381 accaaaggaa aggaccaagc tcggttgagg cgcggcccag ccgcagccgc agtcacagcc 76441 tcagccgcag cggccgtgct acctaggtga tagcggagcg gMtgggtagg aagcaattgt 76501 tctcaaactt cactagcccc gtcggcgcgg acgcttgtcg agaatgcaga ttcotgggta 76561 ctgccagata cggttggtga tcttRtaggg ctggagtgga agccatgaat ctgcattttc 76621 atcatttctg gccctctgcc cgggctgggg tgattcacgg ggattcgtag tggccccaaa 76681 ggagcacgca gaacctcggc tgctgtgcat ttatcacctc ttttgttccc ggaggccgca 76741 ccccaggtcc agtttacaca gctgccaact ccttttcttg gttcccactg gaatctagga 76801 agaaaactcg ccctttactt ctccgcccca cacccgacga cggagtgtct agaggtctgg 76861 tcggccttgg ctgtgcggag ggctaggcct gacgagcggg cgctgatgcg gcgcagaccc 76921 cgccggacct cttggtcggc ccggggtagg ctggggagcc gcgggaacag gactggatag 76981 ggaaagcggc accgcagcgt ccacgggcaa gctgaaagtc cgcttgatgW ctttgcatca 77041 cagtggcgcc ctccccgcag gaacgcccgg ccgcotgcac cgaacgtttg cctgcaggga 77101 acggccaacc cgccctgaaa tactcttttt gtgggctgca gctttcgggt attttaagcc 77161 atggttctgt gcccttcctt gttttcaaaa acaccacagc caaaggctgc gggttgtgtg 77221 ctttcatttt gtgttaagtt ctgtggtgga gacctggagt ctgtttttcc aaataggcac 77281 cttgaaatag atacgcttct taagcgggga aagtacgagt aggtcctatt atttgcaatg 77341 ttttagcctt tccagactcc gtacaaatga ctaaatgaag attggatcgt attttcaggc 77401 actgcaccaa tgatagaaaa ttctcaactt ggggtcaaaa gcaagggcag ctttcgtttt 77461 tcttaaatat gcttctgatc aaatatctaa agtgttgaaa gaaacctaac ccttaatagc 77521 acaatttaca ggagtgcata atttcctagg actgacattt agttccaaat gttttaaagt 77581 caattacaac atcatctoac cctatagtaa¹ gctgtccata tattctcatt attattttta 77641 aattatttct attaaatcag cttcatttga actttaacca taaatgcata aatcgttttt 77701 gggaaggggg tacagtcgcg cttgaagagc aaRggatttt gtcattgcgg gagttgtctg 77761 gcttcagaat aatattggaa taatatattt tcgtgtttca tattttagaa aaacctttta 77821 catatgtgct cccaaaccaa tcttttttta ttttttattt tttttattat tatactttaa 77881 gttctagggt gcacaacttg caggtttgtt acatatgtat acatgtgcca tgttggtgtg 77941 ctgcactcgt taactcgtca tttacattag gtatatctcc tagggctatc cctcccccct 78001 ccccccaccc cacgacaggc cctggtgtgt gatgttcccc accctgtgtc caggtgttct 78061 cattgttcta ttcccaccta tgagtgagaa catgtgtttg attttcctgt ccttgccatg 78121 ggctcccaaa ccaatcttta cacatcttgt ttacatcttc atgaagaggg aaaacccaaa 78181 atattaaact gttaggcaga atagtgttta aataagtaca tctaaagttt aggaattagg 78241 tcctgatatg atttgactct gtgtccctac ccaaatctta tatcgaattt taatccccac 78301 gtatggaagg attaaagtga ttggattatg aggacgtttt ctcccatgct gttctgatag 78361 ttaagtgaat tctcacacga tctgatggtt ttataaatgg tagtttttcc tgtggtctca 78421 catgctctct ctcacctgcc gtcatgtaag acctgccctg taagacgtgc ctgcttcccc 78481 ttcctccatg attggaaaat tttgtgaggc cgcccaggca tgtgcagctg agtcaattaa 78541 acctctttcc tttataaatt acccagtctc ggtatttctt tatagcagtg tgagaatgga 78601 ttaatatagg gccccaaatc tgaagtgtct cataattaaa gttcatgaaa cttaactttt 78661 tttgtaatcg ttttgtcaaa ttattacaga atgttgatgg gacagataag aaaaaataca 78721 gacaatgtag aactcagacc agtaatacat agctagcatt tattgaatac ataatgtagg 78781 ccggggagct attgtatacg ctttttttgt ttttgttttt gtttttttga gtcagggtct 78841 cactctgttg cctaggctgg agtgcagtgg cacgatctta gctctgtgca acctcaacct 78901 cccgggctca aatgatcttt ccacctcagc ctcctgagta gctgggacta caggtgcatg 78961 ccaccgtgtc tggctaattt ttgtattttt ttatagcgat ggggttttgc catgttagct 79021 aggctgatct caaactcctg gcctcaaacg agtcacccgc attggcctcc caaagtgctg 79081 ggattacggg tatgagccac caggcctggc ctatacactt gtaaatttat taagtctttt 79141 actgttcaca acaattttat cagttgatta accttatttt acagataagg aaattaagca 79201 caaagaggta aataacttgc cccagttcca agaactaatt agtggcagaa cctggattag 79261 gtgtgatgct ggttgtggga actacaaact gtgtttatgt gcatacttga tttatattag 79321 gcagaaaact attgtgaata atattacagt aatgtattag gtaaggaggc tgagccttac 79381 cattaaaaag gaccctgatc agccaccaag aagtccttgg ccaggcatgg tggccaatgc 79441 ctgtaatcct agcactttgg gaggacaggg caggaggatt gcctgagccc aggagtttga 79501 caccagggca ccatagcaag accccatctc tataaaaata ataaatgcat aaataataca 79561 taaaataata ataacaagaa aaagtcctcc attgttctaa tctctaagac caacttttct 79621 ctccaattct tctgccatca ctctgggctt actatcaatt tccttaacca atctcttagc 79681 taccagacaa tctctatcaa atttatccta cacacagaaa agcactttat ctaaaataca 79741 gacattaaag tctttttttt ttttttttga gatgaggttt cactgttgct caRgctggag 79801 tgcagtgRtg ccatcatggc tcactgcagc ctcaacctcc tgggttcagg tgatcctccc 79861 acctcagcct cccgagtggc taggactaca ggcacgcacc accaccacca caccaggcta 79921 atttttgtat tttttgtaga gatgaggtct cgtcatgttg cccagggtag tcttgaactc 79981 ctgggctcaa gtgatcctcc tgcctcagcc tcccaaagtg ttaggattac aggtatgagc 80041 tactgtaccc agcctaaagt cattttttta ctcaaagtta tccccttttt ggcatgatca 80101 actctttaac tgggcattta aggttttcat taaactggtt ttgcttttct tttttacttt 80161 ttacagagac agggtcttgc tatgctgccc aggctgctct caaactcatg ggctcaggca 80221 atctgtccgc ctctgcctcc caaagtgctg gggtggcagg catgagccag ccaccacact 80281 gacccaaaac tgtttttgct tttaaaattt gttttcaatg ttacacagtg acagtgctag 80341 gtgggaagta aggcaactat ggacaggaat gtctggagct ccctctcctt agctagtgat 80401 cttgtgatgt gtagtttact tgttctggct taaaggccca agtttgaggt attctttttg 80461 ttgttttgtt ttgattttaa tttttatcca agcaatgcaa gcatagagtt taaaaattca 80521 agtagaacta aaaatattat agacaataac aaaaaaacat ttcttggctc cttcttcaga 80581 tgcaatccct tgtaacattt tatgccattc aggagttcca gaccagcctg ggaaacatag 80641 caagaccctg tctcaaacaa caacaaaaac aaatccagta actcttaggt ttgtgaaaat 80701 tgtcagaatc aagatagagt cactagtgtg ggggaaaaaa acaaacaaac aaaaaaaccc 80761 agacaaatag aacccaggaa ggccattaag aggattctca tgcacagatg cctgctaaca 80821 aaaactgtca caaaacactg caaaaccaca accttgcaca aacgctgtca aaatcttaga 80881 caaaaaatag ttcttcaagg acatctcccc agcaactccc tgtgcagtct tgggctgctg 80941 tcacccttgt tactgatctt tgtagccaaa gataattatc tcaaaataat tattataatc 81001 ctccacattt tttcctttaa aaacctttgt cttcccttac ctccctgaat gtgcacatag 81061 tttactatgg cacacatatt cccactggaR tgctgtattc ccaaataaac atcgttttct 81121 tctagagagc ctccctctgt tatttagatt gaaagattaa tactactgtt tttagtttcc 81181 acttccctga agcaggaaaa aatttatatt cctctacttg tgtaagaatt tgcctatgca 81241 aatgttaatt ggctctatag ttactgatta ttccagtgat atttcagtgc ccctttcaga 81301 taaatgattt gggcaacgcc ccaactgctt accttttaat ccagatctgg ttgtggttaa 81361 aaaaaagagc aggaatatac aaaaattaac tgggcatgat ggggtgcaag cctataatcc 81421 cagctgctcc ggaagctgaa gcaggagaat tgcttgaacc caggaagtgg aggttgcaat 81481 gagctgagat cacactgttg cactccagcc tgggtgacag agcgagactg tctcaaaaaa 81541 aaaaaaaaaa ggccaggcgc agtggttcat gcctgtaatc ccagcactat gggaggccga 81601 ggcaggcaga tcacctgagg tcaggagttt gacaccagcc tggccaacat agtgaaaccc 81661 cgtctctact aaaaatacaa aaattagctg ggtgtggtgg tgcacgcctg tagtcccagc 81721 tactcaggag gctgagacag gtgaatcact tgaacccagg aggcagaggt tgcagtgagc 81781 tgagattgaa ccattgcact ccagcctggg caacagagtg agactccgtc tcaaaaaaaa 81841 gaaaaagtca ggattggtgt gtacagcagg tacagcagaa ggtgaaggag ggcagttcac 81901 tcagaaaaga actgtggcag atattgcaac atctctagtg taattctctt tgatttataa 81961 aaggctaatt actttgttac tttaaatcat gaaatcatga cacacctcac aaataaatgt 82021 catatactcc ttttctaaac cctgtagttg aaactattgg tctagaaaat aaactaatta 82081 ttgggcccca aattgagagg cttgaatatt acaaatcaga cactttctca tattttcggg 82141 gagaaggaca ggtttacttg tattgagaac ccaagtttca aataataata atttaattaa 82201 aataattttt ttgagatggg gtctcactct gtcgcccagg ctgaagtgca gtggcacaat 82261 cttggctcac tgccacctcc gcctcctggg ctccagtgat tctcccacct cagcctccct 82321 ggtagctggg actacaggtg cccaccccca ctcccagctt tttttttgta tttttggtaa 82381 agatggggtt tcaccgtgtt gcccaggctg ggctcaaact cctgagctca agtgatctgc 82441 tcaccttggc ctcccaaagt actgggatta caggtgtgag ccactgcacc tggtccatta 82501 ataatcattt gtctggaaca tacagagtac cttcacaatc tctctctcat ttgaaacttg 82561 agacaactta tttaattaag cagggaggta ttcttatccc tatttacaag gaatgaggaa 82621 tctcaggttt agagaagttg atgggtttat gcaaaactat atgcaacata cagtttttgg 82681 aatagacagt gcttggatca gttttcctga ttcagatcag tgtcttttat acttcctttt 82741 cttaagaaag ttttcaggat tgggataatg cagttacaaa gtacttctgc taagttattg 82801 atcttgggct aaataatata gtcagaactg tcatttggaa aaatagtatg ttcttccaga 82861 gttgccctct tacagaaggt gaaaattaat cttactccct taactttctc gggaaggttg 82921 atgttaaact tttaaaagcc atccctttaa aaagaatgct agatatagac aatttttaaa 82981 gccaaagtga aggtttacag gtcatttaaa cactcaatta cttggggaga aactgaaatg 83041 ccagcagatg gggttattta tagcactgtg ctgagagcca gtatatatat ttatttgtac 83101 gagagtggaa tcctggotct ggatcatttc ctgacttgtt tgagactcta agcaagtcat 83161 ttattatgtc tgtattttgg aattatagcc ttgcctcaaa ggtgtgctct gtgattaaat 83221 gaacttctat ttgtaaatct tgtttaaatt tctctgatga aaggcatatc agtgttgata 83281 gctgtggagg ataagaacgc tgacaataat aatgagtacg ataatatcag tgccttggat 83341 ttatgcagta tcattacttc ggggctttgc gtgcctccta tgtagYatgt agtctataac 83401 aaaaaactgt aattacaaac atttcacaag aaatcattct tattgtgata tttttattac 83461 ttgcagaatt gagcatacca caaaaaagtt ctcattttgt gtcctcccat cccattctcc 83521 tcactaacca aaggtaacca cagttaattg ttttttatat atccagatgt atatgtatat 83581 atattagtgt atatgactga tatattttat aaattattcc acaatttata aaatatttat 83641 aatattttgg ccttatcaat atgccttgaa gaaattttca tgtcagcatg taaatctttc 83701 tttttaatag gtgcatagtt tcccagttga tttatttaat cattccctta tgaaaagatt 83761 cttgagttgt ttctaatttt tcaacattag aaacaatgct acaatgaatg tcctgtatat 83821 acatcatctt tgcacatcta tgtgtgtact tctgtaggtt agatttctaa catggcttaa 83881 actttcaggc tgaaaggata tgtattaaat tgtaccccag aaagccttac caatgtacac 83941 ttccataaat agYacacaac agtatctttc tcctatggtc aacgttgctt tgtatagtat 84001 cagtctttct aaattttgcc atgaagatta aaaactcatt ttaattttct taactactaa 84061 tgaggttgag catctttttg taagtttatc aaccatttac atttattctt ctgtgaactg 84121 cctgttcaga ggctttccca ttttccctgt ggggtgagtt tctgtttctg tttctctttc 84181 attctttctt tctctccctt ttctctcttt ctttctttcc ttcttttttg tttctttcct 84241 tctctctttt tctctttcct ttcctttcct ttccttttcc tttcctttcc tttccttttc 84301 ctttgctttc ctttcctttc ctttcctttc ctttcctttc ctttcctttc ctttcctttc 84361 cttctccttt ctttccctcc ccacttcctt ccttccttcc ttccttcctt ccttccttcc 84421 ttccttcctt ccttccttcc ttctttcttt cttgacaggg tctcactctg tcacccaggc 84481 tggagtgcag tggtgcagtc atgactaact acaacctcaa tctcctgggc tccagtgatc 84541 ctcttgcctc agcctcccaa gtagctggga ttacaggcgc atgccaccat gtctggctga 84601 tttttattta tttattactt ccatttttct gtagaaacga ggtctcacta agttgcccag 84661 gctggtctgt gtcttattga ttgtaaaatc tcttaaaata ttttgattat gaatactggg 84721 ttaggtatgt ttcccacctt gctgttacat tgttatcttt tttcttgctg aagaaaaagt 84781 ttttaatatt tatgaaatca agtctggtgt ggtggtgcac acccatagtc tcagctgctt 84841 gggaggctga ggggggaggg ttgcttgagc ccaggaagtt gagactgctg tgagccatga 84901 tggcaccact gcactccagc ttgggtgaca gagcaagacc ctgtctcaaa aaaaataaat 84961 aaaattatga aatcagtctt ttcatttgtc aggcttttaa ataattttta aaaagtcagg 85021 cttttaaaga attaacgtta gttaattctc agaagttaca atgttagttt tattcagagt 85081 cttactgagc aYtgcaaccc gggagagtct ttcagagagt ctctgttaga ctgcttcaaa 85141 gcagcgtttc agccctcgct tctatacagg cggtggaggt tctgcatgtg ctcggaagtt 85201 acctaaaggt gctcagaggt tacattagag caaaatctca tcaaagtcca ggagcgagag 85261 tacgtctggt tatagattac agaggtatat tcattaatcc tgtcagatgt tatcttatgg 85321 ataggaaaag gcaacggctc attgaactta tcttttccaa aaatgcagtg attcagacat 85381 gggaaactgt gctctatcct gcttatggtc ttcaagcatt tttacagaga gctgagctca 85441 gtcactgagt caggggtttg ggaggtttat gctgacaagc agaatgagca aacgtggttc 85501 ttcacagcaa gggcagacgg tgtggctagc cagaggcaga tgtttgctac tttgcctcac 85561 acatttatga cttttgggat ttgtgtcttc ttaagaagga cactcttcaa ctacccctac 85621 cctaagatta taaaatagtg tccttatatt tctgctattt ttaaaagcat caggtgctct 85681 ttaatccttg tgaggtgcat tctgaatagc tgtgagaaag gaacctattt tattatttta 85741 ccaaatgttt agccagttgc ttcaaatgtg ctaattagtt cattttaatc ccagtaattt 85801 gaaatgccat ctttcaaaaa tatcaaacat ttgtaattct tgattctgtt tctagacaga 85861 gccatttgcc taattcagta ttaatattgc attatttaat ttttactatt ttctgcaact 85921 gcataatcta tcttgatatc tgatatacaa tgttttccct cattcttttt ttccccccag 85981 aattgcaggg caaaatcttg tgcatttttt cttcagtagt aacattagaa tgagcttttt 86041 agactctata aataataaca ctgggatttt ggttaggaat tatagattaa atgtaggaga 86101 gttggcattt ttatagtagt gagtcttttc agtctggatc atcatgtgtt tttccattta 86161 tttaggccac catttaggtc tgcttttgtc tttttttttt ttttaggatt ttcagtatat 86221 ttgtgtaatt ttctttatct gagtttatta caaagttaat tctctgttat tttatagtta 86281 tggtttttat catgaataca gttgtaaaat tctattttct aatacttaat tattgatgag 86341 agaagttatt tattattaat attttttctg tatcctacct gataatttaa tttttctttt 86401 attatggaag atttcaaata tatacaaagt aaacagaata gttatgaact gccacgtacc 86461 caccccaaag tttcaacaat gatcaacatt ctgccattct tgttttgact cccttcctac 86521 tttccactcc caaaattgct cttacttttt acagttcttt tttacctctt agattaaaaa 86581 aatttaaagt ttattttgag ataactgtgg attcacatgc agttgggaga aataatacag 86641 agagatctca tgtacccttt actcactttt ccccagtagt aaagtcttac acaactccag 86701 tacaatatca caacaaggat gttgacattg atacaatcaa gataaagaga atttccatca 86761 cctcaagaat ctctggtgtt gtccatttat agttacactc atttctctgc cactcccact 86821 taacccctgg caaccactaa tctgttctct gtttctgtag ttttgccatt tcaagaatgt 86881 tatataggcc aggtacagtg gctcatgcct gtattcccag tacattggga ggccgaggca 86941 ggcggattgc gtgagctcag gagtttgaga ccagcctggg caacatggtg aaacccccat 87001 ctctactaaa atataaaaaa ttagccagcg cctgtagtcc cagctactca ggaggctgag 87061 ggtggagaat tgcttgaacc ctggaggcag aggttgcagt gagctgagat catgccattg 87121 cattgcaacc tgggcgacag agagtgttat ataaatggaa tcatacatta ttagataact 87181 ttatgagatt gaagtttttt cacttagcat aattctttgg agattcaccc agatagtata 87241 acaatagttc attccttttt attgctgatc agtattccat ggtatgggta taccacaatt 87301 tgtttaaccc gttacatgtt gaaggacatc ttggttattt ccaatttttg gctattatga 87361 ataaaggtgc tataaacttt tgggtacagg ttttgtgtga acatgagttt tcattttcca 87421 ggatataggc ctaagagtgc aattatatgc atggtataat ggatggtaat tgcatgtcta 87481 actttttaaa aaattgaaaa actattttcc agtttggctg taccatttta catttccatt 87541 agctatgtat gaatgatcag gtgtttccac attcttgcca atatttggca ttgttacgat 87601 ttatgtttta gccatcctaa taggtgcata gtgatatctc actgtagtat taatttgcgt 87661 ttttcccatg gctaatatgt ttgaacatct cttaatgtgt tatttgccat ctgtatatct 87721 taattgataa aatgtctctt catgtctttt tgtttatttt ctgattggat tttttttttt 87781 ttttactgtt gtgttttagg attttttttt gttttggtgg gggcacagga tcgtgctctg 87841 ccacccaggc cggtgtacag tggtgcaata atagcttact ggaaccttaa actcctggga 87901 tcaaatgatc ctgtggcttc ggcctcccaa gtagctagga tgcctggcta attttgtatt 87961 tttttagaga cagagtctca ctatgttgcc caggctggtc tcgaacttct ggtctcaagc 88021 agtcctccct ttttggcctc ctaaagtgcc gggattatag gcgtgagaat tctttacata 88081 ttctagatgc tagtcctttg ttgaagttta atattttcta tttgtctatt ttggtttttg 88141 ttgcctgtgt ttttgaagtt ttagccataa atctttgcct ggactaatgt tcctgaagca 88201 tttcctctat attatcttct agtatttttt ataattttgg gtcttaagtt tatgttttta 88261 attcattttg aattgatttt tgtatgtatg atgcctccag ctttgttctt cttgcttagg 88321 attgctttgt ctattcagga tctcttttgg ttccatacgc attttaggat tttttttttt 88381 tttttttttt gagacagagt ctcgctctgt caccaggctg gagtgcagtg gtgcaatctt 88441 ggctcgctgc aatctctgcc tcctaggttc aagtgatttt cctgcctcag cctcctgagt 88501 agctgggact acaggcacct gccatcacgc ccggctaatt tttgtatttt tagtagaaat 88561 ggggttttac catgttgccc aggatggtct ctatctcttg accttgtgat ccacctgcct 88621 cagcctctca aagtgctggg attataggca tgagccaccg cgcccagccc aggatttttt 88681 ttttctattt ctgtaaagaa tgtaattggt atttttgtag ggcttgcatt gaatctgtaa 88741 attgctttga gtagtatggc cattttaaca atattaatcc ttccaattca taaggatgag 88801 atgtctttcc atttttttgt gtccttttca atttctttca ttggtgattt atagattccc 88861 ttgtagaggt ctttcacttc cttggctaaa tttatgccta ggcattttgt ttgtagctat 88921 tgtaaatggg attattttat tgatttgttt ttcagctagt ttgttattgg tatataaaaa 88981 tgctactgat gtttgtatgt tgattttgta ttctgcaact ttactgattt catttattgg 89041 tcctaaaagt tttttggtgg catctttagg tttttctata tataagatca tgttgtctac 89101 aaagaaggac aatttgactt cctcttttac tttttttttt ttttttcctg agagagagtt 89161 tcactcttgt tgcccagcct ggagtgcaat ggcgcgatct ctgctcactg caacctctgc 89221 ctcccaggtt caagtgattc tactgcctca gcctcctgag tagctgggat tacaggcaca 89281 tgccaccaca cctggctaat ttttgtattt ttagtagaga cggggttttg ccatgttggc 89341 caggctggtc tcgaactcct gacttcggct gatctgccca ccttggcctc ccaaagtgtt 89401 gggattatag gtgtgagcca tggtcctggc cacacttcct ctttttcaat ttggatgcct 89461 tttatttctc tcttttgcat gattgcttgg gtaggacttc cggtactatg ttgaataagt 89521 gtggtgaaag tgagaatttt tgtcttctag ttcctagagg aaaggctttc agcttttctc 89581 attgagtaga ttagctgtgg gtttgtcata tatggccttt agtatgtttt ggtatgttcc 89641 tcctgtgcct aatttgttga gagtttttat tgtgagggga tcaaatactt atctacatct 89701 gttgagataa tcatatagtt tttttgatgt aatgcaactg ttaatgtaat atattaattc 89761 aactggtacc ataacaatca atgagtggta ggaaactccc tattccattt tatttgttca 89821 ctttcatcaa catttctttt tttaattggg catccaattt agtaatgcct tttgccagat 89881 aatggagata acattattct ttatctgagg tgggaagatt gcttgagtcc acgagtttga 89941 gaccagcctg gatgtcttag caaaacctca tctctacaaa aaatacaaaa attagccagg 90001 catggtggtg tgtgcctgta gtcccagcta cccaggtggc tgaggcggga ggattgcttg 90061 agcctgggag gcagaggttg cagtgagccg agaacaggct gctgcactcc agcctgggca 90121 acagagtgag attgtctaaa aacaaacaaa caaacaaaca aacaaaaaac aaaagttatt 90181 attgatatgt gagaacttat ttctgtcatt ttgttgtttt ctgcttgtct gtatatcctt 90241 ggtccctttc ttcctctttt actgtttacc attgaggttt agtggatttc tgtagcagta 90301 atgtttgact tctttctctt tcttatttat atatctactg taccagtttt acatttgcat 90361 gggtttgctt gttggcaaat attgtccttt tgctttcaga tataggactg acttaagcct 90421 gtcttgtagg accagtctag tggtgatgaa ttccctcagt ttttgcttgt ctggcatttt 90481 atttctcttc attttcgaag gatatctttg ctaggtttag tatttttggc tggtagtgtt 90541 tttctctcag cactttaaac ataccattgt attctcttct ggcctgtaaa gtttctgctg 90601 agaaatctgc tgtttgtctg atggggattc ctgtatacat gacttgatgc ttttatcttg 90661 ctctttttag aattctcttt gtctttgact tttgatagtt tgactataat atgtcttgaa 90721 gaagaccttt ttgggttgaa tctatttgag gatctctgag ctgtatctgg gatgtctaaa 90781 tctcttgcca gacttgggaa gttgtcagct attattttgt taaatagatt tcctatgcct 90841 ttgctcgttt ctcttcottc tgaaactccc agaatttgaa catttggtca ctttgtggtg 90901 ttctatatgt tatgtaggct ttcttcattt tttttttccg agttgtcttc aagttcagaa 90961 attccctccc cttccccttc cccttacccc tccccttcct ctttctttcg ttctttcttt 91021 ctttctctct ctttctctct ttccttcctt Scttcctttc tttttttctg agatggagtc 91081 ttactttatc acccaggcta gagtgcagtg gtgcaatctc agctcactgc aacccccgcc 91141 tcctgggttc aagtgattct cctgcctcag cctcctgagt agctgggact acaggtgtgt 91201 gccaccacgc ccagctaatt tttgtatttt tagtagagac atggtttcac catgttggcc 91261 cagctggtct cgaattcctt acctcaagtg atctgctcac ctcggtctcc caaagtgtta 91321 ggactacagg catgagccaa tgtgcccagc cagaaattat ttcttacgcc taatctagtc 91381 tattgttgaa gttgtctata gtatttttta ttttattcat caaattcttc agttccagga 91441 tttctgtttg ttttttcttt tttctttttt tttgagacgg agtctcgctc tgtcgcccag 91501 gctggagtgc agtggcgcga tctcggctca ctgcaagctc cgtctcccgg gttcatgcca 91561 ttctcctgcc tcagcctcct gagtagctgg gactacaggc gcccgccacc acacctggct 91621 aatttttttg tattttttag tagagacggg gtttcaccat gttagccagg gtggtcttga 91681 tctcctgacc tcgtgatccg tccgcctcgg cctgccaaag tgctgggatt actttggcgt 91741 gagccaccgc acccggccac ctgtttgttt tttattaaat gatatctatt gcattgttga 91801 atttttcatt cagatcataa attgtttctt tgatttctat tttttacctg tgttcttttg 91861 taactcactg agtttctctg ttcttttcaa gcatttcata aatttccttt tctttcagat 91921 ctgttatcag agaattattg tgttcctttg gaggtgtcat gttttgtgtt tgtgtgtgtg 91981 gtttgagaca gggtctatct ttatcaccca ggctagagtg catagttcgc tgcagcctca 92041 aagtcttggg ctcaagggat ccatctgcct cagtccccca agtagctagg actatgggca 92101 tacactacca ggcctggcta cgtttttatt tttcatagtg atagggtctt gctatgttgc 92161 ccaggctggt ctccaactcc tggccgtaag caattcccct tgttgcctta ttaagcactt 92221 aYttatctgt caggcacttt attttatttt attattaatt tttgagatga agtctcgctc 92281 cgtcgcctag tttggagtat agtggcatga tcttggctca ctgtaaccct gccttctggg 92341 ttcaagcaat tctcatgcct cagtctcccg agtagctggg attacaggca tgcatcacca 92401 tgctcggcta attttttgtg tttttagtag agacagtgtt tcaccatgtt gatcttgaac 92461 tcctgacctc aggtgatctg cccccctcag actcccaaag tgctgggatt acaggtgtga 92521 gccaccacac ccagcctcca gtgcctttaa gtaattttaa ttttttttcc agattttatt 92581 attgttatct aaatgagggt tagtataacc aaggtactct gccagtatgg gcagatgaaa 92641 gtccctagtt actgaatttt gtgtgttgat ctttttttaa aagttttaat tttaaaacat 92701 ttaaatagtt tttggagtac aggacaagtt ctttagtggt gatttctggg atttggtgca 92761 tctgccacct gagcagtgta cattgtaaca aatatgtagt cttttatctc cctcccaccc 92821 ttcccccacc ccaagtctca aaattctgtt aattcattct tatgcctttg tatcctccta 92881 gcttagctcc tccccactta taagtgagaa catgtgatat ttagttttcc attcctgagt 92941 tacctacctt agaataatgg cctccagctt catctgagtt gctacaaaag acattatttc 93001 attttttttt tatggttgag tagtattcca tggtgtatat atacaccata tttctttatc 93061 cactggttgg ttgatgggta cttaggttgg ttccacattt ttgcagttgc gagttgtgct 93121 gctataaatg tgtgtacatg tgtctttttc atataatgac ttgttttcct ttgggtagat 93181 acccagtagt gggattgctg gattgaatgg tagttctatt tttagttctt taaggaatct 93241 ccatactgtt ttccttaatg gttgtacgag tttacattac caccagcagt gtaaaagtgt 93301 tcccttttga ccatacccac accaacatct attgattttt aacttttaaa ttatgcccat 93361 tcttgcagga ttaaagtggt atctcattgt ggttttaatt tgtgttttcc tgataattag 93421 tgatgttgaa cattttctca tatgtttatt gcctcctttt tttttttttt tgagacaggg 93481 ttttgctctg ttactcaagc tggagtgcag tggtgtgatc tcagctcagt gcaacctctg 93541 ctttctgggc tcaagtgatc ctctagcctc agcctcctga gtagttggga ctacacgtat 93601 gagccaccat acctggctaa tttttgtaca gataggtttt caccttgttg cccaggctgg 93661 tcttgaactc ctgagctcaa agtgactcac ctacctcagc ctccaaaagt gctgggatta 93721 caggctacca cgcccagcct gtatatcctc ttttgagaat tttctattcg tgttccttgc 93781 ccatttttca ataggcttat ttttttttct ttgtttgagt tccttataga ttctggttat 93841 tagtcctttg ttggatgcat agtttgcaaa tattttctcc cactctgtga gttgtctgct 93901 tactatgttg attatttctt ttgctatgca gaagctcttt gtttaattag gtcccattta 93961 tttattcttg ttttgttgca tttgcttttg ggttcttagt catgaattcc ttgoctaagc 94021 caatgtctag aagggttttt ctgatgttat cctctagaat ttttattcag atcttagatt 94081 taagtctttg atccatcttg aattgatttt tgtgtaagct gagagatgag gatccagttt 94141 cattctctat aggtggcttg ccagtttccc cagctccatt tattgaatag agtatccttt 94201 ccccagtttg tgtttttgta tgctttgtca aagatcagtt ggctgtaagc atttggtctt 94261 atttttggat tctctgttct gttccattgg tctacatgcc tatttttata ccagtaacat 94321 gctgttttgg taactgtagt ctcatagtat aatttgaagt caggcagtgt gatgcctcca 94381 gatttgttct ttttgcttag tattgctttg cctgtatggg ctcttttttg gtgccatatg 94441 aatttaagaa ttgttttttc tagttttgtg aagaatgatg atggcatttt ggtgggaatt 94501 gcattgaatc tgtaaattgc cttaggcagt atggtcattt tcacaatatt gattctactc 94561 attcatgagt atggcatgtg tttccatttg tttgtgttat ctatgacttc cttcagcaat 94621 gttttatagt tttccttgta cagatctttc acctccttgg ttaagtatat tcctgagtat 94681 tgtattgtat tttgcagctg ttgtaacagg gattgagttc ttgatttgat tctcagcttg 94741 gttgttggtg tatagcagtg ctactgattt gtgtacattg attttgtatc caaagagtgt 94801 actgaattcg tttatcagat ctaggagatt tttggatgag tctttagggt tttctagtta 94861 tatgatcata ctgtcagtga acagcaacag tttgatttcc tgtatttcta tttggatgcc 94921 ctttatttct ttctcttgtc tgatttcttt agccaggcct tccagtagta tgttgaatag 94981 aagcagtgaa aatggcatct -ttgtcttgtt ccagttctcg ggggaatgct ttcaactttt 95041 ccccattcag tattatgttc agtgtgagtt tgtcgtctat ggcttttatt gctttgagtt 95101 atgtcccttc tatgttgaga gtttttatca taaagtgata ctggattttc taaaatgctt 95161 tttctgcttt tttgttttta attctgtttc tgtagtatat cacatttact gacttgtata 95221 cattaaatca ttcctgcatc tctggtatga aacccacttg atcatgatgt attatctttt 95281 gatatgtgat tggatttagt tagctagttt tttgtttttg ttttttagga tttttgcatc 95341 tatgtctatc agggatactg gtctgtagtt ttcttttgtt aagtcgtctc ctggttttgg 95401 tRtttggatg atactggctt cacagaatga cttagggagg attccctttt tctccacttt 95461 tggaatagtt tcagtaggat tggtaccaat tcttctttga atgtctgata gaattcaatt 95521 gtgaatccat ctggtcctgg acttattttt gttgcaattt ttaaaaatta ctgattcatt 95581 gttactgctt gttattggtc tgttccaggt ttctatttct tcctgattga atctaggagg 95641 gttgtatatt tccacaaatt tgtgtgttga tcttgtattt gcccattctt tactaaatat 95701 cttattagtt ctaaaatttc agctgtaaat aatatttccc tttctcatgt tggtacctct 95761 taattacttt tcttatcaaa tctcattgtc tacaacttat agtctaaact tggagatgac 95821 acagcaggta tccttgtctt gttcctgact ttagtaagaa tacttccagt gtttcatcat 95881 gaaagcatga tattttaggt aggcttctaa taattcttcg ttaaggagtt tctcttttta 95941 aatttagaaa taagtattta atctttacaa tgctgttttt agcatttacc aagatgaaca 96001 catgattttc tccttcaatc tgagtttatg taattaatta cattatacat ttcccaatgt 96061 tgaggcatcc tgacgttctt agaataaatc ctacYgggtc atgatgaatt gatttttaaa 96121 aatattataa tgttagattt aattaggtaa tacatattta taattttaaa attcatattt 96181 gtaattgaga cttgccagag atttcttctt ttgttttcat ggtctattgt cctccagctt 96241 tgacatcagg tttatgctaa tctttaacag acacttagcc tgccaacttg atgtaatcca 96301 cagtaatgtc tccctgtaag atttctgaag agattggtgt gaggtagata ttattatcat 96361 catttttttt cagatgtggt aactgaggca cattgagaat tatagtgtct aacgtttatg 96421 atataagtca gtgactagca aactacttct tatttatgaa aatactacaa ttattctttt 96481 aatttctggg gttgagagga gggcaaagaa ttattactcc tgtgatcctc tccagctact 96541 caaactaata ttgttgttta tttctgtttc tctctgtttt tactaggcta ggaattatct 96601 gtgaatgtag gaccactgga tttgcagtct tcatctgaca ctgtggagag tttctaggaa 96661 tgaaacagat atatggcctt gggtcccctt tttttttctt tttttttttt ttaatagaga 96721 cgagcatctc actatgttgc ctagggtagt cttgaactcc tggcctcaag caatccccac 96781 ccgactccgc ctctcgaagt gatgggatta caggcRtaaa ccaccacgcc tggccagaag 96841 gtgctttaac accaaatctg aaaattgttc agaagagaaa cattgagcat gaacaccatc 96901 tgtgcgagtc atttacttat tgcccctcac ctctaaatct accttctgta ctcttcttcc 96961 ctgtaatgat ggggctagtt gtcctcaaac tgtttctcag acttcttttt aagcttgctt 97021 cctgttcagt tctgccaata ggggtcacta gagagagact gggaggcaga aggagagaat 97081 atgcttcctg ttttttctgt tcttgttaat gttgcttaca ggaccagcaa tgcttcttca 97141 cctagagaca cttctcccag cagtggcagt gccacttcag cttctttcag cactactgga 97201 atcagcctca gtgattcccc ctgtacccgc tcagagatta tccacagcag ccagatggtt 97261 ctaccttcca caaagattgt ggttgcaatt ctgggcttct aagttctggt tacttcatat 97321 ttttcctttt gttcctccag ccctagaggt ggtagctgct ttctgaagtt attatttcta 97381 gatgactttt ggtttttcag cctttgtatt ttgcttttca gccctctaat gcctgtataa 97441 ccaatttccc tgtaataaat aaatttcctc cattgaaata cctagtatgg cttttttttt 97501 gtttgttttt ctgactggac tgacataaag aggactgctc attatatgcc agctcagaac 97561 cacttaatta tgaaaatagt atattcattg tctccactcc tccaaaaatt ctgagattaa 97621 tttgtagatg tcgccggcct tgaatgaaat gcttagttcc ttgccaatgg aaaacaagat 97681 tctggtaatc tataacataa gtaggatcat gattaattaa agtatcatct atggtttctt 97741 gggaaaaaat acctattgaa gtagttgcct tcagggatca agtggctgct gcattttacc 97801 attgtggtag tacagatgac aacaaggact gtgagtggga tgacatctat gcactggaaa 97861 ccttacaggc agaaagtgac aaattgaaga ctttgaagtc taagttcaag tcaaattgag 97921 acagagaact tctatagcaa ctttgaaaaa agtttctgat ttcttatagc tataagatca 97981 acattattaa aaatataact aggtgggttg cagaattaaa atggaaatta aatttagaga 98041 ctcatcaagt catttatgtg acaatcaggg cactgggagc aagcgggatt ctaagacttg 98101 cgttggactt ggatgaagct aaatgcccag gtccctctga ataagcagaa gcagtccctc 98161 ttataacaga gaagattgcc aggcgcggtg gctcacgcct gtcatctagc actttgggag 98221 gccggggagg gcggatcacc tgaggtcggg agttcaagac cagcctgacc aacacggaga 98281 aaccttgtct ctactaaaaa aatacaaaat taaccagacg tggtggtgca tgcctgcaat 98341 cccagctact caggaggctg acgcaggaga attgcttgaa cccgggaggc tgaggttgcg 98401 gtgagccgag atcacgccat tgtactccag gctgggcaac aagagcgaaa ctccgtctcg 98461 _v ggaaaaaaaa aaaaaaaaaa aaaggctggg tgtggtggct cacgcctgta atcccagcac 98521 tttgggaggc cgaggcgggt tgcggtgagc cgagattgcg ccattgcact ccagcctggg 98581 caacaagagc gaaactccgt ctcaaaaaac aaaaacaaaa acaacagaga agattgacct 98641 ttccttcttg aaaactctat aatcaattca tctgaagcag ctgccttaca agggatactt 98701 attatcctca agacccatcc ccattgctga ttatttttta gtctagacct aaacttgagt 98761 tagatctcag catactcaaa cagaatggag attcagacct ggggataaat tgcctatMcc 98821 taaaaaaaaa aaaaaaaaaa aaaaaaaaag caggattttg ataattcata tagaaaaaaM 98881 caagaaaata tgtgtgagaa tagtatacaa gggtgttagg ctaaaaggaa cagaatataa 98941 ttttgtctca ggattaacat attgatataa gaacatttac cagatagtct .agatttaatg 99001 ttttagataa agctagaaat ggctctaata gctttctgga atgactaaat ttttgcctca 99061 ttgatggcct acattcgatg aagtttggtg ccataacttc

[0286] FollowingisagenomicnucleotidesequenceofaRegionAlocus(SEQIDNO:3).

>6: 62187501-62285000

1 aagaacagtt atagtagata tagatcatac atatgattat atgtgaatat cattaatcat

61 tactttttag caattactct atattccaat attataataa tcatcactct acaatcataa

121 cctaagaaag aacaggccat acaaagatag aagctgaagg gacatagtga gaggtgagag

181 gtgactagaa ctactgaatc aaaaggaagg tttaagtctg tgagatgaat gcaYgcaaca

241 caaaccacct tctcagaaat cttctttcta cttcttatct gaagatattt tctttttcac

301 cataggcctc aatgtgctcc caaatagccc tttgcaggtt gtacaaacac agtgttttca

361 aactgcggaa tgaaaagaag ggtataactc tgcgagatga atgcacacat cacaaagtgg

421 tttctcatat agcttccttc cagtttttat cctgggatat tcactttttt gccattggcc

481 tcaatgagct cccaaatgtc cattagcaga atggacaaaa acaatgtttc ccaactgctg

541 aatgaaaaga aaagtttaac tctttgagat taatgcacac aacacaaatc aatttctcag

601 aaagcttctt tctagttttt atctgaaagt attttctttt tcatcttcat cctcaaagca

661 ctcccaaata tcccttcgca tattccatga aaacagtgtt tccaaactgc tgaattaaaa

721 caaaagttta aatctgcgag atgaatgcac tcatcacaaa gcagtttctc aggtagcatt

781 cttctagttt taatcctggg atagtcactt tttcaccatt ggtctcaatg atatctcaaa

841 tgtccattca cagagtggac aaaaagagtg tttccaaatt gctaaatcaa aagaaagttt

901 ttaatctgtg agatgaatgc acacattaca aggcagtttc tcagaaagac ttcacttttt

961 ctctgaagat gttttcttat tcgccatagg cctcaaagtg ctcccaagta tcccttcaca

1021 gatcctacaa aaagacttta tctaaactgc tgaatgaaaa gaatggttta actctgtgag

1081 atgaatgcat acatcacaaa gcagtttctc agatagcttc cttctagttt ttattctgga

1141 atattcactt tttcgccatt ggcttcagtg agctctgaaa tatccattca cagaatgggc

1201 aaaaagagtg tttccaaact gctgaatcaa aagaaaggtt taactgtatg agatgaatgg

1261 gcacatcaaa aagtagaata tcagaatgtt ctttctagtt tttatcggaa atattttatt

1321 tttcaccata ggcctcgata cactcccaaa tatctctttg aggattctgc aaaaacagtg 1381 tttacaaact gcttaatgaa aaagaaaggt ttaactctgc gaattgaatg cacacatcgg 1441 aaagtggtta ctcagagagc ttccttctag tttttatcct gtggtattca ctttttcact 1501 attgacctca atgacctccc aatgtccatt tgcagaatgg acaaaaagtg ttttgaaaca 1561 gctgaatcaa atgaaaggtt aaactctttg agatgaatgc acacataaca aagcagtttc 1621 acagaagctt ctttctactt tttatatgaa gatattttat tttacacctt aggccttaat 1681 gtgctcccaa atttcccttt acagattctg caagaaaagt gtttccaaac tgctgaatga 1741 aaagaaaggt ttaaatatgc aagatgaatg cacacatcac aaaggggttt ctcagatagc 1801 ttccttctag ttttatcctg ggatattcac ttttttgcca ttggcctcaa tgaccttcca 1861 aatgtccatt tgcagaattc acaaaaacag tgtttcccaa cttctgaatc aaaagaaaat 1921 -tttaaccctg ggagatgaat gcacacatca aaagctgttc ttcagaaagc ttctttctac 1981 tgtttatctg cagatatttt cttttgcacc atagaactca atgacctcca aaatatgcct 2041 tcacaggttc tacaaaaaca gtatttccaa cctactgagt gagaaaaaag gtttaactct 2101 gtgagatgaa tgcacacatc agaaagcttt ttgtcagata gattccttct agtttttatc 2161 ctgggatatt cacttttttg ccattggcat tagtgacctc cgaaatgtcc actctcagaa 2221 aggacaaaaa cactgtttcc aagctgctga gtctaaagaa aagtgtaact gttttagatg 2281 aatgcacaca tcacaaagca gtctcacaga tagttccttt ctacttttta tctgatgata 2341 tttacttttc accatcgacc tcaatgcact ccaatatatc cctttgcaga ttctacaaaa 2401 cagtgtttcc aaactgctga atgaaaaaaa tggttcaaca ctgtgagtta aatacagaca 2461 tcacaaagca gtttctcaga tagcttcctt caagttttta tcctgggata ttcacttttt 2521 cccctttggc ctcaactagc tcctaaatgt ccagtcacag aatggacaaa aacagagttt 2581 ccaaactgct gaatcagaag aatggcttaa ctctgtgaga tgaatgcaca catcacaaag 2641 cagttcccca ggaagattct ttctagtttt tatctgaaga tattttcttt ttcaccatag 2701 gcctcaatgc actctcaaat atcccttcac agattgtaca aaaatagtgt ttccaaagtg 2761 ttgcatgaac acaaacattt atccctgtgg gatgaaagca cacatcacca agcagttctt 2821 caggtgcctt aattctagtt tttgtcctgg gatattccct tcttcaccat tggcctcaat 2881 gggctccaaa atgtccattc acagaatgga caaaaacagt ttttccaaac tgctgaatca 2941 aaagaaagtt ttaactctgt ttgatgaatg cacacatcac aaagcagatc ctcagaaagc 3001 ttctttctac attttatctg aagatatttt ctttttcacc ataagataca atgcgctctc 3061 aaatacctct ttgcagattc tacaaaaaca gtgtttacaa actgcttagt gaaaaaaaac 3121 gttgaacttt gtgagttgaa tgcacacatc aaaaagcagt ttctcagata gcttccttct 3181 agtttttatc ctgggatatt cacttttttg Ycattgtact caatgtgctc cccaaagccc 3241 attcacagaa tggacaaata agtgtttccc aactaaggaa tcataaaaaa cggtttaact 3301 ctgtaagatg aatgcacaca tcacaaagca gtttctcaga aagcttcctt ctagttttta 3361 tcatgggata ttcacttttt cgccattgac ctcaataagc tgacaaacat ccattcacaa 3421 aatggacaaa aaccatgttt ccaagctgct gaatcaaaag aaaggtataa ctctgtgaga 3481 tgaatgcata cttcaaaagg cagtttctca gaaagcttct ttctactttt tatctcaaga 3541 cattttcttt ttcaccatag gcctcaatgt gcttccaatt atctctttac agattctaca 3601 aaaacagtgt tttcaaactg ctgattgaaa aaaaggtttc acactgtgag aagaatacac 3661 acatcagaaa gccttttctc agatagcttc cttctaggtt ttttcctgtg atattcactt 3721 tttctccatt ggtctcaatg agctcccata tgtccattca cagaatggac aaaaaaagtg 3781 tttccaaact gctgagtcta aagaaatgtt tacctctgtg tgatgaatgc acacatcgca 3841 aagcagtttt tcagaaagct tctttctact ttttatctga aggtattttc tttttcacct 3901 tagacctcaa tgcactccca aatatccctt cacagattct acctcaaata gcttccctct 3961 agtttttatc ctgggttatt cactttttca tcattgcctc caggtgctcc ctattgtcca 4021 ttcacctgac tgacaaaaga gtgtttccaa actgctgaaa caaaagaaag gtttagctct 4081 gtgacatgaa tgcgtacatc acaagacatt cttttgttga atcaaaagaa tggttgaatt 4141 ctgaggtaaa ggcagacatc acaaagaatg ttctcagaaa gcttctttct agtttttatc 4201 tgaagatatg ttctttttca ccataggctc aatgtgctcc caaatatcca ttagcagatt 4261 ctacaaaaac agtgtttcca aactgctgaa tgaaaccaaa gttttaactt gcaaaatgaa 4321 tgcacacatc acaaagcagt ttctcagcta acttccttct agtttttatc ctgtgatatt 4381 ctcctttttg cctttgtcct caatcaactc ccagatgttt atttgcacaa atcacaaatc 4441 agtgtttcca gactgctgaa tcaaaagaaa agtttaacac tgtgagatga atgcacacag 4501 cacaaagtga tttctcagat agcttccttc aattttttat cctgggatat ttgctttatc 4561 tccattgacc tcaatgagct cccaaatgtc cattcacaga atggacaaaa gcagtgtttc 4621 caaactgcgg aatcacagga aatgtttaac tctgtaagat gaatgcatac acccaaagca 4681 gtttctcaga aagcttcttt ctggttttta tatgaagata tttacttttt caccttaggc 4741 ctcaatgtgc tcccaaatat ccctttgcag attctacaaa gacagtgttt ccaaactgct 4801 gattgaaaag aaatgtttaa ctctgtgaca tgaatgcaaa catcacaaag cggtttctca 4861 ataccttcct tctatttttt atcctgggat attccctttt ttgacattgg cctcaaagac 4921 ctcaaaaata tccattatca gtatggagaa aaacagaata tttgaaactg cttaatcaaa 4981 ggaaaggttt aactctgtga gatgaatgca tacatcacaa agcagtttct cagaaagctt 5041 cttttagttt ttatgtgaag atatttactc tttcaccata ggcctcaatg ggctcccaaa 5101 tatccctttg caattctaca aaaacagtga ttccaaactg ctgaatgaaa acaaaggttt 5161 aactctgtga gctgaatgaa cctatcacac tatcacaaaa cggtttctca gctagcttcc 5221 ttctagttta tatcctagga tattcccttt tttgacatta gtctcaaaga gctcaaaaat 5281 atccatttgc agaatggaga aaaacagtgt atacaaactg cataatcaaa agaaagttac 5341 aactctgtca gatgaatgca cacatacaaa gcagttcctc agaaagcttc tttctacttt 5401 ttgtctgaag atattttctt ttacaccaga ggcctcaatg tgctcccaaa tatcccttct 5461 cacattctac aaaaacagta tttccaaact tctgaattaa aggaaaggtt taactctgtg 5521 agatgaatgc aaacatcaca aagaggtttt tcagagagtt tccatgcagt ttttatcttg 5581 ggatattctc tttttctcca ttagcctcaa tgatcttcca aatgtctgtt tgcagaatgc 5641 acagaaacag tgtttccaga cagttgaatc aaaagaaagt tttaattctg tgagatgaat 5701 gcttacatca caaagcagtt tgtcagaaat cttctctcta gtttttatat gaagatattt 5761 tctttttcac cataatcctc aatgctctcc caaatatccc tttgcagatt ctacaaaaac 5821 agtgtttcca atctgcatta tgaaaataaa attttaactc tgcaagatga atgcacacaa 5881 ctgaaagcag tttctcagat atcttccttc taattttttc ctgggatatt ctctttttct 5941 ccactggcct caatgagctc ttaaatgtcc atttgcagaa tggacaaaaa cagtgtttca 6001 aattgttgaa tcaaaaggaa gttttaactc agtgatatga atgtccacat cataaaccaa 6061 tttgtcagag ggcttctttc tagattttat cttaaggtat tttctttttc aacataggtc 6121 tcaatgtgct cctaaatgtc acttcccaga tgctacaaaa acattgtttc caaactgctg 6181 aattaaaaga aaggtttgac tctgcgagat gaatgcagac atcacaaatc agtttctcag 6241 atagcttcct tgtagttttt accctgggat attccctttt ttgccattgg cctcaaagac 6301 ctcacaaatg tccattcRca gaatggacaa aaacagtgtt tccaaaatgt tgaatgaaat 6361 gaaaggttta atgctgtgag atgaatgcac acatcacaaa gcagtttatg agaaagcttt 6421 ttctaatttt cgtctgaaga tattttcttt ttcactatag ggcaaaatat cccttcacag 6481 attctatgaa aaaaaaaaaa aaaaaaaaca gtgtttccaa actgctgaat gaaaagaaag 6541 gtttaactct gccagatgaa tgcacacatc acaaaaccat ttctcacata gcttccttga 6601 agtttttatt ctgggatatt cacttttcta catttggtct caaagagctc ccaaatcttc 6661 attcgcacaa aggacaaatc agtgtttcca aactggggta tcaaaagaaa tatttaactc 6721 tgtgagatga atgcagacat cacaaagcag tttgtctgaa agattctttc tactttttat 6781 ctgaagatat tttctttttc accataagac tcaaggtgct ccccagtatc cctttgcaga 6841 ttctacaaaa aaagtgtttc taaactgctg aataaaaaga aaggtttaac tctatgagat 6901 gaaagcacac atcacaaagc agtttctaac atagcttact tctagttttt atcctgggat 6961 atctcttttt tgccattggc ctcaatcagc tacctaatgt acatttgcag aatggacaaa 7021 aacagttttt ccaaactgtt gaatcaaaca aaaggtttaa ctctgtgagg tgaatgcacc 7081 catcacagag cagtttctca gaaaacttct ttctactttt tatcttaaga tactttccct 7141 ttaaccataa gcctcaatga gctcccaaat ttctctttgc agattctaca aaaacagtgt 7201 ttccaaagtc ctgaatgaaa agaaaggttt acctctgtga gatgaatgca cacatcacaa 7261 agtgttttct cagatagctt ccttgaaggt ttgtgagaca aaaacagtgt tttgaaactg 7321 ctctattgaa agaaatgatt aaattggtga gatgaatgca cacatcacaa agcagtttct 7381 cagaaagctt ctttctaact tttatctaga tataatttct gtttcaccat aggccttaat 7441 gcactcccaa atattgcttc ccagattcta caaaaacggt gtgtccaaag tgctgaatga 7501 agagaaaggt ttaactctgt tagatgaaag cacacatcac aaagcagttt ctcataaagc 7561 ttctctctac tttttatctg atgataattt ctttttcacc ataggcctca atgcacttcc 7621 aaatatccct ttgcagattc tacaaaagca gtgtttccaa atgttgaatg aacaggaagg 7681 tttaactctg tgagatgaat gcacacatca caaagctgct tctcagatag cctacttcta 7741 gtttttatcc agggatactc acttttttgc ctttggcctc aaagagctcc taaatgtaca 7801 tttgccgaaa ggacaaaaac aatgtttcca atcagctgaa tcagaagaaa agtttaactc 7861 tgttagatga aatcacacct cacaaagcag tttctcataa agtttctttc tactttttat 7921 ctgatgataa tttctttttc accataggcc tcattgactc tgaaatatcc ctctgcagat 7981 tctacagaag cagtatttcc aaatgttgaa tgaaaaggaa gctttaactc tgtgagatga 8041 atgcacacat cacaaagctc cttctcagat agcctacttc tagtttttat ccggggatat 8101 tcgctttttc gcctttggcc tcaaagagct cctaaatgta catttgcaga aaggacaaaa 8161 acaatgtttc caatcagctg aatcaaaaca aaagattaac cctatgagat gaatgcacac 8221 ataaaaaagc agtttctcaa aaaccttctt tctacttttt atctgaagct aatttatttt 8281 tcaccacagg cctcaatgca ctctgaaata tccctttgca gatcccacaa aaacactgtt 8341 tccaaactgc tgaatgaaaa gaatggttta actctgaaag gtgaatgtgc acatcacaaa 8401 gtggtttctc agataacttc cttctaattt ttatccaggg atatttcctt tttcaccatt 8461 ggcctcagtg agctaccaaa tgttgatttg ctgaatggac aaaaaccgtg tttccaaact 8521 gctgagtgaa aagaaaggct taactccatg agataaatgc aagcatcata aagctgttcc 8581 tcacaaagtt tctcccaact ttttatatat agatgttttc tttttcacca taRacctcaa 8641 tgcactctca aatatccctg cagagatttt acgaaaacat gtttccaaaa agctgaatga 8701 aaagaaagat tcaattctgt gaggtgaatg tgcaaatcac aaagcagttc ttacatagct 8761 tccttatagt ttttatgctg ggatatttcc ttttttgcca ttggtctcaa tgagctccca 8821 aatgtccatt tgcaaaatgg ataaaaacag tgtttccaaa ctgttgaatc aaaagaaaag 8881 tttaactctg tgagatgaat gcacacattg caaagcagtt tctcagatag ctttcttcta 8941 gtttttatcc tgggatattc tcttttttgc ctttggtctc aatgagctcc taaatgtcca 9001 tttgcagaat gggcaaaaac agtgtttcca tactgctgaa tcaaaggaaa tgtttatatc 9061 tgtgagatga atRcacacat cacagagcag cttctcaaaa agcttctttc tactttttat 9121 ctcaagatat tttatttttc tctataggct ttaatgcact cccaaatatt ccttcacata 9181 ttccacaaaa agagtgtttc caaactgctg aatgaaaaga aagatttaac tctgtgagat 9241 gaatccacac atcacaaagc agtctctcag aaagcttctt tcaacttttt atctgatgat 9301 atcttctttt ttaccataKK cctcagtgca ctcccaaata tcacatcata gattctacaa

9361 aaacagagtt tccaaactgc tgaatcaaaa gagagtttta actctgtgag gtgaatcaac

9421 acttcacaaa gcagtttcta aaaagcttct ttcaactttt tatctgaaga tattttcttt

9481 ttaaccataa gtatcactgc actctgattt atcccttcac ggattctaca aaaagattgt

9541 ttccaaaatg ctgagttaaa acacaggttt aagtttgcaa tatgaataca cacttcacaa

9601 agccatttct cagatagctt ccttctagtt tttatcctgg gatattcact ttttcacctt

9661 tttcctcaat gagctccaaa atgtccatcc tccgaatgga caaaaacagt tttttcaaac

9721 tactgaatca aagaaaggtt taaatctgtt agatgaatgc acacatcaca aagtagtttc

9781 tcacaaagct tccttctttt tatctgaagt tattttcttt ttcaccatag ctttcaatgt

9841 gctcccaaat atcccttcac agattctaaa aagacagtgt ttccaaactg ctgaatgtaa

9901 agaaagtttt aaaactctgc cagatgaatg caaacatttc caagcagttt ctcagacact

9961 tccttctagt ttttatcctg Yaatattcac ttttttgcca atttcctcaa tgagatccca

10021 aatatccttt cRcagaatgR acaaaaacag tttttccaaa atgctgaatc gaaacaaagt

10081 tttaactctt tgagttgaat gaacatatca caaagcagtt tctctgatag cttcctYcta

10141 atttttaccc tgggataatc actttttctc cattcaccca ataggctacc aaatgtccat

10201 tagcagaata ggcaaaaaca gtgattccaa actgctgaat caaaagaaag gtttaactgt

10261 gtgagaagag tgcacacatc acaaagcgtc ttgttagaaa gcttctttct agttttcatc

10321 tgaagatatt ttctttttca ccataggcct ccatgcactc ccaaatatcc cttcatagat

10381 tccacaataa cagtgtatcc aaattcctga atgaaaagaa acttttaaat ctatgagatg

10441 gatgcacaca tcacaaagca gtttctcaga gaacttcctt ctacttttta tcataggatt

10501 ttctcttttg ccattggcct caatgagctc ccaaaagtcc atttgcagaa tggggaaaaa

10561 ctgtgtttct aaactgtgga atcaaaataa aagtttaatt ctgtgagatg aatgcacaca

10621 tcacaaagca gtttttcaca aagcttcttt ctagttttta tctgaagata ttttcttttt

10681 caccttaggc atcaaaagac tcccaaatat cccttcacag attttacaaa aacagtgttt

10741 ccaatctgct gaatgaaaaa taaagtttaa atctgtgaga taagtgcatt catcacaaag

10801 cggtttgtca gatagcttct ttctactttt tatcctggaa tgtttgattt ttcgccattg

10861 gcctcaatga gctcccaaat gtccattcac ataatggaca aaaagagtgt ttccatactg

10921 ctgaatgaaa agaaagtttt aactctgtga gatgaatgca caaatcacat gagagcttca

10981 cagaatgctt ctttctagtt ttcatctgta aatattttct ttttcaccat aggcaacact

11041 gcgctcccaa atataccttc aaagtttgca caaaaacagt gtttccaaac tgctgaagga

11101 aaacaaaggt ttaactctgc aagatgaatg cacacatcac aaagcagtat ctcagatacc

11161 ttcctgctag tttctatcct gggatattcg ctattttgct tttggactca atgagctccc

11221 aaatatccat tcacagaaag gacaaaaaca gtgtttccac tctgctgaat caaaggaaac

11281 ttttatctct gtgagatgaa tgcccacatc acaaaccagt ttctcagaaa gtttctttct

11341 agcttttaac tggagataat atctgcttca ccataggcct caatgtgttt ccaaatatcc

11401 cttcgcagat tccacaaaaa cagtgtttcc aaactgctga gtaaaaagaa aggtttaact

11461 gtgggatgaa tgcccacatc acaaagcagt ttctcagaaa ggttctttct agcttttatc

11521 tggagataat ttctgtttca ccatatgcct caatgcactc ccaaatatcc ctttgcagat

11581 tctacaaaaa cagtgtttcc aaaaaggctg aatgaaatga aagcttttac tctgcgagct

11641 gaattcatat attacaaact gctttctaag atagcttcct cctagttttt aacctgggat

11701 atacgctttt tcacatttgg cctcaatgag ctcccaaatg tctgttcact gaaagggcaa

11761 aaccagtttt tccaaactgc tatatgaaaa gaaatgttta aatctgttag atgaatgcac

11821 acgtcacaaa gcagtatctc agaaagcttc tttctacttt ttatttgaag attttttttg

11881 accataggcc tcaatgtgct cccaaatatc cctgcacaga ttctacaaaa acagtgtttc

11941 caaactgctg aatgaaaata aaggtttatc tctgctatat gaatgcacac atcacaatta

12001 agtttctcag atagcttcct tctagttttt atcctgggat attctttttt ggccatcggc

12061 ctcaatgago ctccaaatgt ccatttgtag aatggacaaa agcagtgttt ccaaactgct

12121 gaatcaaaag aaagttttaa ctctgtttga tgaatgcaca catcacaaat cagtttatca

12181 gaaagcttct tactagtttt taactggaga tattttcttt ttcagcacat gcctcattgt

12241 gotcccaaat atcccttcac agattcttaa aaaaaatgta tccaaactgc tgaattaaaa

12301 gaatggttta actaagcatg atgaatacac acatcacata gaggtttctc agatagcttc

12361 cttctagttt ttatctggga atattggctt ttttgccatt tgcctcaatg agattccaaa

12421 tgtccattca cataatggac agaaacagtg tttccaaact gctgaatcaa aagaaaggtt

12481 ttactatgtg agatcaatgc acacatcaca aagcagtttg tcagaaagct tctacttttt

12541 atctgaagat attttcttta acaccatatg cctcaaagtg ctcccaaata tcccttcact

12601 gattctacaa aaacagtgta tctaaactgc tgaataaaaa gaaaggttta actctgtgag

12661 atgaatgcac aaatcacaag gcagcatcac agaattcttc Kttctagttt tcatctgaag

12721 atattttctt tttcaccata ggcaacaRtg cRctccccaa tatccttttg cagtttctac

12781 aaaaacagtg tttccaaact attgaatgaa aagaaagttt taaatctgtg agttgaatac

12841 acacatcaca aagtagtttc tcagataggt tacttctagt ttttgtcctg ggatattcag

12901 ttttctgcct ttggcctcaa agagctccca aatgtccatt cagagaatgg acaaaaacag

12961 tgtttccaaa ctgctgaata aaaagaaatt tttaactctg tgaaatgaaa gcaaacaaca

13021 caaagcagtt tttcagaaag cttctttctc ctttttatct gaagatattt tctttttcac

13081 catgtgcctc aatgtttaat gaaaaggagg ttttatctct gtgagacgaa tgcacacttt

13141 accaagcggt ttctcacata gcttccttct aggttttatc ctgggatatt ctcctttttg

13201 ccattggcct caatgaccac ccaaatgtcc attcccagaa tggacaaaaa cacagtttcc 13261 aaatgctgaa ccaaaagaaa ggtttatgtc tgtgagatga atgcacatat cacaaagcag 13321 tttttcagaa agcttccttc tagtttttac catgggatat ttgcttttat gccattggcc 13381 aaaatgagct cccaaatgtc cattcacaga atgggcaaaa acagtgtttc caaactgctg 13441 aatcaaaaga aagttttaac tgtgggagat gaatgcacac atcaaaaaga agcttcttgg 13501 aaggcttctt tctagttatc atctgaagat atattttttt caccatagcc ctcaatgcac 13561 tcccaaataa catttcatag attctacaaa aatagagttt ccaaactgct caatctaaag 13621 actgttttaa ctctgtgaga tgaatgcaga catcacaaag cagtttctaa aaagcttcca 13681 tctacttttt ctctgaagat attttctttt tccttaaagg ccttgatgtg ctcccaaata 13741 acccttcaca gattctcgaa aaacactgtt tccaaacagc tgactgaaaa gaaagattta 13801 actctgtgag atgaatgcac atatcacaaa gtagtttcta agaaatctta ttttaggttt 13861 atctggatgt attttctttt caccataggc ctcaaggcac tcccaaatat ccctttgcag 13921 actctacaaa aacatgattt ccaaactgca gaatgaaaaa aaaggtttaa ctctgtgaga 13981 tgaatgcaca aatcacaaag cagtttctga gatatcttcc ttgaactttt tttaaatcct 14041 gggatattat ctttttcact tttggcctca atgaattccc aaatgtccat tcacagaatt 14101 gacaaaaaca gtgttttcaa actactgaat caaagaaagg tttaactctg gaagatgact 14161 gcacacatca caaagcagtt tctcagaaag tttctttcta ctttttatct gaagatattt 14221 tctttttcac cataggcctc catgcactcc caaatatacc ttcatagatt caacaataac 14281 agtgtatcca aactcctgaa tgaaaagaaa cttttaactc tatgagatgg atacacacat 14341 caccaagcgg tttctcagag agcttccttc taggttttat cctgggatat tctcttttgc 14401 cattagacta aatgagctcc caaatgtcca tttgcagaat gggcaaaaat tgtgtttcca 14461 aactgtggaa tcaaaagaaa agtttaactc tgtgagatga atgcacacat cacaaagcag 14521 tttttcagaa agcttcttac tagtttttat ctgaaggtat tttctttttc accttaggcc 14581 tcaaaagact cccaaatatc cctttacaga ttctacaaaa acagtgtttc caatttgctg 14641 aatgaaaagt aaggtttaaa tctgtgagat aagtgtgctt atcacaaagc ggtttgtcag 14701 ataacttctt tctacttttt atcctggaat gtttgctttt ttgccattgg cctcaatgag 14761 ctctcaaata tccattcaca taatggacaa aaagagtgtt tccaaactgc tgaatgaaaa 14821 gaacgtttta attctgcgag aagaatgcac agatcacgtg agagcttcac agaatgcttc 14881 tttctagttt tcatctgtaa atattttctt tttcactgta ggtaacactg cactcccaaa 14941 tataccttca cacaaaacat accttcatac aaaaacagtg tttccaaact gctgaatgaa 15001 aataaagttt taaatctccg agatgaatgc acacatcaca ccacagtttc tcagatagct 15061 tagttctagt ttttatcctg ggatattcac ttttttgcct ttggcctcaa tgagctctca 15121 aaagtccatt tgcagaatgg acaaaaacag tgtttccaaa ctgctgaata aaaaaaaagg 15181 tttaactctg tgaaatgaat gcacacagca caaagcagtt tctcagaaac cttctttcta 15241 ccttttatct gaagaaattt tctttttcat tacaggcctc agtgagctcc caaatatctc 15301 tttgcagatt ctacaaaaag tgtttccaga ctgYtgaatg aaaagaaagt tttatctctg 15361 tgagatgaat acacatcaca aagtagtttc tcagatagct tccttctaat ttttatcctg 15421 ggaagtatgc tttttcacca ttggcctcaR tgaactccca aatttccatt cacagaatgg 15481 acaaaaacaa tgtttccaaa gtgctgaatc aaaagaaagg tttattttgc atgcatcatg 15541 aagcagtttc tcaaaagttt ctttctactt tttatttgaa gatattttct ttttcaacat 15601 aggactcaat gcgctcccaa atatccattc acagattcta taaatacagt gtttccaaac 15661 ttcagaatga aaaaatgtgt taactctgtg agatgaatgc agacatcaca aagaggtttc 15721 tcagatagct tccttctagt ttttatcctg ggatattcac ttttttgcca ttggccccaa 15781 tgagctccaa aatgtccatt cacagaatgg acaaaaagag tgtttccaaa ctgctgagtc 15841 aaaagaaata tttaactctg tgagatgaat gcacacatca caaagcagtt tctcaaatat 15901 ttctttctag tttttatctg tagatatttt tttttcacct taggcttcct ctgagaccag 15961 cactttctgg cagactctaa cccaatggca ctagaggaat taaagacaca caaaaaaata 16021 tagagttgta aagtgggaaa tcgtgtgtct cacagccttt aaagctgaaa gtcctgaata 16081 gagatttaca catgtatatg ttaacagcaa actagtcatt agcattgttt ctgtagatat 16141 taaattaact aaaattatcc cttatgggat atgaatggat gggccaaatt aaaggaatag 16201 gttgggctag ttaactgtgt caggagcatg tccttaaggc acaagttgct catgctattg 16261 tttgtggctt aagaaagcct ttaaacggtt ttccaccatg gacaggccag gtgttccttg 16321 ccctcattct ggtaaaccca caaccttcca gtgtgtgagt tagggtcaca aagcacatgt 16381 cacagtgttg cagagatttc atttatggcc agtttggggg ccagtttatg gacagatttt 16441 ggagggcttt ctcccaacMt gtccccattc tttgatttgc aaattgataa aagcaaaggc 16501 agctttgtca cagtgagttc cttctcacag gagtcacatc cacaactaca gactacacaa 16561 agaaaaacaa catagattaa aagcacaatc atcattgaaa tcacagagct tccaagtgtt 16621 tttatccatt ttaatgggtt actagctgct aatttttctt cagctccttt aagcactcag 16681 tttctggcat taatgtgagg tgtgcctggg atgctttaaa tgtttgttct tttaattttg 16741 gcatatScaa aaacaagttt gtagagtgtc cttatagatt ttttttatcc tttcccaaat 16801 tttgatctta ttaagagcat ttaatagttt ccgcaaatcc ttatgttaag ctcccagtgc 16861 gggccatatc atttgaggtt gaggtgccac aatactgcca tggttccaga taataggaag 16921 ttttgtcgta cttcttatca tatctaccat ctgaccactt ggttcagatc atctgaacat 16981 agtgtggcca cggcacacag actgagaggt gcaattcaag ctaaacctct ccttagggga 17041 atgattaata atgattccat agSaatcatt gtgcagcacc tctgcctgtt ctgcaatgca 17101 atcttcctaa acaagtacgt tcattttttc taactgggtc caatcctgtt tacaagtagg 17161 tttagatgaa tgcacacatc atgcagcagt ttctcagaaa gctactttct agcttatatc 17221 tgaagatatt tctcttttca ccataagcct caatgcactc ccaaatttca ttttgcagat 17281 tctataaaaa cagtgtttcc aaagggcaga atgaaaagaa aggtttaact ctaccagatg 17341 aatgaacaca tcacaatatg gtttctcaga tagcttcctt ctaattttta tcgagggata 17401 tttgctgttt tgtcattggc ctcaatgagc tccaaaatcc ccattctgtg aatggacaaa 17461 aacagtgttt ccaaactgct gaatcaaaag aaaagtttaa ctctgtgaga tgaatgcaca 17521 catcacaaaa cggttcctaa gaaagcttct ttatactttc tatctgaaga tattttgttt 17581 ttcaacatag gcctcaacat gctcccaaat atccctttgt agcttctata aaaacagttt 17641 ttccaaactg ctgaaagaaa agaaaggttt tactctgtga gattaatgcc cacaacacga 17701 agcagtttct cagatagctt ccttctagtt tttatcatgg gatattcact ttttagctat 17761 ttgcctcaat gagctctgaa atgtccattY gcagaatgga caaaaactgt gtttccaaac 17821 tgctgaatca aaagaaaggt ttatgtctgt gaggtgaatg cacacataac aaagcagttt 17881 ctcagaaaac ttccttcta.g ttttatctga agatattttc tttatcacca taggcctcaa 17941 agtgctccca aatatccctt cacagttcta caaaaaagtg tttccaaact gctgaaagat 18001 taactctgtg agatgaattc ccacatcaca aatcagtctc tcagaaagtt tctttctatt 18061 tttatcagaa gagattttcc ttttcaccgt aggtctcaat gcgctcccaa acatcccttt 18121 gcagatttta caaaaacaga gtttcaaaac tgttgaatga aaagaaaggt ttaactctgc 18181 , aagatgaatg cacacatcac aaagcatttt ctcagacagc ttccttctgg ttttaatctt 18241 gggatattcg cttttctgcc attggcctca ataagcttcc aaatatccag tcacagaaac 18301 acaaaaacag tgattccaaa ctgctgaatc aaaaggaagg tttaactctg tgagatgaat 18361 gcacacattt aaaagcagtt tctcagaaag cttctatcta ctttttatct gaagatattt 18421 tgtttttcac cataggcctc aatgcattcc caaatatcca tttgtagatt ctacaaaagc 18481 agtgtttcca aaaagctgaa tgaaaagaaa ggtttagttc tgtgagatga atgcacacat 18541 cacaaagtgg ttttcagata gcttccttct tgtttttatc ctgggatatt ctcttttttg 18601 ccattggact caatgagctc caaaatgtcc actcacagaa tgtaaaaata cagtgtttcc 18661 aagctgctga atcaaaagaa agttttatct ctgtgtgatg aatgcacaca cctaaaagct 18721 gttgctcaga aagcttcttt ctaattttta cctgaagtta ttttcttttt caccataggc 18781 ctcaatgcgc tcccaaatat cccttcacat attctacaga aacagtgttt ctgaactgat 18841 gattgaaaag ataaggttaa ataagtgaaa tgaatgcaca catcacaaag cagtatatca 18901 gatagcttcc ttgtagtttt tatccttgga tattcacttt ttcaccattg gcctcaatga 18961 gctcccaaat gtctatttgc agaaaggaca aaagcagtgt cagcaaactg ctgaattgga 19021 agaaagcttt aatgccttga ggtgaatgca aacatcacaa ggcagctttt cagaaagctt 19081 ctttctagtt tttatctgaa tagattKtct ttttctctat aggcctcaat gcactcccaa 19141 atataccttc atagattcta caaaaacagt gattccaaac tgctgaatga aaacaaaggt 19201 ttaactctgt gagctgaatg gacctatcac caagtggttt ctcagatgat ttcttccagt 19261 ttttatcctg agatattcac ttattcacca ttggcttcaa tgagctccca aacctaatgc 19321 acaatggaca aaaacagtgt ttcaaaactg gtgaatcaaa agaaaggtac tataagaaca 19381 gtgtttccaa actggtgaat gaaaagaaag gtttaactct gccagaagaa tgagcacatc 19441 acaaaggttt ttctcagata gattctttct agtttttgtc tagggatatt tgcttttttg 19501 ccaatggcct aagtgagctc caaaatatcc atttgcagaa aggacaaaat caatgtttcc 19561 aaactgctga atctaaagaa aggtttagct ctatgagatg aaggcacaca tcacaaagca 19621 gtttctaaga aatcttcttt ctagttttta tccggggttt ttctcttttt cgccattggc 19681 ctcaaagagc tcccaaatgt ccatttgcag aatggacaaa aacagtgatt ccaaacttct 19741 gaatcaaaag aaaggtttaa ctctgtgaga tgaatgcaca catctaaaag cagtttctca 19801 gaaagcttct atctgctttt tatctgaaga tatttctttt tcaccttagg cctcaatgcg 19861 ctcccaaata tcctttcaca aattctacaa aaacagtgtt tccaaactac tgaatgaaaa 19921 gaatggttaa cttgtgtgag atgaatgcac acatcagaaa gcagattctc atattgcttc 19981 cttctagtta ttaatctgtg atgtttgctt gtccaccatt ggcctcaatg agcttcctaa 20041 tatccattca cagaatggac aaaagcggtg ttttcaaaat gctgaatcaa aagaaaggat 20101 taactctgca aggtgaatgc acacatcata aatcagtttt tcagatagct ttcttctagt 20161 ttttgtccag gtctagttgt tttttcacca ttggcctcaa tgagctccca aatgtccatt 20221 cacagaatgg acaaaaacag tgtttccaaa caggtgaatc aaaagaaagg tttaactctg 20281 tgagatcaat gcaaacatca caaagcagtt tctcagaaag gatctttcac gttttcatat 20341 gaagatattt actttttcac cataggcctc aaagggctcc caaatatccc ttcgcagatt 20401 ctacagaaac agtgtttcca aactgctgaa tcaaaagagt agtttatttc tgtgagatga 20461 atgcaacatc agaaagtagt ttcgcagaaa gcacctttct actttgtatc tgaagatatt 20521 ttatttttca ccaaaggtat caatggactc caaatatccc ttcacagatt ttaccaaaac 20581 agtgtttcca aaaagctgaa tgaaaagaaa ggtttaactc tgtgagatga atgcacacat 20641 cacaaagcag tttctcagat agcttccttc tagtttttat cttggaatac tcactttttc 20701 tccattcaca tcaatgagct ctgaaatatc catttgcaga aaagacaaaa acagtgtttc 20761 caaaatgctg aatcaaaaga aagatttacc tctgtgagat gagtgcacac atcacaaagc 20821 agtttctcag aaactgtttt tccttttgtt tttatgcttt tgtttttatc ttattttctt 20881 tttcaccata ggcctcaatg tgctgaaaat ttcccttcac atattgtaca aaaacattgt 20941 ttcccaactg ctgtttgaaa aggaaatttt aacttggcaa gatgaataca cacatcataa 21001 agtgctttct cagaaagctt ctttctagtt gttatctgaa gatattttct ttttcaccat 21061 aggcctcaat gtactcccaa atatcccttt gcatattcta caaaaacaga ttttctaaac 21121 tgttgaatga aaagtaaggt ttatgtctgt gagatgaatg cacacatcac aatgtggttt 21181 ctcagattac ttccttgcag tttttgtcct ggaatatccc cttttttttg ccaatggcct 21241 caatgagttc ccaaatgtcc tttcacacaa cggacaaaaa cagtgtttcc aaactgctaa 21301 atgaaaagaa agttataact ctgtgagatt aatgtacaca tcacaaaRga gtttttcaga 21361 aagattcttt ctggttttta tctgaagata ttttcttatt cacagtaagc ctcaatgcaa 21421 tcccaaatat cccttcacag attctacaaa aactgtgttt ccaatctgct gaatgaaaag 21481 aaaggtttaa ctctgtgaga tgaatccaca catcacaaag cagtctctca gatagtttcc 21541 ctctagtttt tatcctgggt tattcacttt ttcaaattat gcctgaatta gcttctaaag 21601 gtccatttgc agaaaggatg aaaacagtgt ttccaaactg ttgattgaaa agaaaggttt 21661 aactctgtga aatgaaggcc ctcatcacaa agcagtttct cagaaagctt ctttctactt 21721 tttatctgaa gataatttcg ttttcaccat aggcctcaat gtgatcccaa atatcccttc 21781 aatgattcta cagaaacagt gtttccaaac tgccgggtga aagaaaggtt taactctgtg 21841 agatgaatgc acacctagca aagttgtttc tcatatagct tcgttctagt ttttatcctg 21901 ggacagtcac cttaagtcaa ttggtctcaa tgagctccca cgtcttttca cagaatggac 21961 aaaaacgtgt ttccaaactg ctgcatcaaa agaaaggctt aacactgtga gatgaatgca 22021 cccatcacaa ataatttctc agaaagcttc tttctatttt ttatcagaag atattatctt 22081 tttcactgta ggctcaaggc agtccaaaat gtgacttctc agattctaca aaaacagtgt 22141 tcccaaactg ctgaatgaaa agaaaggttt aactctgtga gatgaatgca cacatcagaa 22201 agcagtttct cagaaagctt ctttctactt tttattctag gatactcatt ttttcaccat 22261 tggcctcaat aagttcccac atgtccattc gaggaatgga caaaaacagt gtttccaaac 22321 tgctgaatta aaagtaaggc ttaaatctgc aagttgagtg tgcacatcag aaagctgttt 22381 ctcagacagc ttccctctag tttttatcct gggatattcg cttttttact agtggcctct 22441 atgagcaaca aaatgtccat tcacagaatg gataaaaaca gtattgccaa actgctgaat 22501 ctaaggaaat atttaattct aagagatgaa tgcacacata acaaagcagt acctcagaaa 2256.1 tcttctttct actttttacc tgaagatatt ttcttttata ccataggcct cattgctctc 22621 acaaatatcc cttcgcagat tctacaaaaa cagtgtttcc aaacagctga ttgaaaagaa 22681 aggcttaact cagtgagatt aatccacaca ccacaaagca gtttctcaga tagcttcctt 22741 ctagttttta tcctgggtta ttcacttttt caccttaggc ctcaattagc tcccaaaggt 22801 tcatttgcag aaaggacaaa aacagtgttt ccaaactgct gaatcaaaag aaaggtttaa 22861 ttctgtgaga tgaaggtact catcacaaag tagtttctca gaaagcttcc ttctatttta ^'22921 tcttaagata atttatttta cccataggcc tcaatgtgtt cccaaatatc cctttgatga 22981 ttctacagaa acactgtttc caaactgctg aatgaaagaa aggtttaact ctccaagatg 23041 aatggacaca tcacaaatca gtttctcatg tagctttctt ctagttttta tcctgggata 23101 gtcgcctttt gtcaattggc ttcaatgagc tcccaaatgt ccattcgcag aatgatcaaa 23161 aacttgtttc caaactgcta attctaaaaa ggtattaact ctgtgagatg aatacgccca 23221 tcacaaataa tttctcagaa agcttctttc tatcttttat cagaatatat tatctttttt 23281 accataggac tcaaagcact ccaaaatatt actttgcaga tcctacaaaa acagtatttc 23341 caaaatgcag aatgaaaagc aaagtttaac tctgtgggat gaatgcaccc atcacggagc 23401 agtttctcag atagcttcct tctagtttta tcccaggata ttcacttttt tatcattggc 23461 ctcaatgagt tctcaaatgt ccattcacag aataaagaaa aacagtgttt caaaactgcc 23521 gaatgcaaag agaggtttaa ctctgtaaaa tgaaatgcaa acatcaaaaa gtggtgtctc 23581 agaaagcttc ttcctacttt tttatctgag ataatttctt tttccccata ggcctcaatg 23641 cactcccaaa tatcccttca cagattctat gcaaacagtg tttcaaaact gctgaatgta 23701 aagaaaggtt taactctgtg agatgaacgc acacaacgca aagcagtttc tcagataKct 23761 tccttctagt ttttatgttg ggatattcac ttttttgtca ttggcctaaa tgaattcaaa 23821 aatgtacatt tgcagtataa acaaaaacag tttttccaaa ctgctgaatg aaaagaaagg 23881 tttaactgtg taagatgagg gcacacatca caaagcagtt tcccagaaat cttctttcta 23941 cttttttatc tgRgaatatt ttctttttca ccataggtct caaggcactc ccaaatatcc 24001 ctttgcagat tatacaaaac agtgtttcca aactgctgaa tcaaaagaaa ggtttaactc 24061 tttgagatga atgcacccaW cacaaataat tYctcaggaa gtttctttct attttttatc 24121 agaatatatt atctttttca ctataggcct taaagccctc caaaatacta cttcggagat 24181 tgtaSaaaaa ctgtgtttcc acactgctga atgaaaagaa aagtttaaat ctgcaagatg 24241 aatgcacaca tcacaaagca ttttttcaga aagcttcttt ctagttttta tcctaagata 24301 cttgcttttc accattggcc tcaatgagtt cccaaatgtc cattYacaga atggagaaaa 24361 ¹acagtgattc caaactgaag atacaaaaga aaattttaac tctgtgagat gaatgcacac 24421 atcattgtga tgtttctcag aaagcttctt tctaattttt atctcaagat attttctttt 24481 tttaccattc ttttttacca tttggagcct caatgtgttc caaaatatcc attcacagat 24541 tctaaaaaaa cagtgattcc aaactgctga atgaaaagaa agttttaact ctgtgagatg 24601 aatgcatata acacaaagca gtttctcaga taacttcctt ctagttttta tcctggaata 24661 ttcacttttt tgccattggt ctaaatgagt tcccaaatgc acattcacag tataaacaga 24721 aagactgttt ccaaactgcc gaatcaagag aaactttaaa ctccataaga tgaatgcaca 24781 tatcacaaaR cagtttctca gaaatcttct ttctgatttt tatctgagaa tatttttttt 24841 tcaccacagg cctaaatgca ctcccaaata tcccttcgca gcttctacaa aaacactgct 24901 tccaaattgc tgaatgaaaa gaaagtttta acgcagcgag ataaatgcac acatctcaaa 24961 gcagtttctc agatagtttt cttctaggtt ttgtcctgtg atatatgctt ttttgccaag 25021 cttctttcta gtatttatct aatgataatt tgtttttcac ttttggctct atgagctctt 25081 aagtgtacat tcacagaatg gacaaatgca gtgtttacaa actgctgaat caaaagaaaa 25141 ttttaactct gtgagatgaa tgcacatatc acaaagcagt tttcagaagt cttctttcta 25201 tgttttatct gaagatattt tctttttcat cataggcctc agggcactct gaaatatccc 25261 tttgaagatt ctacaaaaac attgtttcta aactgctgaa ggaaaagaaa ggtttaaatc 25321 tgtgagatga atgcacacat tacaaagcag tttccctcct agcttccttt tagtttttat 25381 ccttggatat tccccttttt tgccattgcc ctcaatgatt tccaaaatgt cctttctcag 25441 aatggacaaa aacagtgttt ccaaactgct gaatcaaaat aaaggtttaa cactgtgaga 25501 tgaatgtgca catcatgaag cagtttctca gaatgcttct ttcttatttt tatctgaatt 25561 tattttcttt ttcacgatag gtttcaattt gctcccaaat atcactttgc agattctaca 25621 aaaacagtgt ttccaaactg atgaatgaaa acaaaggttt aactatgcaa gatgaatgta 25681 tgcatcacaa agcagtttct cagagtgctt ccttccagtt tttatcctgg gatattcact 25741 tttttgccat tggcctcaat gagctcccaa atgtccattc gcagaatgga caaaaacagt 25801 gttttgaaac tgctaaacca aaagaaatgt taaactctgt gatatgaatg cacacattca 25861 aagcagtttc tcagaaatct tctttctcct ttttgtctga agacactttc tttttcacca 25921 gaggtctcaa tggtctccca aattcacaga ttgtacaaaa tatagtttcc aaactgctga 25981 atgaaaagaa aggtttaact ctgtgagatg aattcacaca tcacaaagcR gtttctaaga 26041 tagcttcctt ttgtYtttct gctgggatat tcactgtttc accaatggcg tcaatgagct 26101 ccctaaagtc cattcataga atggactaaa actgtttcat aactgctgaa ggaaaagaaa 26161 ggtttaactc tgtgagataa atgcacacat cacaaagcag tttctcagaa atcttctttc 26221 tacttcttat ctgaagttat tttctttttc aacataagcc taaatacgct cccaaatatc 26281 ctttgacaga ttctacaaaa acagtgtttc caaactgatg aatggaaaga aaggtttaac 26341 tctatgagat gaatgcatgc atcacaaagt ggtttctcag atagcttatt tctagttttt 26401 atcctgggat attcactttt tcaccattgg ccttaatgag ctccctaatg tccatttgca 26461 tgttggacag aaacaacatt ttccaaactg ctgaaacaaa agaaaggttt aactctgtga 26521 gatgaatgca cacatcaaaa agcagtttca cagaaaggtt ctttttagtt tttatctgaa 26581 tatattttct ttttcaaσac aggcctcaat gcgctcccaa atataacttt tcagattcta 26641 ccaaaacagt gtttccaaac tgctgaatga aaaaaaggtt taactctgtg agatgaatgc 26701 aagcataaca aagcagtttc tcagatagct tacttctagt ttttatcctg ggatattcac 26761 tttttcacca ttggactgaa tgatctccct gatgtccatt cacaaaatgg agaaaaacag 26821 tatttccaaa ctgctgaatc aaaacaaagt tttaactctg tgagatgaat gcaaacatca 26881 caaagccgtt tctcagagag cttccttcta gttttatctg aagatatttt ctgtttcatg 26941 attggYctca atgctctccc aattacccct ttgcagaatc tacataaaca gtgtttccaa 27001 actgctgaat gaaagaaagg tttagctctg cgagatgaat gcacacatca gaaagaggtt 27061 tctcagatat cttccttcta atttttatac tgggattttc cattttttgc cattggcctc 27121 aaagagctcc caaatctcca ttcacagaat ggacaaaaac agggttttca aaactgctga 27181 aacagaagaa aggtttaaat ctgtgagatg aatgcacaca tcaaaatgca gtttttcaga 27241 aagcttcttt tcagttttca tctgaagata tattcttttt caccataggc ctcaatgtgc 27301 tcccaaatat aactacacag attctacaaa aacagtcttt ccaaactgct gaatgataag 27361 aaaggtttaa ctctgtgata taaactcatg catcccaaag cagtttctca gatagcttac 27421 ttctagtttt tatcacggga tattgacttt ttcaccaacg gtcttaatga gctccctaat 27481 gtccattctc agaatgcaca aaaaacagta tttccaaatt tctgaatcaa tagaatgttt 27541 taactctgtg agatgaatgc acacatgact aagcagttcc tcagaatgct tccttcttgt 27601 tttatctgaa gatattttct gttacaccat aggcctcaaY gctttctgaa atatcccttc 27661 acagagtcta caaaaacagt gtttccaact gctgaatgaa agaaaggttt aactctgtga 27721 catgaatgta cacatcacaa agagttatct tatatagctt ccttctagtt tttatcttgg 27781 gatattcact ttttctccat tgccctcaat gagctcccaa atgtcccttt gcagaaaaga 27841 gaaaaactgt ttttccaaac tgctgaatca aaaggaaggt taaactctat aagaagaacg 27901 cccacatcac aaagaagttt ctctgaaatc ttatttctac tttttgtctc aagatatttt 27961 ctttttcacc atagacctca atgcactccc aaatatccct tcaaatattg tacaaaaaca 28021 gtgtttccaa actactgaat gaaaaggaaa atttacctcc atgatgtgaa tgcacacatc 28081 acaaagcagt ttctcagaca gcttccttct agtttttatt ctgggatatt cactttttca 28141 ccattggcct caatgatccc cctaatgtcc attcRcagaa ttgacaaaaa gagtttttcc 28201 aaactgctgc atcaaataaa gtgtttaact ctttgagatg aatgaacaca tcacagagcc 28261 atttcccaga aaggttcttt ctagttttta tctgaagata ttttctattt caccataggc 28321 ctcaatgagc tccaaaaaat ctcttcacag attctacaaa cacagtgttt ccaaactgct 28381 gaatgaaaag aaagatttaa ctctgtgaga tgaatgcaca catctgaaag cagtttctca 28441 gatagcttcc ttctattttt tatgctggga tatctgcttt tttgccattg acctcagtga 28501 gctcccaaat gtccatacgc agaatggaca aaaacagtgt ttccaagctg ctgaatcaaa 28561 agaaagattt aactctatca gatgcatgct cacatcaaaa atcagtctcc cagagaggtt 28621 ctttcagctt tttatctgaa gatctttctt tttcaccata gaccacaata tgctcccaaa 28681 tatccctttg cagattctac aaaaacagtg tttccaaact gccaaatgaa aagaaaggtt 28741 taactctgca agatgaatgt acacatcaca aaactgtttc tcaagtaatt tctgtagagt 28801 ttttgtcctg ggatattcac ttttttccat tggcctcaat gagctcccaa aagaccattc 28861 acagaaggga caaaaacagt gtttccaaag tgctgaatca aaagaaatgc ttaactctgt 28921 gagatgaata cacacatcac aaagcagttt ctcagaaagc tcctttctag tgtttatctg 28981 aagatatttc tttttctctg taggcctcaa ggctctccca aatttccctt cacagattct 29041 acagaaacag tgtttccatt tgctgaatga aagaaaggtt taactctgtg agatgaatgc 29101 tcacatgaca aagagttttc ttagatagct tccttctagt ttttatcttg ggatattcac 29161 ttttttgcca ctgccYtcaa tatcccacaa taaaaacttc aaggaagcta tctgagaaac 29221 cactttgtgg tgtgtgcatt catctcagag ttaaaatttc ctttccattc agcagtttgg 29281 aaacactgtt ttcctagaat ctggcatggg acattgggag cacattgtgg tctatgatga 29341 aaaacaaaat aaattcagaa ttaaaacttt cttttgattc aacagaataa aaaaactgtt 29401 tctgtccatt ctgtgaatgg acatttgggt gctcattgag gccaatggta caaaagcaaa 29461 tatcccagga taaaaactag aaggaaggta tctgaaaaat ggctttatga tgtgtgcatt 29521 catctcgcag agttaaaact tacttttcat tcaggagctt ggaaacacag tttttgtaag 29581 atctacaaag ggttatttgg gagcacaatg aggcctcgta tgaaaaagaa aatagcttca 29641 gattaaaagt acaaagaagc tttctgagaa actactttgt gatgtgtgca ttgatctcac 29701 agagttaaaa ctttcttttg attcagaagt ttggaaacac tgtttttgtc cattctgcaa 29761 atatacattt ggaagctcat tgaggcaaat ggtgaaaaag caaatatccc aggataaaaa -^29821 ctagaaggaa gctatctgag aaaccatgtt ttgatgtgtg cattcatctc acagaaataa 29881 acctttcctt tatcagcaaa ttggaaacac tgatttgtag aatccacgaa ggaatatttg 29941 ggattgattt gaggcctgtg gtgaaaaaga aaataccttc agataaaaac tagaaagaag 30001 ctttcttaga aactcctttg tgacgtttgc atttatcagg cagatttaaa gctttctttt 30061 cattcagtag tttggaaaca ctttttttgt acaaccagtg aagggatatt ttagagcgca 30121 atgaggccta tggcagaaaa gaaaatatct tcaaataaaa agtagaaaaa agcttttgag 30181 agactgcttt gtgatgtgtg cattcatctc ccatagttaa aactttcttt tgattcagta 30241 gtttggaaac actgttattg tccattcagc aaatggacag ttgggagMtc attcaggcca 30301 atgatgaaaa agtgaatacc acaagataaa agctagaaga atccgatttg agaaactgct 30361 ttgcaagctg tgcattcatc tcacaaagtt aaacgtttct tttcattcag cagtttggaa 30421 acacYgtttt tgtagaatct gtgatgggat gtttcagagc actttgaggc ctatgatgaa 30481 aaagaaaata tcttcagata aaaactagaa agaagctttc tgagaaactc atttgagatg 30541 tgtgaattca tctcacagag ataaactttt cttttgattc agcactttgg aaacactgtt 30601 tatttccatt cagttaatgg acatttttct agctcattga agggaatggt gaaaaaacaa 30661 ataccgtagg ataaaagctg gaaggaacct atctgagaaa ccactttgtg atgtgtacat 30721 tcatctcaca aaggtaaacc tttcttttca ttcagcaatt tggaaacact ctttttgtag 30781 aatatgcaaa gggatatttt agagtgYctg aaggcctatg gtgaaataga aaatatcttc 30841 agataaaaac tagaaagatg ctttctgaga aacttctttg tgatttgtac attaatctga 30901 cagctttaaa ttgtactttt cattaagcag tttggaaccc gtttttgtca attctgtgaa 30961 tggacatttg ggagctaatt gaggccaaag gcaaaaaagc gaatatccca agaaaagaac 31021 tagaaggaag ctatctgaga aactgcattg taatgtgtgc actcaactcg cagaggtaaa 31081 actttctttt cattcagcag ttcggaaaaa ctgtttttta gaatctgtgt ggtatacttg 31141 tgtgtgcttc gagatctatg ctgaaaaaga aaatatcttc aaataaaaag tagaaagaag 31201 gtttctgaga aactggttta tgatgtgtgc attcatctcc cagagttaaa aatttatgtt 31261 gagtcagcag tttagaaaac tgtttttgtc cattctgtga atggacattt gggagctctt 31321 tgaagccaaa ggcaaaaaag ataatatccc aggataaaaa ctagaaggaa gctatctgaa 31381 aaaccgctaa ttgatgtgtt cattcatctc tcagagataa aactttcttt tcattcagca 31441 gtttggaaac actgtttttg tagaatctgc aaaggcatta tttgggagtg tattgaggca 31501 gatggtggaa aagaaaatat cttcagaaaa aaactagaga gaagctttct gagaaactac 31561 tttgtgatgt gcggatttat agtgaagagt taaacctttg ttttgattca gcagtttgga 31621 aacactgttt ttgtccattc tatgaatggg catccgggag ctcaatgaag cctatggtga 31681 atacgggaat aacctggcac aaaaatgaga aggaagctat cttccaatca gctatatggt 31741 agctgattga ggccaatggt aaaaaagcaa atatcccagg gtaaatctag aaagaagcta 31801 tctgagaaac cactttgtga tttgtgcatt catcttgaag aattaaatct tccttttaat 31861 tcagcagttt gaaaacactg tttttgtaga atctgtaaat ggacatttca gagcacgttg 31921 aagcctatag tgaaaaagaa aatatcttca gataaatact acaaggaagc tttcttagaa 31981 actgctttat gatgtgtgtt ttcatctcac agatttaaac ctttctttta attcaacagc 32041 ttggaaacac tgattttgtc cattctgcaa atggacattt gggagctcat tgaggccaat 32101 ggatgaaaag caaatatctc aggataaaaa cttcaaggaa gctatctgag aaactgcttt 32161 gtgatgtgtg cattcatcta gcagagttaa acatttcttt tgattgagta atttggaaac 32221 actgcttttg tagaatctgt gaagggatat ttgggagcat cttgagacct atggtgaaaa 32281 agaaagcatc ttaagataaa aagtagaaag aagctttctg ataaacttct ctgtgatggg 32341 tgcattcatc tcacagagtt aaaacctttt taagattcag cagtttggaa agactgtttt 32401 tgtagaatct atgaagggat atttgggagc ccattggacc aatgatgaaa aagtaaatat 32461 cttcatataa aaactgaaaa gaagctttct gagaaactgc tttgtgatgt gcacattcat 32521 ctcacagagc taaacctttc ttttcattca gcagtttgga aacactcttt ttgtacaatc 32581 tgcaaagaaa taYttgggag tgaattggtg aaaaagaaaa tatcttaaga taaacagtag 32641 aaagaaaata tcttaagata aacagcagaa agaagctttc tgagaaagtg ctttttgatg 32701 ggtgcattca cctcacagag ttaaacattt atattgatat aagagtttgg aaaaaatgtt 32761 tttgtccatt ctgcaaatgg acagtcgtag ctgattgagg ccaatggcaa aaaagcaaat 32821 atcccaggga aaaaactaga aggaatgtat ctgagaaacc actttgtgat ttctgcattc 32881 atttcactgg ggtaaacctt tcttttcatt cagtagtttg gaaacactgt ttttgtagaa 32941 tctgcaaacg gatattttgg tgctcattga ggcccatggt gaaaaagaaa atatcttcag 33001 atgaaaacta gaaagaagct ttctgagaaa ttgctttgtg atttgtgttt ttgtcacata 33061 gagttaaaac tttcttttga ttcagcattt tggaaacact gtttttgttg attctgtgag 33121 tggacatttg ggagctcact gaggccaatg gcgaaaaatc aaatatccca ggataaacac 33181 tagaaggaag ctgtctgaga aaccactttg tgatgtacgc attcatctcc cagagttaat 33241 cttttcttct cattcagcag tttggaaacc ctgtttttgt agaatctgtt aaggtatatt 33301 tctgagtgca ttgaggcctc tggtgaaaaa gaaaatatct tcagataaaa actagaaaga 33361 aactctctga caaaaggctt tgtaatgtgg gcacttattt cacagagtta aacctttctt 33421 tttattccac tgtttggaaa cactgttttt gtccattctg tgaatggaca tttgggaact 33481 cattgaggcc aatggagaaa aagcgaatat ctaaagataa aaactacaat gaagctatct 33541 gagaaattgc ttggtgatga gtacattcat ctcgcagatt taaacctttt tttttcattc 33601 agcggtttgg aaacactgtt tttggagaat ctgcaaaggg atatttggga gcgcattgag 33661 tcctatggtg aaaaagaaaa tatgttaaca taaaaagtgg aaagaagctt tctgggaaac 33721 tcctctgtga tRggtgcatt cacctcacag agttaaacct ttctgttgat ccaggagttt 33781 ggagacactg ttttgtagaa tatgtgaagg aatattttgg agcacattga ggcttatggt 33841 gaaaatatct tcagataaaa actagacaga agctttctga gaaactgctt tgtaatgtgt 33901 gctttcatct cacagaggta aagctttctt ttgattcaac agtttggaaa cactgttttt 33961 gtccattctg agaatggaca tttgggagct cattaaggcc aatagagaaa aagggaatat 34021 cacaggataa aaagtacaag gaaggtatgt gagaaactgc tgtgtgatgt gggcattcat 34081 ctcatagagt ttaacttatg ttttctttca gaagtttgga aacactgttt ttgtagaatc 34141 tgcaaaggga tatttgggag cccattgagg cctctggtgg aaatgtaaat atcttcacat 34201 aaatctaaaa agaagctttc tgagaaactg ctttgtgatg tgtgcattca tctcacagag 34261 taaaaatttc ttttgtttca gcagtttgga aacactgctt ttctccattc tgcaaatgga 34321 cattttggag ctcattgagg tcaatggaga aaaagtgaat atcYcaggat aaaaactgta 34381 aggaatctat ctgagaaact gcttttggat gtgtgcattc atcttgcaca gataaacctt 34441 tctttacatt cagcagtttg gaaacactgt ttctgtagaa tctgtgaaga aatatttggg 34501 aatgcattga gacctatggt gaaaaagaaa atattttaag ataaaaagta gaaagaagct 34561 ttctgagaaa gtactctgtg atggttgcat tcacctcaca gaattcaaca tttcttttgt 34621 tccagcagtt tggaaatgct gtttttgtag aatctgcaaa ggatattYca tagtgcattg 34681 aggcctttgg tgaaaaacaa tgtatcttca aataaaaact agagagaagc tttctgagaa 34741 agttctttgt gatgtgcaca ttcacctcac agagttaaac ctgtcttttg attcaataat 34801 atggaaacac tgtttctgtc cattctgcga atggacattt cggagctcat tgagaccaat 34861 ggataaaaag tgaatatccc aggataaaaa cttcatggaa gccatctaag aaaccacatt 34921 gtgaagtgtg cattcatctc aoagaattga acctttcttt acattcagca gtttgaagac 34981 actgtttttg cagaatctgc atagggatat ttgggagcac actgagacct atgtttaaaa 35041 agaaaatatc ttaagataat aggtagaaag aagctttctg agaaactgct ttgtgatgta 35101 tgcattcatc tcacagtgtt aaaactttct tttgattcag cagtttggaa acactgtttt 35161 tgtccattct gcaaacggac atttcagaac tcattgaggc caatggagaa aaagcaaata 35221 tcccaggata aaaactacaa tgaaggcatc tgagaaactg atttgtaatg agtgcattca 35281 tctcacagag ttaaaccttt cttttcattc agcagttttg gaacactgtt tttgtagaat 35341 ctgcgaaggg ctatgtggga gtgcattgag acctatggtg aaaaagaaaa tgtcttaaga 35401 taaaaagtag aaagaagctt tctgagaaag tgctctgtaa tgagtgcatt cacctcacag 35461 aattcaacct ttcttttgat tcagcagtct ggaaacactg tttttttttt cattctgcaa 35521 atggagattt ggtagctaat tgagaccaaa ggcaaaaaag caaatatccc agggtaaaaa 35581 ctagaaggaa cgtatctgag aaactgcttt gtgatgtgtg cattcatcag gcagagttaa 35641 acctttcttt tcattcagca gtttggaaac actgtttttg tagaatctgt gaagggatat 35701 tttggagtgc attgaggact atggagaaaa agaaaatatc ttcatataaa aactagaaag 35761 aagcattctg agaaactgct ttgtgatggg tgcattcatc tcagagagtt aaaactttct 35821 tttgattcag ctgttaggaa acactgtttt catccattct gcaaatggaa atttgggggt 35881 tcattgaggc caatggtgaa aaatcgaata tcccaggata aacaatataa ggaagttatc 35941 tgagaaacag ctttatgatg tttgcattca tcatgcagag ttaatccttt attcccattc 36001 agtagtttga aaacactggt tttgtagaat ctgttaaggg atatttcaga gtgcatttag 36061 gcctatggtg gaaaagaaaa tatcttcaga taaaaactag aaagaagctt tctgacaaac 36121 tgctgggtga tgtgtgaact catttcacag agttaagact ttcttttgat tcaacagctt 36181 gaaaacactg tttttctcca ctctgcaaat ggacatttgg gaactcattt aagccaatgg 36241 ggaaaaagtg aatatcccag gataaaaact tcaaggaagc tatctcagaa accactttgt 36301 gatgtgtgca ttcatttcac agagttaatc ctttcttttg attcagcagt ttggaaacac 36361 tgcttttgta gaatctgcta agggatattt tgtaacccat tgagtcctat ggtgaaaaag 36421 taaacatctt catataaaaa ctgaaagaag catcctgaga aactaatttg tgatgtgtgc 36481 attcatctca cagagttaat tctttctttt gattcaatag ttttgaaaca ctctttttgt 36541 ccattctgcg aagggatatt taggagcaca ttgagcccta tggtgaaaaa gatcttcaga 36601 taaaaattag aatgaagctt tctgaggaac tccttgtaac gtgtccattc atctcacaga 36661 attaatcctt tcttttaatt caacagtttt gaaccactgt ttttcttcat gctgtgaatg 36721 gatatttggg agctcaatga ggccaatgga gaaaaaggga atatctcagg ataaaaactc 36781 caaggaagct atctgagaaa ccgctttgtg atgtgtgcat tcacctagta gaggtaaacc 36841 tttcttttca ttcagcagtt tggaaaaaca gtttttatag tatctgtgaa gggatatttg 36901 ggagtgcatt gagatctatg gtgaaaaaga aaatacctta agaaaaaaag tagaaggaat 36961 ctttctgaga aactgctgtg tgatgtttgc attcatgtca ggggtaaaca tttcttttca 37021 ttcagtagtt tggatgcact ctttttgtcc attctgcaaa tgcacatttt gtagctgatt 37081 taggccaatg gcaaaaaagc acatatccct gtataaacac tgcaaggatg ctatctgaga 37141 aaccactttg tgttgcRtgc cttcatctct cagagttaat ccttttttct cattcagcaa 37201 tttggaaaca ctgtttttgt agaatctgtt aagggatatt tcagagtaga ttgaggccta 37261 tggtgaaaaa gaaaatgtct tcagacaaaa actagaaaga agctttctga caaactgctt 37321 ggtgatgtgt gaactcatct cacagtgtca aatcatactt ttgattcaac agtttggaaa 37381 cactgttttt gttcatgatg tgaatggata tttaggagct cattgaggcc aatggagaaa 37441 aagtgaatat cccaggataa aaatttaagg aagctatctg agaaaccact ttgtgatgtS 37501 tgcattcatc ccacagttaa acctttctac acattcagca gtttggaaac actgtgtata 37561 gtctttgaag ggatatttgg gtgtgcattg aggctatggt gaaaaagaaa atatcttcag 37621 ataaaaagtc gaaggaagct ttctgagaaa gtgctttttg atttgcacat tcatctcaca 37681 gaattaaacc tttcttttga ttcagcagtt tgaaccagtg tttttgtcca ttcagcgaat 37741 ggacagtttg tggctcattg aggccaatgg tgaaaaactg aatatctcag gataaaaaca 37801 aaaagaagct atctgagaaa ctgctttgtg atgtgtgcat tcatcttgca gagataaagc 37861 ttacttctca ttcagcagat tgcacacact gttttcatag aatctgtgaa gggatatttt 37921 ggagtgcaag gagacctatg gcgaaaaaaa tcttcagata aaatgtagaa agaagctttc 37981 tgagaaactg ctttgtgatg tgtgcactca tttcacagag ttaaccattt cttttaattc 38041 agcagcttgg aaacactgtt tttgaacatt ctgcaaatgg acatttggga gctcattgag 38101 accaatggcg aaaaagtgaa tataccagga taaaaactag aaggaagcta actgagaaca 38161 cactatgtga tttgtgcatt catctcacag agttaagcct ttctttttac tgagcagttt 38221 gtatacactg tttttctcca ttgagtgaat ggacatttgg gagctcattg aggtaaaggt 38281 gaaaaagaga atatcccagg ataaatacta gaaggaacct ctctcagaaa ctgctttgtg 38341 atgtgggtat tcatctcgaa gagttaaaac ttcctcttca ttaagcagtt tggaaacact 38401 gtttttgtga aatatgagaa gggatatttg gacctgcatt aaagcctatg gtcaaaaagt 38461 aaatatcttc agattaaaaY tagaaagaag ctttctgaga aattgttttg tgatgtgcat 38521 tcatcttgca gagttaaact tttctttttc atttagccat ttggaaacac tgtttttgtc 38581 cattttgtaa aaggatattt gggagctcat caaggccaat ggtgaaaatg cgaatatccc 38641 aggataaaaa ctagaattaa gctatctgag aaactgcttt gtgatatgag cattcatctc 38701 acagagataa acctttcttt tcattcagca gtttggaaac actgtttttg tagaatctgc 38761 aaagggatat atgggagcWc attgaggcct atggtgaaaa ggaaaatatc ttcacattaa 38821 aactagaagg aaggtttctg ggaaactgct ttgtgatgtc tgcattcatc tcacagagtt 38881 aaacatttct tttgattcag cagtttgtaa acactgtttt tgtctgttct gtgaatggac 38941 atttgggagc tcattgagtc cactggtgaa aaagcaaata tccagggata caaactagaa 39001 ggaagctacc tgagaaactg ctttgtgagg tgtgaattca cctctctgag ttaaaccttt 39061 ccttttattt ggtatttttg aaacactgtt tttgtagaat ctgtgaatga atatgtggga 39121 gtgcattgag gcctacggtg aaaaagaaaa catcttcaga taaaaagtag aaagaaggtt 39181 tctgagaaac tgctttgtaa tgtgtgtatt catctcacag agttaaaact gtcttttaat 39241 tcagcagttt ggaaacactt tttgacaatt ctgtgaatgg acatttggga gatccttgag 39301 gccaatggtg aaaaagcRaa tataccagga taaaaactag aagaatgtta cctgttaata 39361 tgcattatga tttttgcatt caactcacag agttaaaagt ttttgattta gcagtttgga 39421 aacactgttg tcatccattc tctgaatcta catttgggag ctcatcgatg ccaatgacaa 39481 aaaaaaagaa tatcccagga taaaacctag aaggaattta tctgagaaac aactttgtga 39541 agtgtgcatt catgttgcac agttaaaagt ttcttttcat tcatcagttt ggaaacactg 39601 ctttttaaga atctgtgaag ggatatttgg gagcacattg aggtgaaaag aaattaactt 39661 cagataaaaa atagaaagaa actttctcag aaatggcttt gtgatgtgtg catttatcac 39721 acagagttaa acatttcttt taattcaaaa ctgttttgaa gaatctgtgg agggatattt 39781 gggagcacat tgaggcctat gctgaaaaag ataatatctt cagataaaaa ctaaaaagag 39841 gcatcctgag aaactccttt ttgatgtgtg cattcaccgc acagagtaaa accttacttt 39901 gccagcagca gtttggaaac actttttgta gaatctgcaa agggatattt gggagtgaat 39961 ttaggcctat ggtgaaaaag aataaagcct ccaagaaata tgggactatg tgaaaagacc 40021 aaatctacgt ctgattggtg tacctgaaag agacagggag aatggaacca agttggaaaa 40081 cactctgcag gatattattc aggggaactt ccccaatcta gcaaggcagg ccaacattca 40141 aattcaggaa atacagagaa caaccacaga gcaactccaa gacatacaat tgtcagattc 40201 accaaagttg aaatgaagga aaaaatgtta agggcagcca gagagaaagg tcaggttacc 40261 cataagggga agoccatcag actaacaggt gatctctctg cacctgttgg gggccaatat 40321 tcaacattct taaagaaaag aattttcaac ccagaatttc atatccagcc aaaccgagct 40381 tcataagtga aggagaaata aaattcttta cagacaagca aatgctgaga gattttgtaa 40441 ccaccagacc tgccctacaa gagctcctga aggaagcact gaacatggaa tggaacaacc 40501 ggtaccagcc actgcaaaaa cgtgccaaat tgtaaagacc atcaatgcta ggaagaaatt 40561 gcatcaacta atgagcgaaa taaccagcta acatcataat gataggatga aattcacaga 40621 taacaatatt aaccataaat gtatatgggc taaatgccca tttaaaagac acagattggc 40681 aaattggaca aagagtcaaa acccatcagt gtgctctatt caggaaacac atctcacatg 40741 tagagacaca taagataggc tcaaaataaa ggaatggagg aagatctacc aagcaaatgg 40801 aaaacaaaaa aggcaggggt tgcaatctta gtcttggata aaacagactt taaaccaaca 40861 aagatcaaaa gagacaaaga agggcattac ataatggtaa agggctcaat tcagcaagaa 40921 gagctaacta tcctaaatat atatgcaccc aatacaggag cacccagatt cataaagcaa 40981 gtcctgagtg acctacaaag agacttagac tcccacacaa taataatggg agactttaac 41041 aacccactgt caacattaga cagatcaatg agacagaaaa ttaaaaagga tatccaggaa 41101 ttgaactcag ctctgcacca agcagacata atagacatct acagaactct ccaccccaaa 41161 tcaacagaat atacattcgt ttcagcacca caccacacct attccaaaat tgaccacata 41221 cttggaagta aaacactcct cagcaaatgt aaaagaagag aaattataac aaactgtctc 41281 tcagaccaca gtgcaatcaa actagaattc aggattaaga aactcactca aaaccactca 41341 actacatgga aactgaacaa cctgctcctg aatgatgact gggtacataa ggaaatgaag 41401 gcagaaataa agatgttctt tgaaaccagc gagaacaaag acaaaacata ccagaatctc 41461 tgggacactt tcaaagcagt gtgtagaggg aaactcgtag cactaaatgc ccacaagaga 41521 aagcaggaaa gatctaacat tgacacccta acatcacagt taaaagaact agagaagcaa 41581 gagcaaatac attcaaaagt agcagaaggc aagaaataac taagatcaga gcagaactga 41641 aggaaataga gacacaaaaa acccttcaaa aatttaatga atccaggagt tggtttttgg 41701 aaaagatcaa caaaattgat agaccgctag caagactaat gaagaagaaa agagagaaga 41761 atcaaataga tgcaataaaa aatgataaag ggaatatcac cactgatccc acagaaatgc 41821 aaactaccat caaagaatac tacaaacacc tctacgcaaa aaaaaaaaaa ctagaaaatc 41881 tagaagaaat gcataaattc cttgacacat acaccctccc aagactaaac caggaagaag 41941 ttgaatctct gaatagacca ctaacaggct atgaaattga ggcaataatt aacagcttac 42001 caaccaaaaa aagtccagga caagatggat tcacagccga attctaccag aggtacaagg 42061 aggagttgga accattcctt ctgaaactat tccaatcaat agaaaaagag ggaatcctcc 42121 ctaactcatt ttatgaggcc agcatcatcc tgataccaaa gccgggcaga gacacaacga 42181 aaaaagagaa ttttagacca atatcactga tgaacatoga tgcaaaaatc ctcaataaaa 42241 tactggctaa ctgaatccag cagcacatca aaaagcttat. ccaccatgat caagtgggct 42301 ccatccctgg gatgcaaggc cagttcaaca tatgcaaatc aataaatgta atccaacata 42361 taaacagaac caaagacaaa aaccacatga ttatctcaat agatgcagaa aaggcctttg 42421 acaaaactca acaaccattc atgctaaaaa ctctcaataa attaagtatt gatgggatgt 42481 atctcaaaat aataagagct atctatgaga aaaccacagc caatatcata ctgaatggac 42541 aaaaagtgga agcattcctt tggaaactgg cacaagacag gaatgctgtc tctcaccact 42601 cctattcaac atagtgttgg aagtgctggc cagggcaatt aggcagaaga aggaaataaa 42661 gggtattcaa ttaggaaaag aggaagttaa attgtccctg tttgcagatg acatgattgt 42721 atatctagaa aaccccttca tctcagctca aaatcgcctt aagctgatag gcaacttcag 42781 cagtctcagg atacaaaatc aatgtgcaaa aatcacaagc attctcatac actaataaca 42841 gacaaacaga gagccaaatc atgagtgaac tcccattcac aattgcttca aagagaataa 42901 aatacctagg aatccaactt acaaggtaca tgaaggacct cttcaaggag aactacaaac 42961 cactgctcaa tgaaataaaa gaggatacga acaaatggaa gaacattcca tgctcatggg 43021 taggaagaat caatatcagg aaaatggcca tactgcccaa gataatttat agattcaatg 43081 ccatccccat caagctacca atgactttct tcacagaatt ggaaaatcta ctttaaagtt 43141 catatggaac caaaaaagag ccaacattgc caagtcaatc ctaagccaaa agaactaagc 43201 tggaggcttc atgctacctg acttcaaact atactacaag gatacagtaa ccaaaacaga 43261 atggtactgg tatcaaaaga gcgatataga ccaatggaac agaacagagc cctcagaaat 43321 tatgctgcat atctacaact atctgatttt tgagaaacaa gacaaaaaca agcaataggg 43381 aaatgattcc ctatttaata aatggtgctg gaaaaactgg ctagccatag gtagaaagct 43441 gaaactggat cctttcctta caccttatac aaaaattaat tcaagatgga ttaaagactt 43501 acatgttaga cctaaaacca taaaaaccct agaagaaaac ctaggcaata ccattcagga 43561 cataggcaag ggcaaggact tcatttctaa aacaccaaaa gcaatggcaa caaaagccaa 43621 aattgacaaa tgggatctaa ttaaactaaa gagcttctgc acagcaaaag aaactaccat 43681 cagagtgaac aggcaaccta caaaatggga gaaaattttt gcaacctcct catctgacaa 43741 agggctaata tccagaatct acaatgaact caaatttaca agaaaaaaac gaacaacccc 43801 atcaaaaagt gggcaaatga tatgaacaga cacttctcaa aagaagacat ttatgcagcc 43861 aaaaagcaca tgaaaaatgc tcatcatcac tggccatcag agaaatgcaa atcaaaacca 43921 caatgagata ccatctcata ccagttagaa tggcaatcat taaaaagtca ggaaacaaca 43981 ggtgttggag aggatgtgga gaaataggaa cacttttaca ctgttggtgg gactgtaaac 44041 tagttcaacc attgtggaag tcagtgtggc aatttctcag ggatctagaa ctagaaatac 44101 catttgaccc agccatccca ttactgggta tatacccaaa ggattataaa acatgctgct 44161 ataaagacac atgcacacat atgtttattg cggcactatt cacaatagca aggacttgga 44221 accaacccaa atgtccaaca atgatagact ggattaagaa aatgtggcac atatgcaccg 44281 tggaatacta tgcagccata aaaaatgatg agttcatgtc ctttttagag acatggatga 44341 agctggaaac catcattctc agtaaagtat cgcaaggaca aaaaaccaaa cgctgcatgt 44401 tctcactcat aggtgggaat tgaataatga gaacacatgg acacaggaag ggaacatcac 44461 acacaagggc ctgttgtggc ctcgggggag gggtgaggga tagcattagt agatatacct 44521 aatgttatat gaagagttaa tgggtgcagc acaccaacat ggcacatgta tacatatgta 44581 acaaaccttc acattgtgca catgttccct aaaacttaaa ctataataat aaaaaaaaga 44641 aaatacctcc cattgggttg cttaaagaaa gagaatttgt aatatcaaag ttctggaggc 44701 tcaaagtcca agacttattg tcaggYttgg tttctcctaa agtctgtctt tggcttgcag 44761 acagctgcca tagggttgca ttcattccca cttggcattt cctctgtatg catatccctg 44821 atgtctttct gtctgtccag atttcctctt cttataagaa cccataagag accattctaa 44881 tggcttcgta tgtgcccatc ctaagggcct cataaoccaa ccatatcttt acaggaccca 44941 gcttcaaaca gtcatattct tgtgtactgt ggtttagggc ttcaacatat gaattttgag 45001 gagtcacgat tcagcccata acactcacga tttgtcactg cagactggga caaactgtaa 45061 tttatccaca ggcagcagtc atgcccaatc taatgtcctg gtacaataat ttctctctac 45121 ttcttctgtc tactttgtta cctagatttc ttatgttaat gtacttgttg aactgaatgt 45181 ctgtaattag aagataacac aggatagaag gtaaaagtca gtctgtattt atagccttag 45241 cttcacctWt tgctaggaat gagatccttg aaggtctctt gcttcaattc tcttatcttt 45301 aagatgggta taataacagt atatatgtca aagagttgtc aYttccatta aatgagttaa 45361 tgtacataaa gctctttgca ccaaacacgt tgtagtatct atataagtga ctgttatata 45421 taaactaatt ttatgcaaca catttgtgta atatgatttt taaaatgtat gaatgaataa 45481 aacataagca aatacctaac tggtgacata tttttagaat gccacctgaa atagattata 45541 aatacatact tgtattcaca attcttttaa cctgatagtt tatcaaatct tcattccata 45601 gctatatttc ctttgaattt ccttattttg tcacttcatt tggataatgt acattttctc 45661 agtcatcact agaagccccc tacctgcact gctttacctc ccaccagctt ctccaaggcc 45721 actacagaac ttgtcaccta actcagcaaa tactattata tctatgtttc atatatggaa 45781 atacaagttt gggaatcgca ctgctattac tctcccgtgg tcagcaggtt ccacttctcc 45841 tgcctaatgc tctgtggatg ctttactgtc aatatctaag atgatttata cactttgggc 45901 tactattatg agaaatagaa atgatctatt tctcatttca ctttgtgcta ctcagatctg 45961 tgtctataga aatgatcttc aggcttttgt aggattttct tatttcagca ttgctgactt 46021 tggtcttttt cctctgttcc aggfggtgtg cttcctctat aaagcaagaa gcctcagact 46081 tcatactgtg attttcagaa taagaatgca atagactcag tacaactcac tactatagtc 46141 ttcattttat ccccttgccc tacttctctg ctgacaactt tgcttcctat tttattgaca 46201 acaaaaaatc agataatgcc ttcttgtttt tccccagctc caaaacaaat agcctatctg 46261 gacctgtgcc caggtcttct gctccttctt ctatcactat aaRttatcac caatcctgcc 46321 ctcccactgg ttccagacag cccttccttc cactggttcc cagacagtgc caccttcttg 46381 aggacttgga tcctataatg atccctcttc ttatatcatc atcttcttcc tctgtattgg 46441 atcatgttta ctaacaaaca aaacataaaa ccaaaaatat ttccttgacc ccaggtcatt 46501 gtccagttat tgcattactt gcctgctttt cttgatagct gaaagacagc agaatatcca 46561 atataaaata tgccactttg gcttaagaat tattttgagc tgaaggaaat tcagaagcag 46621 atacaagaaa agtctctgcY tcttctctgc tgggactcac aaaacaatat cccaaaacaa 46681 aggcctcaga agcaaaagtt tttctctgaa cttctccaac cctcctgtat ctcagtccca 46741 ttctctgcca aggctagcca tagaaactag aatccctctt cctcaagtag ggttatagaa 46801 accaagaacc cttttttcYt aaaaccagtc ataaaaccta aaaatattac tctaaotttc 46861 cctttgccct atctttgtaa aagctggtca taaagaaatt atctgacctg cactgtttca 46921 ctgtgtcctt ccttgaccac ccatatttct acatggctgt ccatactttg ttgaccttca 46981 gcataaaaat gagcaatttc ctctgtatct ttgggtcttc attctgaagg ctactgtgta 47041 cacgtgttaa acacatttac atgtcttttc ttgtactaat ctgccttgtg caagcagatt 47101 tttcagagaa ccttccaaag gggaagttcc ccattggccc ccacactcta ttaacctaaa 47161 agcaggacct acatttaaaa agtgtccctc catccccctc taccaggaaa gacaggctga 47221 tcactagaga ttacttcaga ccattacaaa cctggatatg gaaccagagg aatctatata 47281 acaaacttca ctaactacct tttatctacc ataaatttcc catatctggc ctccccaaca 47341 cccttctttc tttctttgag ttgaagatgc tgtatcacag ccagagttct aggctgcctt 47401 gttgagatat gctcttttcc cctatctccc atgtatatat gagatataca tgataaatct 47461 gtttgtttgt ttttccatta gtaaactatc tttttcctag ctaagaacta tgaaggatag 47521 agagaaaatt atttttctcc tctcctacac agtcaaattc tctaaagatt tgtctaccat 47581 caatgtctcc attttctcac atttcattct ctctggaatc cactgtaatc aagaattcag 47641 cctcaacaga actttgaaac tgttcctttc aatgccaata gtgatcttct ggtcatagcc 47701 aaaggtcagt tctcacttcc cttattcaac ttctcagtag cattgaacat ggttgaacaa 47761 tccctgttct tggaccttgc tttacttggc ctgaacagca tggacatacc aaaaatacca 47821 caaattttag agtcaggcag atgtaaacat aaattctgga ttttctacat tRtatttgct 47881 tgatgtctct gaaattattg aacctcacct caatttttta catttctata agataaagat 47941 aacagtactc ttcctgtagg agtattaaag acagtatata taaaacctca gcttaattta 48001 tggcacaoca taagtactca ataaatgata acaataatca ttattgctKt tttctttact 48061 tcttgcttcc atacttctgt ttatattttt acatctgtgt ggtaggcagt gttttatccc 48121 caaaatttat ttcacctgtg gaaatcccac cctaacctta aaatccatct ccaatttatt 48181 ttttccatga agtcatcctt gtttgtttct gaaagaaaat gacccttcct aggaatcatt 48241 agttgcttat tttatctgta attcctatag catccgtgtt atattacttt aattcatgaa 48301 tgtgttttat tgcccttact agttctaagt ttccagtggg cataaccagc tatgtagaag 48361 aaatcagcta aaatttgcct ggtaggtttt ataatttgat gtttcaggtt tggaaagttg 48421 tttaaacatt tgctcaatat agtaatacta cctaatcaag aacccatgaa aaaaatattg 48481 aaattaaaag aaaaatttat ccaacagtca ttgaaagcca gtgcctccaa aaaaatggaa 48541 aaccattcca tgttcatgca taggagaatc aatattgtta aaatggccat actgtccaaa 48601 gcaatttaca agattcaaag ctattcttat caaactacca atgacattct tcacaaaact 48661 ataaaaaaac tatttgaaat tcatatggaa ccaaaaaaag agcctgaata gccaaagcaa 48721 ttctaagcaa aaagaacaaa gcaagaggca ttacactact caactttaaa ctgtaactac 48781 agggctatgg taaccaaaac agcaaagcag tggtaccaaa acagacacat ggacctaYgg 48841 aactgaatag aaagcccaga agtaaggctg catacctaca ataatctaat ctttgacaaa 48901 gctgacaaaa acaagcaatg aggaaaggac ttcctattca ataaatggtg ctgggataac 48961 aggctaccca tctgcagaga attgaaactg gactccttcc ttacttcatg tattagtcag 49021 ggttatctag aaagacagaa ctaatataaa ggggaattta ttaagcagta ctgcctgaca 49081 caatcatgag gtgaagtccc acaatacacc atctacaagc taaagagcaa ggaagccagt 49141 ccgagtctga aaacctcaaa attagggaag ccgacagtgc agtcttcagt cKgtcatgga 49201 aggcctgaga gcccctggYa aaccactggt gtaagtccaa gagtccaaaa gctgaagaac 49261 ttggagtctg atgtttgagg gcaggaagca tccagtatgM gagaaagata aaggctggaa 49321 gaatcagcaa gtctgttctt tctatcttct tctgcctgct ttattctagc tgcactggca 49381 actaattaga tgatgcccaa ccagattgaa agtgggtcag tctctctcag tccactgact 49441 caaatgttaa tgttttttgg caacaccctc acagatacac ctaggaacaa taatttgcat 49501 ccttcaatcc aatcaagttg acactcagta ttaaacatca cacactatat acaaaaatca 49561 actcaagatg aattaaagac ctaaatgtaa aacccaaaat ggtaaaaata ttgggaagac 49621 aactgaggca aaaccattct ggatatagga aagggtaaag atttcatgac taagacccca 49681 aaagcaattg caacaaaaac aaaaattgac aaatgggacc taattaaatt aaagagcttc 49741 tgcacagcaa aagaaactat caacagagta aacagacaac atacagaatg ggagaaagtg 49801 tttgcaaact gtgcatctga caaagttcta atttccagca tctacaaata acttaaataa 49861 atttataaga aaaaacccaa acaacctcat taaaaggtgg gctagggaca ggaacagaca 49921 cttttcaaaa gaaaatatac atgtggctaa caagcatatg aaaaaaagct caacatcact 49981 aagcattaga aaaatgaaaa tcaaaaccat gatgagatac catctcacac cagtcagaat 50041 ggctattaaa aagtcaaaaa ttaacagatg ctggcaaggt tgtggagaaa acaggaaagc 50101 ttatacactg tttggtggga gtgaaaatta gttcaaccat agtgaaaagc agtgtgctga 50161 ttcctcaaag acataaaaac agaactacca ttcaaccctt caatatcatt gctgtatata 50221 tatccaaaga aatataaatc atcgtatcat aaagatacct gcatgcatat gttcattgca 50281 gcactattta gaatagcaaa gacatggagt cagcctaaat acccatcaat ggtaggctcg 50341 ataaagaaaa tgtggtatat atacaccgta tgtatatgta taatacaaaa gaattaaatc 50401 acRttctttg caggagcatg gatggagctg gaggccatta tccttaacaa actaacacat 50461 gaacagaaaa ccaaatacca cactttctca cttataactg aaagttaaat gatgagaaca 50521 catggacata taggggggaa caacagacac tggggcctac cagagggtgt gcggtgggag 50581 gagagagagg gtcaggcaaa ataacttagg gatactaggc ttaatacttg ggtgatgaaa 50641 taatctctac aacaaacccc tgtgacataa gtttacctat ataacgaacc tgcacatgta 50701 ctcctgaact taaaaaaaaa aagagagaaa aggatggctg gcaagatagc caaataggaa 50761 catctctggt tggcagctcc cagcgagatc aatgcagaag gtgggtgatt tctgcatttc 50821 caactgaggt acccagctca tctcactggg actggttaga gagtgattgc agcccacgga 50881 gggcaagctg aagcaggatg gggcattgcc tcaccctgga agtgcaaggg gttgggaact 50941 ccctccccta gccaagggaa actgtgYggg attgtgcctt gaggaatggt gcattctggc 51001 acacatacta tgcttttccc atggtcttca caacccacag accaggaaag tccctcaggt 51061 gcctacacca ccagggccct ggatttcaag cacaaagctg ggtggccatt tgagaagaca 51121 ccaagctagc tgcaggagtt tattttcata ccccagtagt gcctggaact tcagtgaaac 51181 agaaccactc actcccctgg aaaggggatg ctgaagccag gagccaagtg gtctagctca 51241 aggaatctca cccccatgga gcccagcaag ctaagatcca ctgacttgaa gttctcactg 51301 ccaacacagc aatctgaagt ccacctggga tgctctagct ttgtggggga ggggtatctg 51361 ccattactga gggttgagta ggtggttttc ccctcacagt ataaataaag ccacccagaa 51421 gatcaaattg ggtggagccc gttgcagcta agcaaagcaa ctggagccag actttccctc 51481 cagattcccc ctctctggtc agggcatgtc tgaaagaaag gcagcagccg cagtcagggg 51541 ottacagata aaactcccat ctctctggga cagagcacct tgggcaaggg gcaactgtga 51601 gcacaacttc agcagactta aatgttcctg cctactgtct ctgaaaagag cctccaatct 51661 cccagcacag cactcaagct ctgctatggg acagattgcc ttctcaagtg Kgtccctgac 51721 ccccatgcct cctgatgggg agacacctcc cagcaggggt tgacacgcac cacatacagg 51781 agagctccag ctggcatctg gcaggtgccc ctctgggatg aagcttccag aggaaggaac 51841 aggcagcaat ctttgctgtt ctgcagcctc cactggtgat gcccaggcaa acagggtctg 51901 gagtggacat ccagcaaact ccagcagacc tgcaggagag gggcctgaca aaaggaaaac 51961 taacaaacat agagaaatag catcaacatc aacaaaagga catccacaga aaaaccccat 52021 acgaaggtca ccaacatcaa agaccataga tagaaaaatc catgaagatg aggaaaaacc 52081 agtgcaaaaa ggctgaatat tctaaaaact agaatgcctc ttctgttcca aaggatcaca 52141 agtcctcgcc agcaagggag caaaactgga tggagaatga gtttggcaaa ttgccagaag 52201 taggcttcag aaggtgggta ataacaaatt cttctgagct aaagaagcat tttctaaccc 52261 aatgcaagga agctaagaac cttgaaaaaa ggttagagga attgctaact agaataacca 52321 gtttagagaa gaacataaat gacctgatgg agctgaaaaa cacagcaaga gaacttcatg 52381 aagcatacag aagcatcaac agatgaattg atcaagcaga agaaagaata tcagagattg 52441 aagatcaact aaatgaaata aagcatgaag acaagattag agaaaaaaga atgaaaagga 52501 acaaagcctc caaaaaatat gggactatgt gagaagacca aacctacgtt ttattagtgt 52561 acctcaaagt gacagggagg atggaaccaa gtttcaaaac accttcaaga tattatccag 52621 gaaaacttcc acaacctagc aaaacaggtc aatattcaaa ttcaggaaat acagagaaca 52681 ccacaaagat agtcctcaag aagagcagcc tcaagacata taatcgtcag attcaccaat 52741 gaagaagtgg aggaaaaaat gttaagggca gccagagaga aaggtcgggt tacccRcaaa 52801 aggaagccca ttagactaac agcagatatc tctgcagaaa acctatgagc cagaagaaag 52861 tggcggccaa tattcaacat ccttaaggaa aagaattttc aacccaggat ttcatatcca 52921 gccaaactaa acttcacaag caaaggagaa ataaaaccct ttacagataa gcaaatgctg 52981 agacattttg tcaccaccag gcctgcctta caagagctcc taaaggacac actacatata 53041 gaaaggaaaa actgtttaga gctgttgcaa acacatatta aattgtaaag aacatcgaca 53101 ctatgaagaa actgcctcaa ctaaggRgca aaacaactag ctagcatcat aatgacagga 53161 tcagattcac acataataag attaacccta aaccttaaat gtaaatggac taaatgcccc 53221 agctaaaaga cacagactgg caaattggat aaagggccaa gacccattgg tgtgctgtat 53281 tcaggagacc catcttaatg caaagacaca cataggctca aaataaaggg atggaggaag 53341 atctaccaag caaatggaaa gaagaaaaaa aagagtggtt gcaatcctag tctcaggtaa 53401 aacagatgtt aaaccaacaa aaatcaaaaa acacaaagaa aggtatcacg taatggtaaa 53461 gggatcaatg caacaagaag agctaactat cctaaatata tagacaccta atacaggagc 53521 acctagattc atgaagoaag ttcttagaga cctacaaaga gacttagatg cccacacaat 53581 aataatggga gactttaaca ccccaatgtc aatattagac agatcaacaa gactgaaaat 53641 taacaaggat actcaagact tgaactcagc tctggaccaa ggggacccaa tagaaaacta 53701 cagaactctt tatcccagat caacagaata tacattcttc tcagcaccag atcacactta 53761 ttctaaaatt ggccaYataa ttggaagtaa aaaaagtcct cagcaaatgc aaaagaatgg 53821 aaatcataac agtctctcag accacagtgc aatcaaacta gaactcaaga ttaaaaaatt 53881 cactcagaaa tgcatgacta catggaaact gaacaacctg ctccagaatg actactgggt 53941 aaataaggaa attaaggcag aaataaataa gttctttgaa accaatagga acatagacac 54001 aatgtaccag aatctctggg acacagcata agcaatgttt agagggaaac ttatagtact 54061 gaatgcccac agaagaaagc aggaaagatc taaaatcgac accctaacat cacgattaaa 54121 agaaccagag aagcaagagc aaacaaattc aaaagctagc agaagacaag aagtaactaa 54181 gatcagagta gaactgaagg agatagagac atgaaaaacc cttcaaaaMa tcaatgaatc 54241 cagaggctgg ttttctgaaa agattaacaa aatagaccac tagccagatt aataaagaag 54301 aaaggagaga agattcaaat agatacaata aaaatgataa ggagatatca tcattgatcc 54361 cacagaaata caaactacca tcaaagaata ctataaacac ctctacacaa ataaactaga 54421 aaatctagca gaaatggata aattcctggt cacatacacc ctccoaagac taaacaagga 54481 agaagtcaaa tccctgaata caccaataaa aagttctgaa attgaggcca taattaatag 54541 cctaccaacc aaaaaaaaag ccgaagacca gatggattca aagccaaatc ctacaagagg 54601 tacaacgagg agctgatacc attccttctg aaactattcc aatcaataga aaaagaggaa 54661 ctcctcccta actcatttta tgaggccagc atcatcctga tatcaaaacc tggcagagac 54721 acaataaaaa aggaaatttt aggccaatat ccctgatgaa cattgatgca aaaatcgcca 54781 gtaaaataca ggcaaaatga atccagcagc acatcaaaaa gcttatccac cacgatcaag 54841 ttggcttcat tcctgggatg caaagctgat acaacataaa caagttaaac gtaatctgtc 54901 acataagcag aaccaatgac aaaatcacac gattatctca atagatgcag aaaaggcctt 54961 tgataaaata caacacatct tcatgccaaa actctcaata aattagttat cagtggaaag 55021 tatctcaaaa tagtaacagc caatatcata ctgagtggac aaaagctgga agcattccct 55081 ttgaaaacca gcacaagaaa aggatgccct ccctaaccac tcctattcaa cataatattg 55141 gaagttctgg tgagggcaat caggcaggag gaaagaaata aagtgtattc agatagaaag 55201 agaggaagtc aaattgtctc tgtttgcaga tgacatgatt gtatatttag aaaaccccat 55261 tgtctcagcc caaaatocct taagctgata agcaacttca gcaaagtctc tggatgcaaa 55321 atcagtgtgc aaaaatcaca agcattccta tacaccaata attacaaaca aacagagagc 55381 caaatcatga gtgaactccc attcacaatt gctacaaaga gaataaaata cctaggaata 55441 caacttacaa gggatgtgaa ggaactcttg agggagagct acaaaccaag gaaataagag 55501 aggacacaaa tggagaaaca ttccatgctc atggatagga agaatcaatg ccatgaaaat 55561 ggccatattg cccaaagtta tttaaggatt caatgttctt cccatcaaac taccattggc 55621 tttcttcaca gaattagaaa aaaactactt taaatttaat atggtaccaa aaaggagccc 55681 atatagccaa gacaatccta aacaaaaaga acaaagctgg aggcatcaca ctccctgact 55741 tcaaactata ctaoaaggct acagtaacca aaacagcatg gtacttgtgc caagacagat 55801 ataaagacca acggaacaga acagagacct cagaaatact gccacacatc tgcaaccatc 55861 tgatctttga aaaacctgac aaaaacaagc aacggggaga ggattctctg tttaataaac 55921 agtgttggga aaagtggcta gccatatgca gaaaactgaa accggaoccc ttccttacac 55981 tttatacaaa aattaactca agatggatta aagacttaaa cataagacct aaaaccataa 56041 aaaccttaga agaaaatcta ggcaatacca ttaagaacat aggcatgggc aaagacttca 56101 tgactaaaac accaaaagca ctagcaacaa tagccaaaat aaacaaacag gatctaatta 56161 aactaaagag cttctgcacg gcaaaagaaa ccatcataag agtgaacagg caacctacag 56221 aatgggagaa cattttggca atctatccac ctgacaaagg gctaatatcc agaatataca 56281 aggaacttaa acaaatttac aagaaaaaac aaccccatca aaatgtgggc aaagcatatg 56341 aatagacact tctcaaaaga agacatttat gtggccaaaa accatatgaa aaaaagctca 56401 tcactggtcg ttagagaaat gcaagtcaaa atcacaatgt gttaccatct cacaccagtt 56461 ggaatggcga tcattaaaaa gttaggaaac aacagatgct ggagaggatg tggagaaata 56521 ggaacgcttt tacactgttg gtgggaatgt aaattagttc aaccattgtg gaagacagtg 56581 tggcgattcc tcaaggattt acaaccagaa atacaatttg acctagcaat accatgactt 56641 ggtatatacc caaaggatta taaatcacgc tactataaag acacatgcat atgtatgttt 56701 atcgcaacac tattcacaag agcaaagact tggaaccaac ccaaatgccc atcaatgaga 56761 gactggataa agaaaatgtg gcacatatac actatagaat actatgcagc tatacaaata 56821 atgagttcat gtcctttgca gggacataga tgaagctgga aaccatcatt ctcagcaaac 56881 taacacagga acagaaaacc aaacacagca tgttctcact cataagtggg agctgaacaa 56941 tgagaacgca tggacacagg gagaggaaca tcacacacca ggtcttgtca gggggtagta 57001 gggtagggga agaatagcat taggagaagc acctaatgta gatgacgggt tgatggttgc 57061 agcaaaccat catggcacgt gtacacctat gtaacaaacc tgcacattct gcgcatgtat 57121 cccagaactt aaagtatata tatatataga gagagaaaac tcatggctca tagagatgtc 57181 tcaaaactta ccttgttttg actgagcaac aatatccatg ttttgaaaga gaatagaccc 57241 ctgaagtcct ctttttaatc tataaatgtt tgttattgat ttttgagtat tctgcttatt 57301 agatatagac aatttacttt taattatcca gacatgtttt ggattaagca atagagtaaa 57361 acaaacaaat gtactttaaa caataaattg cagtcctgca acctgaactc acatgtaaaa 57421 caaagaatgg atgaaatcct actttaaact ctaaatgcct ttgcRtaagt gttttcctac 57481 tttatattca taagtaaatg taaactttaa tatcaattcc attgcagccc tttctgaaaa 57541 gatttctttg tattgttgac ttcaggggta atttgttctt caagcacaga caaagttata 57601 taagttactt aggaaaatat ctccatgtta gattgtaacc tactgctttt cttttcatgg 57661 aagccatgca aagctatatg tggtagggta gattgaggga agcccagcca gtgtcaacct 57721 gtttcatgaa gaactaatga tatgcctgca tctttactga ggatgctttt gttgccaaga 57781 aagaacacaa ttgagggatg tgggcactca atgtctgcct gacagcagat gtgaatcttt 57841 tctaacaggt acatagcaac aaagctttaa atagaatcca gcagctgtta aatcaagaac 57901 aagaatattt acttcacttt ttctatagtc ccattattct gtaattcaaa cgtcaactca 57961 ccctatttta tttttaagct gtagctgata aggagcaaaa ttcctctact atccaaaggg 58021 ctttgaaggg ttctaacctc atttcacaga ttaagttcag gcagtttact cagattcctt 58081 tttaggacta gaaactgttt ttcccattta cagcgaacag ttttaaaaac gtgtatttca 58141 ggggtaaaca gacatcatct ctgaacagaa ctaggttaga agtaagctta gagatttgtc 58201 tagattaaat ttagatttgc tttcagtttc aaaatgaccc catacattcc atttcaggat 58261 tactttcttt ttctgctgtg aggtggattg gaggctgcct tccctaagat tttcttttca 58321 Ytttttgagt atgcaagtga cattttcctg ttcatccaaa gaatgaagta aacccgatta 58381 gatttgttct ccatctggga gcaggaaatt aactttgaaa atgatttaaa tctcttgcct 58441 ggggagggac ttttactgcc ctgagttcaa tagttcaatt tgacagaagc cttcRccaga 58501 tttctaatac atagttgtgt ttaaaaaaag gatgaaaatg aggctgcttt aaatttcatt 58561 aactgaattc ttatatcaga cYgaatttgg aggcctgtca ggcagaataa gttSgcccag 58621 taaacatttt aagtagacag atattattat actagtttca aagaagaaaa aaaatacatg 58681 cttttgtata ttaagagaaa atctttagga ctgacaatta tgcattacaa tttttttctt 58741 attttgtgac cataagaaca ggcagcataa gcatgaaacc atgaaaactg gttgaacatg 58801 tttagagttt attttggtaa tcaaaacaac aaagctattc tgacatactt ctaatgatat 58861 acataatagt tgtgctgaaa gatgacaaaa tgtccacaca aacaacttta ttttgaatat 58921 ttatttgcag atagatgtca cttttaggat ttttttctca ctttatttgc acatatctat 58981 aattaacatt gatgatgaca atattcccaa tgactatgaa catcatgaaa gcagacattt 59041 gtcacattct ctcacgcacg tttatgttta tatataccat agtccctcta actggggttt 59101 ctttgcttgg gatactttgt ccaaagacaa tattggcaat atttgcatat taagaaaata 59161 tttgtatatt ttttccatga aaacatagta aacactaatt gaacatcttc tgtgtgctaa 59221 tcatgttagt attggtgtca tgaaataatt ataaggactt gaattagaca tttcaaaagc 59281 ctagggttaa taccttgaca actaatctaa aagacacatg ttgattgctc ccataagaga 59341 ggtgtatata ctggggtata tctgaaaagg ctttcccaag aaagtgatgc atgaactagg 59401 tcatgaataa tagaattgtg aaatattaga aagatctgta taagaaaaat tatattccca 59461 atatcatttt tttctttcat gcattcccat ccatactgtt ttcccctcaa accaaggagt 59521 tcttgttcag tatctactca gcagaaaata gttactttgg cccaagttag gctgttgcag 59581 caaatgagtc tcaaatttct ctctctctct ctctcgccct cagctttgtt tcttgcatct 59641 aatatatgtc cattggggat tgagtacagt tctactctat gtcattttct ttccaagact 59701 caggattatg gatcatattc tatctgggat atcatcagat ttatggcaca gaaaaaaaga 59761 gcaaagatgg aaccataaga tgacttctaa atcttctgct tggaagtagt acacatcact 59821 tccctctttt taattggcca gatcaagtca tgttcccaaa ccaaatctca atggacaggg 59881 aatataatta tcccacaagg agtggcttga caggcaggaa tcctagatat ttcaaataaa 59941 tgagactata cccaaaatta aaacacattt tatatgaccc agtatcccag catatatgtg 60001 tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtatata tatatatata tatatatata 60061 tatatatata tatatatata catgttaacc agtgcaggga acatagtagg tgcacaataa 60121 gtatttttta aatggataca tgaatgatta tattaaccaa gaaaatatta tatgatgtac 60181 tctgatgttt ctaagatatt gtatcttttg tattatattc tattttattt ttgtaaagtg 60241 ctaatcatgg cccactaaat tgatttcatg aaccacaatt taaaagcatt cattaacaaa 60301 tataagaatg tgaaagcaat attattttca atgcttgatt ctgttttttt ttatcctatg 60361 aaaacacagg aaacattaat tgaacatctt ctgtgtgcta gttttgtcag tattggtgtc 60421 atgaaataat tataaggact tgaattagac atttaagaag tccagggtta acatcttcac 60481 aactaattta aaagaaacat atggtaatag ctcccataag agagatgtat aaactggggt 60541 agatctgaaa aggttttccc aagaaagtaa tgcttaaacg agggcatgat aatgaataat 60601 atgattctga aacacaagaa agacYtatat aagaaaatta taagtagcat gcaagctttt 60661 ggtaagtttg aagaagcata aatggtgcaa gagaagggag atcagacata ttattgggaa 60721 agttagggtt ttacacatca ccaactagct attcttcaac tactagatat gtcaagaatt 60781 cctggtatgt aattctatct ttaaaaaagc aagtgaaaac agagcaggaa agtggtggaa 60841 atcagagttt tgttttataa acaggtcaga tttaaaggta acaaattcct tatctcacat 60901 agatatgagt ttcttttgtc ttctaagtat attgggctga tttttttctt ttcttaattt 60961 ctcagttggg atttgcactg taccaattat ttggccataa aacaaatcag cctccatttt 61021 ctgatctata cacataaatg cataacatta tatttccatg ccatttttga aatatgtttg 61081 gcaacatgta acaacaacaa caaaatggtt tagattttta gtcacatgag atctatggga 61141 acaggccaga acagatagag tggtacaaac aagaacgttt aggctgagat caatgtgatc 61201 ccgtggcatt tccctcatgc tcaaagataa tcgctgggcc ttcagttata acatcaattt 61261 atcaagaaca agaggaggag gagaaagaaa ctaggaaaat ggggcaagcc tatattagaa 61321 atccccagcc aacttccact tgcaagtaat tggcaacaag accatattca tatcacgtgg 61381 cctcttcaag cttcaaagga ggctgggaaa taaaattttt aaacatattc ctgctgtgaa 61441 taaMattaga gttcccRgta ttataggagg agaaaaccat aactgctaca tcttcttacc 61501 tcgcagggtt gttgagggaa tcagaatgag agtactRgtg taaaatgact tgaaaaattt 61561 caaataatta tgagcaagta aactattttt aaaaagtaag aagtgtacaa aacttaagct 61621 aagctaatta gccatttctg ccataaaata tttgaaaatt ccaacagcaa tacaaaaata 61681 cacacacatg cactcaatcg ttcatacaca tagctgctgt attaacgtgt atagtaaaaa 61741 catgtagtca tctatgtgta taggcctaca tattatttac agaaaattaa tattagttta 61801 taattaactt taacacacac acacatataa aataaagtaa tggtgaaaat caaagacact 61861 atctttcctc ttaattttat actactgaag acacaaaatt ttccataata ttgtgcttat 61921 ttcaagatct caaatcagag tgtttattat ttacaaggca tctttattgt ttccaaggaa 61981 aaccctgata ccaattaata atgggggaga gaggaggcag atatatatat tcaccacaaa 62041 attcacagac aatctgcaaa actcacagag tcagaaaatt tgagtggagt ttaggagatt 62101 tggccctgct ggaaacagaa aaacaagata aaaagaagat atgataactc tcaggtacgt 62161 aaaagtatgc tatagagcag ttaaatagca attattctat aagctgatta ggatagaaca 62221 tggtataaag acctcaaggc tatgaaactc ctaaaataaa catcagggaa actctctaga 62281 acattggctg tggcaaagat ttcttgagta atactccaca agcacaggca accaaagcaa 62341 aaatggacaa atgggatcac atcatgttaa aaaccttctg cacagaaaag gaaacagtct 62401 acaaaatgga cagacaaccc aaagaatggg agaaaatatt tgcaaactat ccatctgaca 62461 agggactaat aaagtatata atgatctcaa aaaaactcta caggaaaaaa tctcataatc 62521 tgatttttta aatgagcaaa agatctcagt agacatttat cagaagaagg catacaagtg 62581 gaaaatagat atatgtagag gtgctcatca atgatcatta gaaaaatgca atgaaatatc 62641 atctcatccc agttaaaaca gcttttatcc gaaagacagg caatgacaaa tgctgacaag 62701 gatgtggaga aaagggaacc ctcatacaot aattgactaa atattaatta gtacaaccac 62761 tatggagtac agtttgaagg ctccttaaaa aaactaaaaa cagagctacc atatgatctt 62821 atccaccaat cccactgcta gatatatacc ccaaagaaag gaaatcagta tatagaagag 62881 atatctacac tcccatattt cttgagcact attcaaatat ccgagatttg aaagtaacct 62941 aattgtccat cagcagatga atggatagca aacatgtggt acatatacac aatggagtac 63001 tattcagcta taagaaagca tgagatcttg tcgtttgcaa taccatggat ggagctggag 63061 gtcattttgt taagtgagat atgccaggca cagaaaoaca aactttgcat gttctcttat 63121 ttgtgggagc taaaaatcga aacaattgaa ctcatggaga cagtgaggag aatgatcatt 63181 accagcagct gggaagggta atggggctgt aggagtaagt gtggattgtt tgtagataca 63241 aaaaaaagta gttggaaaca atgaattaga tctagtattt gatagcccaa taatgtgact 63301 acagtcaata acaattcaag tgtacattta aaaataacta aaagaatata attgtattct 63361 ttgtgctgca aagtataaat gcttgaagtg atagatatgc cattttcctg atatgattat 63421 tatgcattgt atgcctgtat caaaatatct catgttctcc ataaacatat acacctaaaa 63481 attaaaataa ataaaaagta taagttttaa aaaagcatta ttcttaccaa attaactagt 63541 agcttcaaat taactagtag ottcagcaga tttcataatc agcaccttaa ctaagagtct 63601 tatggaaccg ttaatctcat aagtaaaagt tgagggcttt ttgtatttta aaatcatttt 63661 taaaaatttt caagagttta aaaataaaat gttcttagcc tccaagctaa aatagcaaat 63721 agcaaataaa taataaaggg caaagcaatc ttttgtttaa aatgcttatt cctttcccaa 63781 ctaggtttaa ctggggaaag tggtagggaa gagaaaatct tgaaatcatt catttacttc 63841 ctgactctca ggtgtggctg aatgaaagat ttcctgggca ctacattaga taagaggctc 63901 agtaaggagt tctttacaaa aatttgagtt agaatgatag actggattaa gaaaatgtgg 63961 cacatataca ccatggaata ctatgcagcc ataaaaaatg atgagtttgt gtcctttgta 64021 gggacatgga tgaagctgga aaccatcatt ctcagcaaac tatcacaagg acaaaaaacc 64081 aaacaccgca tgttctcact cacagatggg aattgaacaa tgagaacaca tggtcagagg 64141 aaggggaaca tcacacactg gggcctgttg tgaggtggag ggagtggcga gggatagcat 64201 taggagatat acctaatgct aaatgacgag ttaatgggtg cagcacacca acatggcaca 64261 tgtatacata tataacaaac ctgcacgttg ggcacatgta ccctaaaact tcaagtataa 64321 taaaaaaaat tttaaaaaaa tttgagtagg aagctgctcc atgactagct caatgttttg 64381 tctggcttaa gaagtgataa ttggggctgg gcatggtggt tcatgYctgt aatcccagta 64441 ctttgggtgg ctgaggtggg aggaccactt gaggccagga gttggaaacc agcctgggta 64501 acaaagtgag accccatctt tataaaaata aaaatacaaa aagaagtgat aggcactagg 64561 ccatcatccc cagttgcttc ttcctttccc aagatagatt tagtcttctt aatttaagcc 64621 ttgttcttat tatgtggatc ctctgcttca acatgtgctt ttgacataaa attttaggtc 64681 attgtgaagg aaggtggagg ggattatgtt agctcatacg taaaatattt ttagctaatc 64741 tctgtgtgtg tgtgtgtgtg tgtgtgtgtc tttctctgct tgtatatatt tctttctaRt 64801 tttcacacac atacatcaat tcatgctcaa aaacagtata tgtagcatac tgaatatgtt 64861 gagtgagaaa agcaaggtat gtgataaact gagatcctct ctgttataga ctgaatgttt 64921 gcatctgtgt ctcccccacc ccaaaattta ctatgttgaa gctctatttc cagagtgagt 64981 gtatttggag tctctaagga agtaattaag gttaagtgag atcataaggg tggtaggtct 65041 gatgggatta gtggttttat aagcagtgac accagagagc tctctcatga gtgcctgSac 65101 caaggaaaag ccaggtaagc acagagaagg cagccgtctt caacccaagg ggagaggcct 65161 caccagaaag acgcatcgct attccctgat tttggacttc cagtccccag aactgtgcaa 65221 aagtaaattt ctgttgttta agccatacag ctcctcatat tttgtagtag cagcccaagc 65281 tgactaatac agtctctcta aatatttctt cttttgacaa acaYgtaaag atatatgaca 65341 ttaaaccaaa aatctttatc tagtatttct ctcctttaat ctgaggaagt tgccaatgao 65401 aagttttctg acaaaatttt aagtatatca atattaagat atctattaca tttcaaatta 65461 tatattaata agtaggatgt acatatttga tcaaatatta agtatattat aaaatattta 65521 tgaaatagaa tgtaaaaaat aacagaaaat tttaagaaaa acaaaacttt atataaccac 65581 aggttattgt gctaggccaa tttgtgttca tgcattaggc tcacctgaga ttatgtccag 65641 taaatcctca cataatgtca ttgataggtt cttggaaact gtgacttcaa gcaaaataac 65701 ataatgaaac caattttacc ataggctaat ttaaacaaga gttaagtttc tatggcatat 65761 ttctagtcac aaaaatagca tcttcaattt ctaaagacac caagcaattc taatattaaa 65821 cattgaaata aatttgagct atacacacat ttaagaaagg ttaataaaaa acaagtaaga 65881 taattattta tcccatgttt ggtgaatcag tgagtatcag tggtcacagc ggtggtgggg 65941 taaatcaaag aataaatatt ctcaaagcaa aaattatgag gagcacctcc taccaccaca 66001 cagttcaaat accagcactc acaaataggg tagtgtcact gactgctttt gtaccacatc 66061 gtttattatc atgcatttgt atgattatta tatactttac aaatttctgt tttacaataa 66121 tttgtattca ttcattcatY cattttccaa ccagattatt ccagttcaga gtcaagggtg 66181 actggaccct attcaggcaa ctcagggtgc aaggttgaga ccacctctgg acaggatgcg 66241 attccattgc aggacataca Yccacaccca cactcactca gattagggca atttagatag 66301 gccaatgaac ctaacgttca catctttggg atgtgggagg aaaccagagt acccagagaa 66361 aatctacaca gatatagaga gaatgtgcaa actccacaca gacagtggct ccgacaactc 66421 tcaatattat aatgagaaag caatgttgaa tcaaacaacg ttgaggacca gctgtatttg 66481 tatttttgcc tcttcttgga ggataggttt gagaaaattg ccaatacatt cacccttaca 66541 ttcttttaag tgtgcatgca gacttaactt aaaatttgct atttattaaa ctttctataa 66601 tttattccat agtgtaacct cattatcttc cttcaatatt tttgctgttt tcataaaggc 66661 aggttgaaaa caaacatttc catacttctt aaagatatgt aactaaattt gatggaccca 66721 gctaacaaat ttaatcactt tatatactag tacccaggat aagtagactc cttaatgaaa 66781 gatactcctg ttactgtgtg gctgaccaag tcatgtttat ttttggcttt gtgctttggt 66841 agagcagtga ctcttaatcc ctggtttgca tcaottcgag agtttgaaaa aatacaaaca 66901 catgaaaaca atgctggRcc aattaagcca gtgtctctag gagaggatgc cagtactcta 66961 ggttcttaaa atcttctcaa ataattctga agtgcagtca gggtgagatc ggctgcctta 67021 gagggacttg tttaaactcc tataaatttg ttaatacatt ttatatgcat tcttcttccc 67081 caaaaagtcc aatttctctg tcaagctctt gaaccatatg atagtaaatt atgttggcct 67141 ttatagacaa gggcttggaa taattcacag aaatcaaagg tacagcattt taacacttta 67201 ctaatttagt aacacataaa agtaatctcc aaatcaacag ggaagaaaaa atatgcacca 67261 actctgactg atcattccac agagcaaaga atttacacat caatattttc aaggagacaa 67321 aaatctaata ggaactgaaa tgatgaatct aatacttcaa aagagaatag aaaatctgtt 67381 ttaaagaaaa tggattctga aaatacatag aaatatttca gtatttggaa agagacttca 67441 actaactatg gaaaaataac attgaagaca aactaaggaa caagccaaaa catgagatat 67501 tttgtctaat cataacacat tttatgaggg ctatatatat agcaacaatt ttccaataat 67561 aaggcaggaa gctgaaatca ttagagctca aattacccta aaccagtgct cagaaacatg 67621 gtttccataa gaatcacctg gggatcttgt taaaatgcag atttgattaa gtctaggatg 67681 aggcctgaga gtctgcattt ctaccaagat ctcaagggat gtagaagttg ctgtccaaga 67741 actacaattt aagcactagc aaggcaaact attaatcttt aaagtccttg cagataacat 67801 tatccagaag atagtcaaat ttaaaatgta aagtgcataa- tatgaacctg cacttcaaaa 67861 gcaaataata tttgattcat tttacagctt tgtctctata acacactgag ggtccaaatg 67921 ggtgactact agatagagat tgaaaaacag aaaacagacg gactctaatt tttgattagt 67981 gatatcaata ccatcaccac agataagttc tggttgaaaa taggaaaaag tggagttatc 68041 ttttctcaaa aaacacaaat cattggccat taatatcaac ctagaccagg gtatgttgga 68101 gttggccact accactcagg agagtaggct gcgtgcatct ctttccaact ccaacaccat 68161 aaatagttac gtcagtttgg tagcttaaag atctcagcaa acacttggaa tggggtctta 68221 aaaaaaagtc ccccagagtg ggtttgccaa catagcatgg catgtagctt ctggtctaac 68281 acatgattct gaaagaaaag aaatgtaaac ataacgtgaa atacggtgaa taatgcaatg 68341 accttaggat tgtcaagatt agaagacaat agggagatta aggagggcat cttcttgtct 68401 aaacaatgaa aatagRtatt ggaaaaacca taaagtatga gatataagaa aaaaatacaa 68461 aaataacaaa tggatcaatc taaattgcat taaacagtgg tataatgtta aacaatgtgt 68521 tttagttgtc tgtggtactg Kttcaaacac atttggtctc aggactcctt cacagtctta 68581 aaatttttga ataactcaaa gaacatttat ttatatgatt atttcaattg tttatcatat 68641 tcaaaatgaa aagagacaaa ttttaaactt gtttgtgtat taagttgctt atgaataaca 68701 gcaataagcc cattgcatgt taatatacta cttctgagga ataattatat tttccaagac 68761 aaataaaatg taatgagaag agttagctct aataacagta ggatcctcct gtttggttct 68821 gcctgccttc tattgctata tgttttggtg gaagtatatg aagaaaatca ggccatacag 68881 aaataactac tagttggaag agagaaaagc attaactttt tcagacgatt gtgaatattt 68941 ttcttgattt tacaccaaaa cttgataagt aaccttttca gatgattatg aatatatttt 69001 ctgattctac acaaaaattg ggatagtttt agtttcaacc tagcaactaa tctttaataa 69061 accatatcaa tgaacttttt gtattgttac attaaaatct attaggttat attctaggtt 69121 aaatgattct ttttggtcat ttggaaaaat tgtttcactg agttatgcag agcttccaaa 69181 gattgacatg ttttatgatg cactatacaa aaaccattct tttttaatgt aaaaagacat 69241 gaatatttat ttaatccctc tatgcacaga gtttctaagt ttaaatttct tttgaatttt 69301 tattttaggg tcagcggtac ataggtaggt ttgttatatg ggtaaattgc atgtcattgg 69361 ggtttggtgt acagattatt ttgtcaocca ggtaacaagc atagtactcg ataggtagtt 69421 tttcaatcct cgccctcctc ccaccctcca ccgtcaggtc ccagtgtctg tttttccctt 69481 ctttgattct atgtgtactc aatgttcagt tcccacttag tagtgagaac gtgtggtatt 69541 tggttttctg ttcctgtgtt cacttaggat actatcgtcc agttctgtct atgttgctgc 69601 aaagggcatg atctcatttt ttatgctgca tagtattcca tggtgcatat gtaccacatt 69661 tgctttatcc agtctacaat ttatggacat ttagactgat tccatatctt tgttattgtg 69721 atagtgctgc aaggaacaat atgagtgcat gtgtctttat ggtagaatga tttattttgc 69781 tgaggttggg ggatggtggc ttacatactt aaaatgggat tgctgggtca aatggtaatt 69841 ctgttttatg ttctttcaga aattgccaca ctggtttcca taatggctca actaatttac 69901 attcccaaga gcagcatata agtattccct tttctataca acccctccag cacatatttt 69961 ttttttactt cttaataaca gcctttctga ctggttgaga tggtatcttt tttttttttt 70021 tttYctgttt ttgagatgga gttttKctct gtcactcagg ctggagtgta gtgcatgatc 70081 tcggctcact gcagcctcca cctcctgggt tcaagtgatt ctcctcctca tcttcccaag 70141 tagctgggac tacaaggcac atgccaccac gcctggccaa tttttgtatt ttttggtgga 70201 gatggggttt tactatgttt cccaggctgg tctggaactt ctggcctcga gtgatatgcc 70261 tattgcggct ccccaggttg ctgggattac aggcgtgagt caccatgccc atccaagttg 70321 gtatctcatt gtggttttga tttgtatttc tttaatggtt agtgataagc acttttttca 70381 tatgcttgtt ggccacatgt atgtcttctt ttgaaaagcg tctgttgtcc tctgaccttt 70441 tttcaatggg gttgattgtt ttttgcttgt gaatttgttc aagtttctta taagttttgg 70501 ttattagacc tttgtcagat gtatagtctg caaatatttt ttcccatttt gtaggttgtc 70561 tgttactctg ttgataattt cttctgctgt acagaagctc tttagtttaa ttaggtccca 70621 tttgccaatt tttgcttttg ttgcaattgc ttttggcatc attgtcatga aatctttttc 70681 cattcctatt tccagaatgg tatttcctag gttatcttcc atggtttttt agtttattat 70741 tttacattta aatctgtaat coatcttgag ttgatttttc atatggtata agggtggggt 70801 ccagtttcaa tcttctgcat atggctagcc agttacccag caccatttat agaataggga 70861 atcctttccc cattgcttgt ttttgtcagc tttgttgaag accagatggt tgtaggtgtg 70921 cagcattatt tctggactct ctattctgtc ccactagtct atgtgtttgc ttttgtggca 70981 taccatgctg cttgggttac tgtagccttg taatatagtt tgaaattggg taacatgatg 71041 ccttctgctc tgctcttttt gcttaggatt gccttggtta ctcaggcctt ttttttggtt 71101 ccatgtgaat tttaaattag ttttttccta attctataaa gaatgtcatt atatatccca 71161 tgtgaatggg attgcatttt tgatttggct cccaacttgg atgctgttgt tgcatgggaa 71221 tgctactaat ttttgtacat ggattttgta tcccaaaact ttactgaagt tgtttatcag 71281 ctcaaggagc tttggRcatt tctatattat atagaaatag cattgaattt ataaattgcc 71341 tttggtaaat ggccatttta acaatattga ttcctcctgt acatgagcat ggoatatttt 71401 tctatttgtt tgtgtcatcc ctgatttctt tgagtagtgt tttgtaattc taattgtaga 71461 gatctttcaa ttccctggat aactgtattc cttggtgtta ttctttttat ggttattgtg 71521 aatgggattg catttttgat ttggctgcca acttggatgc tgttggtgca tgggaatgct 71581 actgattttt gtacattgat tttgtatact aaaactttgc tgaagttatt tatcagctca 71641 aggagctttt gggtggagac tatgggattt tctaggtata gaatcgtatt gtctgaaaac 71701 agggatagtt tgacttcctc tcttactact tggatgtgtt ttatttcttt ctcttgccag 71761 gttttccagt actatgttga ctaggagtgg tgaaaatggg catcttgtct ttttctgatt 71821 tgcaaggaga atgctttcaa ctgctcccca ttcagtataa tgttggctgt gcatttgtta 71881 tatatatgtc ttattatttt gaggcagatt cctccaatgc ctagtttttt gaggattttt 71941 aacataaagg gatgttgaat tttatcaaaa gccttttctg batgtaacaa aataatcatg 72001 tggtttttgt tttcaattct gtttatgtaa tgaatcacat ttgttcattt gcatgtgttg 72061 aaacaacctt gcatcccaga tataaagcct acttggtcat ggtggattag ctttttgatg 72121 tgctgctcaa tttggtttgc taatatttta ctgaagattt ttgcatctat gttcatcaag 72181 ggtactggcc tgacctgtta ttgttgttgt tattgtgtct ctgccagggt tttggtatca 72241 ggatgatRgt ggcctcatag aatgacttag ggaggactcc ctctcctcaa tgtttggaat 72301 agcttccata ggaataatac Ytgctcttct ttatacaagt ggttgaattc aactgtgagt 72361 tcatctggtt ctgggctttt ttggatagta ggctttttat tactgattca aattcaaatt 72421 ttgaacttat gatttgttca gggattcaat ttattcctgg tttactcttg ggaggttgta 72481 tgtgtccagg aatctatcca tttatcctac attttttcat ttgtgtgtat agaKgtattt 72541 gtagtagtct ctgagagttt ttttgttgtt atggggtaag tggtaacatc ccgtttgtca 72601 tttctgattg actttattct Yatctgccct cttttttcat tattagtcta gcaagtagtc 72661 tgtctatcct atttatttct tcagaaaacc aRcaactcct ggattcattc atcatttgca 72721 tgagttttat gtctcatttt tccttcagtt ctgctttgat tttggttatt tcttgtcttc 72781 aactagcttt ggggttggtt tgctcttgtt tctctagttc ttctatttgt gatgttaggt 72841 tgctgctttg aaatttttcc aactttttta tgttgatgtt tagtgctata aatttccctc 72901 ttgtcacctt agctgtgtcc cagattctgg tatgttatat ctttgttctc attagtttca 72961 aagaatttct tgatttctgc cttgatttca ttatttacca aaaagttatt ctggRtcaag 73021 ttgtttaatt tctgtgtaat tataggtttY cagggacttt cttagtactg attcctattt 73081 ttattgcact gtgatccaag agtgtggtta gtatgatttc aagtttttaa gtgtttgttt 73141 ggagattgtt ttatttccaa ttgtctggtc acttttagag tgtgtgccat gtgctgatgc 73201 aaagaatgta tattctcttg tctgtgggtg gaatgttttg tagatgtctc ttaggtctat 73261 tttgtcaagc attgagttca tgtcttgtat atttatgtta gctttctgcc tcaatgatcg 73321 tcttatattg ctattggggt gttaaagtct tccaatatta ttgcatagtt atctaaatct 73381 cttcataggt cactagaact tgctttatga atctgggtgc tcctgtgttc agtacatata 73441 atttaRgata gttaggtctt cttgttgaat tgagccctta accattaagt aatgcacttc 73501 cttgtttcat ttttttaaaa tctttgttgg tttaaagtMt gttttaYctg aaattagaag 73561 agcaacccct gttttttttt cggtttctca tttgcttggt aaatttttcc ccattccttt 73621 attttgagtc ttttggtgtc accacatgtg agatgggtct cttgaagaca acaaaccatt 73681 tagtcttgct cctttatcta acttgtcaat ctacaccttt caattttaag ggatatttag 73741 cccatttaca ttcaaggtta gtattgacat gtgcaaattt cttcctgtta tcattttgtt 73801 aKtgggttat tatgcagata tttttgtgtg gtttctttat attgtcattg acctatgtac 73861 ttgtgtgttt ttgtcgtggc ttgtaactgt ctttcctttc catgtttagc cctcccttca 73921 ggacctcttg taaggcaaat ctcgtgacag caaaatccga tagcatttac ttgcctgaaa 73981 aacattttat ttcttcttca cttatgaagc ttactttggc tggatacaaa attcttggtc 74041 agaaattctt ctctttaaga atgctggatg taggctccta accccttctg gcttatagga 74101 tttctgctgt aaggcccact gttagcctga tggggttccc tttgtaggtg acctgcccct 74161 tctctctagc tgcttttaac attttttatt tcattttcac cttggagaat ctgatgacta 74221 tgtgtcctgg aggtggtctt cttgtttcac aggggttttt tttgcacttc ctgaatttga 74281 atgttggcct atttagtaag gttggggaaa ttttcatgaa taataWcctg aaatatgttt 74341 tccaagttgt ttKctttctc ttcctgtctt tcaggaatgc caatgagtca taaattgggt 74401 ctctttaaat aatcctatat tattcagaag ttttgttcat tcaactttat tatttttttt 74461 ctttatttga tcttcactgt gttatttcag aaaacaggtt tggagctctg agatgctttc 74521 ctcagcttgg tcaattctgc tgttaatact tgcaaccgta ttctgaaatt cttgaagtaa 74581 gtttttcatc tttgtcagtt cagtttgttt ttttctgaaa atgaccattt catctttcat 74641 cttctgtatc atttattgta ttctttagaa tccatggatt ggatttcaac tttctcttaa 74701 ttgttgatga tcttcattcc tttctatctt ctgaattcta tttctgtcat tttagctatt 74761 tcagcctgat taaRaaaaat tgttggggaa cttgtgtggt catttagagg taaggagaca 74821 ctcttgcctt ttgagttgcc agagttcttg cactgattct tttacatctg tataggctga 74881 tgctccttca actctcgaag ttgctgtcct ttggacattt gtttgtttcg cttgcttgta 74941 tcttctttga tgcccttagg ggtttgattg tcgcataagg tgggttcagt tgactggctt 75001 cacttctggt agattKtttt ttggagggca aggctcagat caacactcct gggctatatg 75061 ctttaacttg ggggcctgtt atctggcccc cagctttctt ctctggccca ctgaggttgg 75121 gaacctgctg tgctggagag gccaaggttt tcctggatca ctcgccacaa cactctaaag 75181 gacagtgtta gccaaagcaa ttcattgggc agtggcagtg gggttcatgc tcgtttgcac 75241 atgccagctg cagtggcagc attacaggat gagttcttgt cacctggggc cactggtggg 75301 cctagggctg cctgcatcca tgtgggcatt ggcagtggca gcaaccaagg tgcaggatgg 75361 aggagggaga cagagctact ggggtccatg cgcattcact cctgcagtgg tggcagtgca 75421 ggggcatggt gctggccacc tttgtgtgtg cattaacacc agcgatgata gcagcatcgg 75481 gcagggggca gagctactgg tggccatgcg tgcattcaca ctggtggcaa tggcagtgca 75541 ggggtggcgg cgggggtgcc aatgtccatg ctagaaaaat cacatttttt taatcactct 75601 ggatctcacc aaaaaatcaa taagaatggg aaagaagtca agcttatggt gacaaataca 75661 agtttttcac aattctaatt tttactccaa aattcaaata cattcattgg caaagacatt 75721 ctaagttgtc ttctttgaag tgataggctc acttcattct tcttgagaaa atgcctacca 75781 aatacccaag tctcaaaaac catagtttgt cagtttttct ttcaggaaaa tatggagttt 75841 agccaaaaaa gaacctaatt cagcttacag caYggtgttt ttctttcagg aaaatatgga 75901 gtttaaccaa aaaagaacct aattcagctt acagcacagt gtttttcttc aagatgttct 75961 gggaactttg gtgtctggta caagtgcttt aagccttcct cacctccatt ttctcataca 76021 gaatattcaa aaggcatgta cfaaagggtc aatatttaat aaaattaata atagttactg 76081 atttatcaag gacatccgta agtgaaattg agattttttt tttttttttt tttttttttt 76141 tttgctttac tgagagtgca tagtggtgaa aaattcaatg actaccaata aagtttgttg 76201 ccaacagctt tatttatgct gaggtgttaa cagttttatt cattatagtt ttgcaccatc 76261 agtgcaagtt ccaacacaat aaaaaaggca aacaatattg tcatattatg gtaaaaatac 76321 ttttgccctc atgtaccacc tgaaatagtc ttgggacccc agagatctgc agctgcagtt 76381 agaagtccac tgcttcacac tagtgcacoa gcacaggatt ttgttttaga ataggagcat 76441 aataatattg cattatatat gcttatactt ttttatagta ttttgtagtt tagtaatgct 76501 cttcacagat attatcttac attaatcaca gtataatagc ataaagttcc catccaattt 76561 ttctagtaaa taaaaacaat aatgaagaaa gcgaaataaa gtgtccagaa atacagatag 76621 aatatatata gagagtgtct ctcctgccat gtcagacaga aggctgtaaa acagcaataa

76681 tattttccct gaatatctcc attgtgaatg gtaggacact tctggaagct ttcattgcct

76741 ttcctttctg ttatttaRta aaacactcct tgctagtatt ttgttgaaaa tttttgtgtc

76801 aatgttcatc aagattattg gcctgtagtt ttcttttttt gatgtgtctt tgtctggttt

76861^' tgatatcagg ataataStag tagcctcata gagYgagttt ggaagtattc tcttctctat

76921 ttttcttaat agtgtaagca ggattgatat tagttgttYt ttaacaacaa ctgaatttgg

76981 taaaattcag cagtgaagct attgggtcct gggctttcct ttgcagagag actttttatt

77041 acaactttga tctctttact tgtcattggt ctgttgaggt tttgcatatc ctcatggttc

77101 aaacttggta ggttacatgt gtctcggaat ttttccattt cttctagatt ttccagttta

77161 ttgtcataca gttgctccaa gtaatctcta atgatccttt gacgctgtat cagttgtaat

77221 gtctcctttc taatttctga tcttatatgt ttgggtcttt tctctttctt agtctggcta

77281 aagagttatc aaatttttaa tctttttttt aaacaacttt ttgtttcatt gaccttttgt

77341 gttgtttcct ttatttcaat ttcatttatt tatgcactga tctttattat ttattttctt

77401 cttctgtttt tgggtgtgat ttgttcttgc ttttctaggt Stttaagatg aatcattatg

77461 ttgtttattt gaagttttct tacttttttg atgtaggtgc ttatagccat aaacttcctt

77521 ggctgggtgc agtggctcac acctgttatt ccaacacttt gggaagctga ggtaggtgtg

77581 ttgcttgagc ccaggagctt gataccagcc tgagcaacat ggcaaaaccc tgtctctaaa

77641 aactacaaaa aatttagctg tacatggtgg tgcatgccta tcRttccagc cacttgggag

77701 attgagatag gaggatagct tgagcccagg atgttgaggc tgcagtgagc cacgattata

77761 ccattgcagt ccagcctagg tgacagcaag aacctgtctc aacaaacaaa caaaaatctg

77821 tttttgctat atctcatagg ttttagtatg ttgtgtttct attattattt atttcaagaa

77881 atttttcaag tttctcctta atttcttcct tgaccaactg gttattcagg agtatatttt

77941 taatttccat ttgtttgtat agtttccaaa atttctgtta ttgctgattt ctcgtattat

78001 tttattttgg tcagagaagt tacttgacag aatttcatta tttttgaatt gtttaaggct

78061 tggttttggg gYctaacata tggtctatca ttgacaatga gtcatatgct gaggaaagga

78121 atatgtgttc tgcagccatt ggttgaaacg ttttgtaaat atctattagg tccatttggt

78181 cttagtgtag attaagtgtg gtgtttttgt tgacttcctg tctggtggat ctgtccagtg

78241 ctgaaagtgt gatgctgaag tctccagttc tttttatgat ggggtctctc tctctctctc

78301 actagctcta atatttgttt tatatatgtg ggtgctgcag tgttggatgc atatatattt

78361 acaagcatta tatccatttg ctgaattgat tttttatcat tatatagtga actattttgt

78421 cttttcctaa agtttttgtc ttgaaatcta ttttgcctga tataagtata gaaactcctg

78481 ctctttctgg gtttccatgt catggaatat tttttccatc cttttcttac cagtgtatgc

78541 atatttttat atgtgaattg tgtttcttgt aggcaacaga ttattgggtt tgggtttttt

78601 tttttctatt cagccagtct atgtctttta attggagagt tcagtctatt tagagtcaat

78661 gttattacta ataaggtagg acctacacct acaattttgt catttgtttt ctggttattt

78721 tgtggtcttc tcttctttct ggtcttcatt ttaaagaagg taattttctc tgatggtatg

78781 ttttaatttc ttgcttgtta cttcttgtgt attcattgga tgttttttca tttgaagtaa

78841 ccatgaagot tgcaaataat attttataac ccactatttt aaactcatga caacataaca

78901 ctgattgcat aaacaaagaa acaagcaaat agacaactta taaaaactct acactttaac

78961 tccaactttt taaacttttt gttgtttctc ttcatatctg attgcactac gtcttgaaaa

79021 gttgttgtag ttattttttt gattggttca tcttttagtc tttctgcata acatatgagc

79081 agtttacata ccacaatttc aatgttataa cattctttgt ttttctgtgt ttacagttaa

79141 cagtgaattt tgtattttca gatgatttct tattgctcat taacatccct tttttcagac

79201 tgaataactc catttagcat ttcttgtagg acatgtgtgg tattaataaa atccctcagc

79261 ttttgYttgg gcaaatcttt atttctcctt catgtttgaa gtatattttg attaaatagg

79321 ctattttagg gtaaggtttt tccttcagca tattaaatat gtcatgccac tctttcacag

79381 cctgaaaatt cccactgaaa agtttgctgt tagacatatt ggagctccat tatatgttat

79441 ttgttttttt actcttgtta aaaaatcaaY gatcctttct ttaactttga cctttagaag

79501 attaataatt aaaggccttg aaatagtctt ctttgggtgt agtctgattg gtgtccaatc

79561 aacttccttg tactggaata ctgataactt cttctaggtt tgggaagttc tgctgttatc

79621 cttttgaata aacttcctac ccctatctcY ctaccttctc cttaagtcca acaactctta

79681 ggtttactcc tttgaggcta ttttctatat cttgtaggca tgcttcattc tttttcattt

79741 ttttaacttt catttcctct gactgtgtta ttttcaaata tcctSttctt aagctcacta

79801 attatttctt ctttttaatt cattctgctg ttaaaggact ctRatgcatt cttcagtatt

79861 ccaattgcat ttttcagatc MagaaRttct gcttgattct ttttagtgtt ttcaatctct

79921 ttgctacatt tctctgatag aattcggaat tccttctcta tggtatctcg aatttcatta

79981 agttttctta acatagctat tttgaattct ctttctgaaa ggtcacttat ctctgtctgt

80041 cttggattgt ctctcatgct ttattaagtt catttgctga gaacatgttt tcctggatgg

80101 tgttgatgct agtacatgtt cttcagtgtc tgggtattga agagttaggt acctatttta

80161 gtctttgcaa tctgagcttg tttgtacccc tccttcttag gaaagctttt caggtattca

80221 caggtacttg ggtgctgtga tctaagtttt tgggcactgc attcttatct gtattaggta

80281 ggcaccccaa acccagtacc gaYgtgtctc ttgcagactc aaagaagtct caccatggca

80341 gcctttaata agatctagaa gaattctctg gattaccaat tagagacttg tcttctcttc

80401 ccttactttc tttcaaataa atggagactc tctctctctc tctccttctc tgtttctgtc

80461 tctcactctg tctctctcct gagctgcctg aaacttaggg aggaatgcca caagcacccc

80521 tgtggctacc atcactgtga ctccactgag tcagacctga agctattaca gtactgaatc 80581 ttacccaaag cccactgtat ctactacctg gctactgcct gtgttctctt aaagccctat 80641 ggcttaaaaa tcagtaggtc cttctacgaa gggcagtgag ttttcctggg ccacaggcaa 80701 gttcagagat gctgtctggg agccaggacc tatagtaaga aaccttaggt acctacttgg 80761 tgttctattc tactgcagct tagctggtac ccaaaccaca agatgaattt cttcccactc 80821 tttccttccc tttccacagg gagaggagct tctccccatg gtcaccccca caacagacac 80881 atgagagtat tgccatggta tcactgatgt tcacttaagg ccaaaagact cttcggtcag 80941 cttgtggtga atgctgccag acttggtact tacccctcag ggcagtgggc tcctctctgg 81001 cccaggatag gtccagaaag acagaatagt agttttgagt cagtctacca atccacaatt 81061 ttgcctacca catatttggt cttcatttta tgcaaatcta tatctcttcc ctccccactc 81121 ccaacagcct actctctagc cacttagata ccaagatatt tgctagtcac ttcttttgcc 81181 aaaacaatac ttccagttat ttcttggctg cttcacatat gtcttoacag ataaaatcac 81241 tataaaccaa aaaaatggcc aaatgaccat gtttaaccaa ctctaggaaa attttcacac 81301 tgtttacctc ataatgacat aaaattctga caacataatt tgacatcata tattcagtta 81361 atttttcttg catatatgta gggcaaaaat atcataaaaa ttcaaaactt ttctcaaatc 81421 atctaggaaa atcgacagtc tgtgaagatg tgatgtttat cYtaacttca tgcaagatca 81481 gagactactc tagcctgaga ggcaaaatca gggagggaac tcaatgttat ctaatttgga 81541 ctttggtaag ttatgcaacc aagagtttcc aagggaatat ctctgttatg atcctttagg 81601 gatcttctca cagggtggtY ctcaagtgtt ggctggtttc atgtatatgc ttctagtata 81661 aagactaata catattaaaa ataagagggt gaattctccc tgttgaaaag aagggaagag 81721 gttttccttt cccccttttt cttagagttt ttactcttta aaactttgta agtactttat 81781 tctctctttg aaatgtatat aaatccttta ggaaaccaga taggcctttt gtcagtacta 81841 tggcctagaa atgtctttct tagggacctc aRagtcaatt atttgaaatg caaacatcaa 81901 ggaagataga acccccatct tccaatcact gtgggagagc agaaacctaa ctttgagggt 81961 accttggtcc aaaacacgaa actatctcct gtaatgaaag tatgtgaagt ttgtttttcc 82021 tctggataaa gccacatagc taacacagat ggttactcca attatgtgtt aaagttttta 82081 taaattattt ttgacaaatg ctgtcaagtc ctcttacatg aRgatgagtt gttatctatt 82141 ttaaaaacat gtatataatg cgttatatct gtttggctat ttcaaaggga aagatttMMt 82201 tctgtttttg cattttagtg gattacctgt gcagaacata ctggcttaat gcttattcaa 82261 taataagagt gcttcctatc accacctttg tcaagaagat ttccaagtta ggagaagata 82321 ttgtttttaa ttatatttcc ctaacactgg ttccccagct atctttctcc tctaccagtt 82381 tcttcaagac tttctggtat caacactaat aagtatttag tgttttcagg tttggtccga 82441 aattgctcaa aatcaagtct taaaaatatc acgttctcaa ctacatttta ttgcttttgt 82501 catgtcaatt tccctgYtac tagtatgcaa atatgaggtc cttgggaagt tctgctttca 82561 gtaagaatgt atttggaaag accatctatg aaatcacatc ttatctatac tcctgagtta 82621 gaaggtttta aacctcctta attttaggta taaaaagaat accttctgac gttctctaat 82681 tattgcctta cagagatttc tgttttaaga ggtaaacatt aattcctaat cttgggttga 82741 attttaactg attgctgacc tttactctac taatggtaat attgatagga acaatttagc 82801 ttattaatga atagaaacaa ggtacaggca ttacaaataa gagtcacagt cgatggaata 82861 tggatttata ggaatcaagg gcaattttag tcacagccct ttttacctcc tgaaaggcat 82921 cctttttatc agtcctgtag ttgcactttt tatacaaaat gtgtagtcat taagatatat 82981 tctaaagata ttattgttga gatctagtca tagaaagtac attatacagc gacRttagag 83041 cctgagagag gataagatag ttaaacaaaa aagctcactg cagtgtgtga aaaagtgttt 83101 tgaaggtcat ttgcacttaa ataaagtttg cttctccatt atacaagtta aagttttaaa 83161 acatgcagca atagaggaat gagagtccgc ttatgacctt ggacagttta ttagtgccag 83221 tagtccatct tagttttcat gtaatactca tcatattctg gtcaagaaga aggattttgt 83281 gtatctctgt gattactgcc acaagatcgt cagtttggag aaaacaagta gttgtctctg 83341 ttaaatgcct cagccatgca gaaaacaaat ttttctcaaa atcttaaaaa gcactaatca 83401 gctacttctt ctctctagct ttaacaagca tggcaattca tttaagttca atttaatggg 83461 cattttatta agcatctacc acatgctttc atgaagtgtt ctgaatacta taaaggtagt 83521 agaaggtaat gtttctgtcc ttcagaaacc ttaatattca aacagaatta gaacaaactg 83581 ggcagaaatc cagaaataat ttttcaactt ttcttgtttt ttaaaataat gatttatgtt 83641 agctcctcca ggtggggcca gctttacatg gcccacattt acataatagc ttcccttttg 83701 cttcttttgt tgtcgtaagt cattgtttgt ctatagcatt ttatggttct ctggtgagYa 83761 cctccctcct ttatataaaa tgaaggtgat ctggtatctt ccaaagcata aatgtaaagt 83821 tgaggatagt atcaatatcc gagagaatga aaaaacagaa ctacaagaca gaagcaagaa 83881 atatccactc ctgcctctgt tgctcRttta ttaaggacag ggaggctgtg gagctggaga 83941 tagggcatta ttgtgtaaaa tgtttcagta ttgaatagtg gctctcagtt ggccctgaca 84001 ttttcccttt ctaggtcagg cttgtctctc ataaatatta tgtagacaaa aaaaggtccc 84061 attcttaatg gccaaagcaa tcctcagcaa aaagaacaaa gatggaaata tcatattacc 84121 tgacttcaaa ttatactaca gagtttagta accaaaatag tatggtgctg gcattaaaat 84181 agacatacag accaatgaga cagaataaag aaataaattt acacatttac agtcaaaccc 84241 agaaataaat tcacagatat acaataaatt cattttcaac aaaggtgcca agaacacaca 84301 ttaagggaag ggacagtctt ttcaacaaat ggtgctagga aaactggata tccaaattca 84361 gaagaatgaa actagacccc tatgtctcac cgtatacaaa tataaaataa aatggattaa 84421 agacttaaat gtaagacctg aaaccatgaa actatgagaa gaaaacattg gggaaatgct 84481 taggacattg atgtggcaaa tgatttcttg agtaagacag caaaagcaca ggcaatcaaa 84541 gcaaaaatgg acaaatggga ttacatcaag ctataaagct tctgcacaac aaagaaaaca 84601 atcaacaaac tggaaagaca acctacaaaa tgacagaaaa tatttagaag tattcaactg 84661 acaagggata aaaaccagga tataaaagca actcaaacaa ctcaatagca aaaaaacaaa 84721 taatttaatt tgtaaatggg caaaaggtct aaatagatgc ttttcaaaag aagacataca 84781 aatagccaac aggaataYgc aaaaatgctc aacatcacta ataatcagag aaatgcaaat 84841 caatccacaa tgagatatta ttttacccca gttaagatgc cctttatcaa aaaataatga 84901 atgttggtga ggatgtaaag aaaggagaat gcttgtaccc tgttggtggg aatgtaaatg 84961 tgggagacta ttgtataaaa tgtttataca catttttata acacagggaa aacagtatga 85021 agattcaaag aaaacagtat gaaatttcct cagaaaacta aaaatagaac tactttgtga 85081 ttcagaaatc tcactgctgg gtatatatcc aaaagcaagg aaatcagtat attgaagaga 85141 tatctacact ctcatgttta ttgcagcact atacacaata gctaaaatat ttgaaataaa 85201 tctgtgtcca tcaacagatg tatgggtaaa gaaaatgtgg tgtgtgtgtg tgtgtgtgtg 85261 tgtgtgtgca tgtgtgtgta tgcaatggaa tattatgcag ccatacaaaa aaaatccagt 85321 cattcacaat gccatggatg gaactgaagg atgtttcatt gtaaaataag ccagacatag 85381 aaagacaaat atctcatgtt ctcactaaca tgtgggagct aaaaaacttg atctcatgga 85441 ggtgagaata gaatgatggt taccagaggc tgagaagtgc agtggggagg cgaggataaa 85501 gagaggttgg ctaatgtgta caaaaattac agttagatag taggagtgag aactagtgtt 85561 ctgtagcaca ataggaatgR ttatagttaa caataatgca taatgtattt taaaataact 85621 gaaggaatgc atttggaatg ttcccaacac aaacaaatga ttaatgttta aagtRttRga 85681 tatcccaatt accctgattt gatcattaca cattctttct tgtatcaaaa tatcacatgt 85741 accccataaa catttataat tattatgtaa tcatgatgta atcaccacac ataatgaata 85801 ccttcccaag gttagtttga cctacgccca ggaatgaaaa aggagagctt aaaggttaga 85861 agcaagatag aatatgttag gtctgatctc tttcactgtc ataatttcct cagttttaaa 85921 ttttgcaaag gtggtttcca taaNtttaaa aaacgttcgc tctttttttg agccaatcaa 85981 actatgtttt caataattta ttcagggatc taagggccac agatccaagg gaagtaaatg 86041 ggtgctgaca ctcacttctt agagtatgca tcaaagatgt cctaaactaa gagtaatggc 86101 aatgtaaaag aaaaattaca tcaaaccagc tcaaaccaaa acagtcaaga aagactttct 86161 ttaagactaa tgcaataggg aagaaagact gaacccaact ctactgaaac aaaagtcagc 86221 aagattttta aatgctggaa tgagctaatg ggacattact agaggacttc agggagaagg 86281 ctggggaatg tgatttggcc atctgtgttt gctagttatc tcttattgaa attagctcct 86341 actctaccat acagactgag agacaaggat gctatctgtt tcaatgatta catttcaaaa 86401 ggatggatcc catgttcttg agaaagatat ttctgggttg tggaagattt atatctcaaa 86461 gggggaaaaa aaagaattta cagctgcaag ttttctaaag taaatgtcct aagaaaaggg 86521 aggccaaggg cctatattca agaaggtYct agatctaaag tttagtcaag gtgaggggga 86581 acattaaggc tgtcttggtc acaaagataa atgtaaaata catcttagac tgtttaggtg 86641 gttgaagcag tRttgcttca gcctattcgt ttgagaccag cctcagcaac aaggcaagac 86701 cctgtctcta caaaaaaagt aaaaataaaa aattagccag gcatggtggt gtgcacctgt 86761 ggtcttagct actctggagg ctgaggcaga aggatcactt gagcctggga gtttgcgcct 86821 gcaatgagag gtgttcgtgc cactgcacWc tagcttgggc aacaaacaga gaccttgtct 86881 taaaacaaaa caaacaMaca aaaaaaagga tttttttctt tctctccctc ctttcccctt 86941 tcttcttctt cctctctccc tccttctctt ccctgctctt ccctgacaca atactctctc 87001 tttccctttc tctttttcta cctctttctt tcttcatctt ttctttttta atctatgaaa 87061 ccaagcctta gtacatccaa tacattaata tagtagcctt tttggatgtg agggtgatct 87121 agctgtgatc gccagRgatg attcagaatt caaatttttt tatctattca gaattttttt 87181 ccatgttttc ttccatcatt ttgtagtttc atgtcttaaa tataagtctt taattcatct 87241 tgagttaatt tttgtatata tagagagata caggtccaat gtcattcttc tgcatgtggc 87301 tatccaattt ttccaagcac tatttattga ataaagtgtc ctctcttcag tgtatatttt 87361 tgttgatttt atcaaatatc agttggctgt atatttgtgg ctttatttct gggttctcta 87421 atctgttcca ttgatttatg tgtctgtttt tatgccagta ctttgttgtt ttgggtacta 87481 tagccttgga tgataatttg aagacaagta aagtgatgcc ttccacttca ttctttttgt 87541 ttaagatttc tttggYtgct caggctctct ttaagttcca tatgaatttt aggatgtttt 87601 tttctaacta tgaataatga cactggtgag agggtgtgtt aagacagcag ataagagaca 87661 gggctaatat gcagctctga cttggatgaa cagaacagca tgtggagact cacagtatga 87721 acttttgtcc aagaacoaca gtaggaacat accaagaaaa cagaaaaaaa tcacagatcc 87781 tttgaatgtt actgcaaatt ctacaaggca ggtgaaaaac tgtgacttcc caaaatgtga 87841 gagtgggaaa cctgactttg aacatacatc tcactggaga atctgaaaat ccacatcaca 87901 ggagaaggat ttgtacctta cctagatctt acatggattt agggagctgt gtgaaatata 87961 aaagtagaag cagcagtggR aagtgcctta caggcactcc cagtctccag ctcaagccca 88021 gggaagccat ccctgactat ctctcacagg ggccctcagg gaaggcagca agggtaacta 88081 gaaagggggt cagagggcaa aagaatcttc caactgaaat tagtaacaat tttgactgag 88141 catgaatttt cttgagcaga atctggggag aaaatgggaa ctactgcaga tataagcata 88201 ggagttgctg ctgacagagt gggcatatgg ggaagtgtga ggtccaaaag ccatgcttgc 88261 tttcttggaa gggaagctca tggcatgggg cagRgtctga ttggggcact gtgggagtga 88321 gactagcctc aacaactgca tgggagctgg gtgaggcctc tcgctactgg ctatccctca 88381 cttccctggc acagcaaagg cagccaaaat cccctctgga acataactcc atgggtctga 88441 gaaccaccct cccgttcccc acagtggcaa caataagccc tgcccaagga Ragtctgagc 88501 ccagaccctc ctaatcttga ccccagctga tggtgttttt ctacccaccc ttgtagccaa 88561 acacaaaaga tagactctct taggggcttt atggccctgc ccatcacctg agaagctaaa 88621 atacttacac tggaaaaatt agagcaagct tagatccccc tatttctgct gcagctggtg 88681 ctctctttaa aatgccacct cctggctgga ggccagtcaa ctcaggccat taYagcaact 88741 catgacagac taaccctgat cccagaaaag agaaatcaac agctaattcc actgcctgca 88801 acatcctggc taatcagagg tccatgcgac aacttcacag ctagcataac cagcattcaa 88861 ggaagccagc acactaaaca tatctacaac caaagacttc cacagagtcc atggcactct 88921 cctagcacct ccaccagagc aggtgctggt atctacagct agaagacctg aagacagatc 88981 tcattacaga actcttcaca gacattctgc agcatcagcc cagagcctgg tagcctggct 89041 gggtggctag attcaaaaga acaataacaa tcattgtagt ctggctcctg ggaagtccca 89101 tccctagggg aaagacgaga acaccatgcc aaggaattac cccatgagac aaaagaatat 89161 gaacagcagg ccttgagttc cagacctttc cactgaaata gtctacccaa atgataagga 89221 actagaaaag taattctggt aWtatgacaa aacagggttt tatagcacac ccaacagatc 89281 acactagatc ttcagcaatg gttccaaacc aagaagaaat ctctgtagtt ctagataaag 89341 aattcagaaa gttgattaat aaggtactca aggagatccc agagaaaggt gaaatccaac 89401 ttaatgaaat ttaaaaatca atacaggata tggatgaaaa ttctccagag aaatagaaaa 89461 gaaaaacaat cacaacttcc agaaatgaaa gacacattca gtgaaataca aattacagtg 89521 caaagtttta gcaatagact agaacaagta gaagaaagaa attcagagct caaagacaag 89581 gtttttaaat taagccagtc agacaaaaac aaagaagaaa gaattttaaa aaacaaagcc 89641 tccaagaaat tttggattat gttaaatggc caaacctaag aataactgtt gttcctgaaa 89701 aagaagagaa atcttaaagt ttgaaaaact tatttgaggg aatgattgag gaaaacttct 89761 ttgaccttgt aagaaatcta gacatcatct aaatacaaga agctcaaaga acacctggca 89821 aattcatcgg aaaaaaatca tcacccagRc acatagtcat caagttatct aaagtcaaga 89881 tgaaggaaat aatttaagag ctgtgagaca aaagtatcag ataacctata gaggaaaacc 89941 tatcagataa acagcagatt tctctgcaga aactttacag ctcagaaggg attggggtcc 90001 catctttagc ttcctaaaac aaaataattg tccgccaaga cttttgtatc cagaaaaact 90061 aagcttcata aacaaaggag agataaagYc tttttcagac aaacaaatgc tgaagagttc 90121 accactacca aaagcataca agaactggta acaRgagttc tatatcttga tacaaaacct 90181 taaaatacac caaaatagaa Ycttcttaaa gcatatgtct cacagggcct ataaaataat 90241 aacacaatga aaaaaaaaca aggtattaag gcaacaacta gcatgatgaa cacaacagta 90301 cctcacatct caatacaaac attgaatata aatggcctaa atgagccact taaaagatac 90361 agaatggcag aatagataaa aatccatcaa ccaagtacct gctgtctcca agagactcRc 904.21 ctaatatata atgactcaca taaacttatg gtaaaggggt ggaaaaagat attccatgca 90481 aatggaaacc taaagcatgc agaagtagct attcttatat caSacaaaac agactttaca 90541 gcaacaactg taaaaaagac aaaaaSggac attatataat gataaaaggW ttagttcaac 90601 aggaaaagat cacaatctaa atatatatgc acctaatact ggaggtctca gattaataaa 90661 acaattacta ctagacctaa taaatgaaat aaatggcaat gcaataataa caRgggactt 90721 tgatattcca ctgacagcaa tagttcatct agacagaaag tcaataaaca atggactgaa 90781 actataccct agaaaaaaat ggacttaaca gaSgtttaca gaacacttga ccctacaact 90841 gcaaaataca cattcttttc ttcagtacag ggaacattct ccaagataca ccatataata 90901 ggtcacaaga caagtctcaa taaatttaag aaaattgaaa ttatatcaag tatcctctca 90961 gaccacagtg gaataaaact ggaaattaac cccaaaagga actctoaaaa tatacaaaYa 91021 catgcaaaac ctctgggaga cagcatacat tgtacaaaag cagtactaag aagaaagtta 91081 ataatattac attcttacat caaaaagctg aaagagtgta aatagatagt gtaaggtcac 91141 atctcaagga attagagaaa caa.aaagaaa ccaaacccaa atcagcagaa gaaaaaattt 91201 aacaaagata aattcagaac taaatgacat tgaaacaaca aaaaatacaa aagataaatg 91261 aaataaaaag ctggttcttt gagaagatat accaaattga tagatcatca gaaatattaa 91321 ccaaacaaag aagagagaag atccaaataa gctcagttag aaatgaaatg ggagatatta 91381 aaactgatat cacagaaata caaacggatt gtccaaggct actacaaaca cctttatgag 91441 cacaaactag aaaatctaga agatgcagat aaattcctgg aaatatccaa ctctcctaga 91501 ttaaataagg aagaaataaa aaaatctgaa caaacatata acaagtagcg agattgaatc 91561 agtaataaaa acaattgcca acaaataaaa gttcaggacc agatggatgc acagctaaat 91621 tcaatgagac attcaaagaa gaatcagtac caatcttact gaaattattt caaaagataa 91681 agagggaatc tcccctgaat aattctatag agcoagtatc acccaaatac aaaaccagga 91741 aaagacataa caaacaaaca aaaaaaacta catatcaata tccctgatga atacagatgc 91801 aaaaatcctc acaaaaatac tagctaacca aatccaaaag catatcaaaa agataataca 91861 tcaagatcaa gtgagtttca taacagggat gcagcgatgg tttaacatat gcaagtcaat 91921 aaatgtgata gaccacataa acagaattaa aagtaaaagt catgatcatt ttaatagata 91981 cagaaaaagc atttgataaa atccagtata cctttatgat taaagccctc agcaaaattg 92041 gcacagaagg gacatacctc aaggtaataa aagccatcta tgaaaaaccc acagccaaca 92101 ttacattaaa cagggaaaac ttgaaagcat tccccttgaa aactggaaca agacaaggat 92161 gcccactttc accacttcta ttcaacatag tactggaagt cctagccaga gtaatcagac 92221 aaaacaaaga aataaagggc attcaaattg gtaaagacaa agtcaaactg tcgctgtttg 92281 ctatttatat gattgtgtac ctagaaaacc ctaaagactc agccaaaaag ctcctagatc 92341 tgataaataa attcagtaaa gtttcaggat acaaaatcaa tgtacacaag tcagtagcac 92401 tgctgtacac caacaatgat gaagctgaga aacaaatcaa gaactcaatc ccttttacaa 92461 cagctgcaaa aaaataaaat acttaggaat atacttaact aaggaagtaa aagatctcta 92521 caaggaaaac tacaaaacac tgctgaaaga aagcataaat gacacaaaca aatggaaaca 92581 cattccatgc tcatggatgg gtagaatcaa tattatgaaa atgaccatac tgccaaaagc 92641 aatacacaga ttcactgcaa taccatcaaa gtatgcccat catcattctt cacagaacta 92701 gaaaaaaaag aaacaactta aaattgatat ggaaccataa aagagccaag ctSggcatgg 92761 tggctcacac ctgtaatccc aacacttttg gaggccaagg caggcggatc acctgagttc 92821 aggagtttga gatcagccta accaacatgg agaaaccctg tctctactaa aaatacaaaa 92881 ttagcctgct gtggtgatgc atgcctgcaa tcccagctac ttgggaagct gaggcaggag 92941 aattacttga actcaggagg tggaggttgc agtgagctga gattgcgcca ctgcactcca 93001 gcctgggcaa caagagcgaa actctgtctc aggaaaaaaa aaaaaaagWa aaagtaaaag 93061 agcctgcata gccaaagcaa gactaagcaa aaagaacaaa cctggaagta tcacattact 93121 caacttctaa ctatactaNN tagtttacaa aacagaacag tgctggtatt aaaaaagaca 93181 catagaccaa tggaacacaa tagagaagcc agaaatgatg ccaaatactt acagccaact 93241 gatctttgac aaagtaaaca aaaacataaa gtgggtaaag gacaccctat tcaacaaatg 93301 gtgctgggat aattagcaag ccatatgtaa aaaaatgaaa ctgtattact cctactgtta 93361 acccaacaca ggcatgccca caaggaaagg ttaaaaaaag taaaaggaac tcggcaaatc 93421 ttaccccgcc tgtttaccaa aaacatcacc tctagcatta ccagtattag aggcaccgcc 93481 tgcccagtga catatgttta acggccgtgg taccctaacc gtgcaaaggt agcatgatca 93541 cttgttcctt aaatagggac ttgtatgaat ggctcgacga ggKttcagct gtctcttact 93601 ttcaaccact gcaactgacc tgcccgtgaa gaggcggaca taatacaaca agacgagaag 93661 accatatgga gcttcaattt accaatgcaa aYaacaccca ataagcccac aggctctaac 93721 ctaccaaacc tgcattaaaa atttcggctg gggcgacctc ggagtataac ccaacctccg 93781 agcaacatat gctgagactt caccagtcaa aacgagttac caYgtacaat tgatccaata 93841 atttgacYaa cggaacaagt taccctaggg gcgtggtagc tcatgcctgt aatcccagtg 93901 gtttgagagg ctgaggcagg tggatacctg agatcaggag tttgggacca gcctggccaa 93961 catggtgggt gttggcccat ctctactaaa aatacaaaaa ttagctgggt gtggtggcgg 94021 gggcccgtaa tcccagctgc tttggaggct gaggcgagat aattgctgga actcagaaat 94081 ggagcttgca gtgagcagag atcatgccat tgcactccag cctgggcaac aagggcgaaa 94141 taccatctca aaaaaagaga aaagaatgaa actggatcct catctctcac cctatacaaa 94201 tgtcaactca agatggatga aaaactttaa gatctgaaac tataaaaatt ctaaaagata 94261 acattggaaa aactectcta gacattggct tatgccaaga gttcatgacc aagaacccaa 94321 aagcaaatac aacaaaaaca aaaataaata gatggcacct aattaaacta aaaagcttct 94381 gcacagagaa agaaataatc agcagagtaa acagacagcc cacagagtgg gagaaaacat 94441 ttgcaaacta tgcatctgat aaaagactaR tgtccagact ctacaaggaa ctcaaacaaa 94501 tcagcaagaa aaacacaaat aatcccatca aaaagtgggc aaaggacatg aatagacaat 94561 tctcaaaaga agatatacaa atagccaaga aacatatgaa aaaatgctaa acatctctaa 94621 ttatcaggga aatgcaaatc aatgagatac caccttactc ctgcaagaat agccataatt 94681 taaaaatcaa aaactaatag atgttggcac gtaaatggta aaaagcaaac acttttacac 94741 tgctggtgag aatgtacact agtacaacca ctatggaaaa cagtatagaa attccttaaa 94801 gaactaaaag tagaactacc acttcatcca gaagtctcac tactgggtat ctacccagaa 94861 gaaaagaagt cattatatga aaaaggcctt gcacacatgt ttacagcagt acaattcaca 94921 attgcaaaaa tatggaacca gcctaaatgc ccagcaacca atgagtggat aaataaaatg 94981 tggtatatat acaccataga atactactca gatataaaaa ggaacaaaat aatggcatct 95041 gcagcaacct ggatggagtt gaagaccatt attctaaatg aagtaactca ggtaaaaaag 95101 accaaatatc atatgttctc acttataatt gggagctaag ctatgaggac acaaaggcat 95161 aagaatgata taatgaactt tggcgaatta gagggaaggg taggagaggg gtgagggata 95221 aaatactaca cattaggtac cgtgtacact gctcaggtga tgggtgcacc aaaatattgg 95281 aaattaccac taaaggcctt atccatgtaa ccagaaacca cttgttcccc caaaacaaaa 95341 caaaacaaaa atWaataaat aagtgacact ggtattttga tagggattgc attgaatctg 95401 gaaattgcct cgggcagtat Satcatttta ataatattga ttcttccaat ctatgagtgt 95461 gaaatgttgg ttcatttttt tgKgttatct aaaatttatt ttatcagtgt tttgtagtgt 95521 tccttgtgta gatccttcac ccccttgatt aagtgtatgc ctaggtatat atattttttg 95581 tagctattgt aaatgggatt gacttcctga tttgtttctc agcttgattg ttattggtgc 95641 atagaaatgc tacagatttt gtatgctgaa actttactga attcattaat caaatctagg 95701 agccttgtgg aggagtcttt aggcttttct aagtataaga tcatatcatc agcagagaat 95761 taacttcttt ttcaatttgg atgcctttta tttctttctt ttgcctgaYg taattaaaag 95821 atgttttgtt cacaaattta tttaggcata attaacacat ttattcaaaa tKttgagctt 95881 ttgagaaata gctttattga gatgtagctg acacaaaata aactgtacat aaactatatg 95941 cttcgataaa ttttaactca agactatccc tgttatacca ttatttacat cacgataggg 96001 aacaaagtct aaaaatttca tcatcctcct ttgtaatccc atgaagtact tatttRgcaa 96061 cctcccacaa attctaatat gttttatttt tattttcatg cagttaaaat actgtctaat 96121 ttcacctttg gagaaactta gcttgactac tttgtttcct atttctcagg atcactgtac 96181 attgttgcct gattctagtg ttcagaaaag tgttgattta tagatcatgt ctagtttttc 96241 agatgggagg ataagtccag tctcttttac tgtattgtgg gtagaatctt atgtaattaa 96301 atttaacagt ctttcctctt atgatacctg gtagttgtgt tttatttagc aaggtctcta 96361 acactcagtt tttKtttttt ttgttttKtt tttttaacca tcaagttttc ttttagtact 96421 ttttggtttg tctttctgaa atttatttgg agtaaaatat gaagtgtaga gccaggatca 96481 ctactcttca ctttacaaat gctgcaggtt ggtgtaccta gccccagcta ccccattcaa 96541 accaccttct tccacgcctg tgtaaggttg cacaaagtac ttgagatctc agcctgaact 96601 ggaggaggaa acacagattc atagcagcaa ttttgtgaac atgagggaaa ggcctacacc 96661 gtgtcagaga cattcacaat gctattttag ggtcactgat ccaataccag caaattgcac 96721 cMtctccaat ctcagacttt tgatatggaa aaaagaaaat attaatatgt tgcttagaRg 96781 actttgaacg tttatatagg atgatatgaa tatttttggt aaatcatata ttttaaggct 96841 tcttttccaa attatgactt ttcagcaaaa atataccatg tggattaaca atagtaaaat 96901 aagaaatata ctaataactg aaatgttctt tatacaatat atgtttttca tagaattagg 96961 aacagagtat agaaatagta ttcttacagt aaaatattta tttttaacat tttattgtaa 97021 ctgttctggg gcagctaaaa tactacagtc attttgtttt tattatccta acatgtcgaa 97081 catgagagct gtaaacattt tagttacgga atgagagcat tttcctccca atttttaatt 97141 caatgatgat ttcacaaaag ttaaacttRa cagcaaaatt aatatcatca aacactataa 97201 gtaaatactt gagaactatt tacttttaaa agtctctctt cattaataaa acttcactca 97261 ttatttttct Ratacataaa gaaatctcat gtcttgaagg tagaagacac tggactgact 97321 cccagaaaaa aggctgaatg ttaaacgtcc tcagcttggt taaaacactc agagcaagag 97381 aaggtggcag ggctgaaggg ttgtgggatg aatagtgggg agatcaggtc actttaaaca 97441 gcaaacaccg caattacttt tgcaccaacc taatagctca ttactggcac attgcatcaa

[0287] FollowingisaLOC391238codingnucleotidesequence(cDNA, SEQIDNO: 4). XM_374365-HomosapiensLOC391238 (LOC391238),mRNA.

CTGGGAATGAGGATGAAGGCTACCTGGGAATGA

[0288] Following is a EIFG4G2 cDNA sequence (SEQ ID NO: 5). NM_001418 - Homo sapiens eukaryotic translation initiation factor 4 gamma, 2 (EBF4G2), mRNA.

CTAACTGAAACTGTTGTGACTGAATATCTAAATAGTGGAAATGCAAATGAGGCTGTCAATGGTGTAAGAGAAATGAGGGCT CCTAAACACTTTCTTCCTGAGATGTTAAGCAAAGTAATCATCCTGTCACTAGATAGAAGCGATGAAGATAAAGAAAAAGCA AGTTCTTTGATCAGTTTACTCAAACAGGAAGGGATAGCCACAAGTGACAACTTCATGCAGGCTTTCCTGAATGTATTGGAC CAGTETCCCAAACTGGAGGTTGACATCCCTTTGGTGAAATCCTATTTAGCACAGTTTGCAGCTCGTGCCATCATTTCAGAG CTGGTGAGCATTTCAGAACTAGCTCAACCACTAGAAAGTGGCACCCATTTTCCTCTCTTCCTACTTTGTCTTCAGCAGTTA GCTAAATTACAAGATCGAGAATGGTTAACAGAACTTTTTCAACAAAGCAAGGTCAATATGCAGAAΆATGCTCCCAGAAATT

GAACTGTTGAAGCAΆATAAAGTTGGATCCATCCCCTCAAACCATATATAΆATGGATTAAAGATAACATCTCTCCCAAΆCTT

AAAAAAAAAAAAA

[0289] Following is an MCPS cDNA sequence (SEQ ID NO: 6). NM_006273 - Homo sapiens chemokine (C-C motif) ligand 7 (CCL7), mRNA.

[0290] Following is a LOC391238 amino acid sequence (cDNA, SEQ ID NO: 7). XP_374365 - hypothetical protein XP_379754 [Homo sapiens].

MPQQLLTSSEKCRHRPHSKSSTKRKNCKPPQKHCSLQLRGSYSSTLLVVGERTRSGKASEM

RASNSSSFLPTFGAKGASTAVKNIKTKEFFFEKQTSDΠCRLARSRWFKRRSEGNTWGMHCF

PVALTDHGNGKPPSTRSWSTAQSSSLLSPSLATVPITHSEPWTLLMTKDTNDDRVCSGGLST

RSSLGNEDEGYLGNEDEGYLGNDDEGYLGNEDEGYLGNEDEGYLGNEDEGYLGNDDEGY

LGMRMKATWE

[0291] Following is a EIFG4G2 amino acid sequence (SEQ ID NO: 8). NP_001409 - eukaryotic translation initiation factor 4 gamma, 2; eukaryotic translation initiation factor 4G-like 1; death-associated protein 5 [Homo sapiens].

MESAIAEGGASRFSASSGGGGSRGAPQHYPKTAGNSEFLGKTPGQNAQKWIPARSTRRDD NSAANNSANEKΈRΓΦAIFRKVRGILNKLTPEKFDKLCLELLNVGVESKLILKGVILLIVDKA LEEPKYSSLYAQLCLRLAEDAPNFDGPAAEGQPGQKQSTTFRRLLISKLQDEFENRTRNVD VYDKRENPLLPEEEEQRAIAKIKMLGNIKJFIGELGKXDLIHESILHKCIKTLLEKKKRVQLKD MGEDLECLCQMRTVGPRLDHERAKSLMDQYFARMCSLMLSKELPARIRFLLQDTVELRE

HHWYPRKAFLDNGPKTINQIRQDAVKDLGVFIPAP]VLA-QGMRSDFFLEGPFMPPRMKMDR

DPLGGLADMFGQMPGSGIGTGPGVIQDRFSPTMGRHRSNQLFNGHGGHIMPPTQSQFGEM

GGKFMKSQGLSQLYHNQSQGLLSQLQGQSKDMPPRFSKKGQLNADEISLRPAQSFLMNKN

QVPKLQPQITMIPPSAQPPRTQTPPLGQTPQLGLKTNPPLIQEKPAKTSKKPPPSKEELLKLTE

TWTEYLNSGNANEAVNGVREMRAPKHFLPEMLSKVIILSLDRSDEDKEKASSLISLLKQE

GIATSDNFMQAFLNVLDQCPKLEVDIPLVKSYLAQFAARAIISELVSISELAQPLESGTHFPL

FLLCLQQLAKLQDREWLTELFQQSKVNMQKMLPEIDQNKDRMLEILEGKGLSFLFPLLKLE

KELLKQIKLDPSPQTIYKWIKDNISPKLHVDKGFVNTLMTSFLQYISSEVNPPSDETDSSSAPS

KEQLEQEKQLLLSFKPVMQKFLHDHVDLQVSALYALQVHCYNSNFPKGMLLRFFVHFYD

MEIIEEEAFLAWKEDITQEFPGKGKALFQVNQWLTWLETAEEEESEEEAD

[0292] Following is an MCP3 amino acid sequence (SEQ ID NO: 9). NP_006264 - small inducible cytokine A7 precursor; monocyte chemoattractant protein 3 [Homo sapiens].

MKASAALLCLLLTAAAFSPQGLAQPVGINTSTTCCYRFINKKIPKQRLESYRRTTSSHCPRE AVIFKTKLDKEICADPTQKWVQDFMKHLDKKTQTPKL

[0293] Modifications may be made to the foregoing without departing from the basic aspects of the invention. Although the invention has been described in substantial detail with reference to one or more specific embodiments, those of skill in the art will recognize that changes may be made to the embodiments specifically disclosed in this application, yet these modifications and improvements are within the scope and spirit of the invention, as set forth in the claims which follow. Also, citation of the above publications or documents is not intended as an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents. Each patent, patent application and other publication and document referenced are incorporated herein by reference in its entirety, including drawings, tables and cited documents.

Claims

What is claimed is:

1. A method for identifying a subject at risk of type II diabetes, which comprises detecting the presence or absence of one or more polymorphic variations associated with type II diabetes in a nucleic acid sample from a subject, wherein the one or more polymorphic variations are detected in a nucleotide sequence referenced in Table 1 or SEQ E) NO: 1-6, a substantially identical sequence thereof or a fragment of the foregoing, whereby the presence of the polymorphic variation is indicative of the subject being at risk of type II diabetes.

2. The method of claim 1 , which further comprises obtaining the nucleic acid sample from the subject.

3. The method of claim 1 , wherein a polymorphic variation is detected at a position selected from the group consisting of rs291102, rs8147, rs351260, rs5988, rsl799999, rsl543540 and rsl 0330.

4. The method of claim 1 , wherein the one or more polymorphic variations are detected at one or more positions selected from the group consisting of rs3835246, rs6106927, rs8117966, rs8123888, rs6114827, rs6114828, rs6083586, rsl883926, rs6083587, rs6114829, rs8121573, 188114991, rs6114830, rs6114831, rs6138352, rs6036883, rs6049883, rs6036884, rs6106928, rs6076250, rs6114832, rs6114833, rs6106929, rs6114834, rs6049884, rs6114835, rs6114836, rs6114837, rs6106930, rs6049886, rs6049887, rs6114838, rs2424621, rs6049888, rs6114839, rs6036886, rs6114840, rs6049889, rs6083588, rs6083589, rs6049890, rs6049891, rs6049892, rs6049893, rs6106932, rs2223829, rs6049895, rs6036887, rs6049896, rs6049897, rs6106933, rs6114841, rs6114842, rs7351911, rs6036888, rs6076251, rs6083591, rs7345410, rs7363529, rs6515520, rs6515521, rs6049901, rs6515522, rs7344627, rs7345403, rs8183524, rs7353085, rs6083595, rs7343729, rs6049905, rs6076252, rs6114844, rs2424624, rs6114845, rs6114846, rs6114847, rs6114848, rs6076253, rs2064435, rs6083596, rs6106935, rs6049906, rs6106936, rs6106937, rs6076254, rs6049907, rs6076255, rs6106938, rs6049908, rs6049909, rs8117631, rs6036892, rs6114850, rs926708, rs8124149, rs2424625, rs6049910, rs6132758, rs6036893, rs2424626, rs7343706, rs6049912, rs6049913, rs7352378, rs7348240, rs7345192, rs2143822, rs7265774, rs8118433, rs7345343, rs2179799, rs2424627, rs6049917, rs6049918, rs6076258, rs6083598, rs2424628, rs6076259, rs6049920, rs6049921, rs926709, rs6138355, rs4815302, rs6114852, rs6049922, rs6049923, rs6049924, rs6049925, rs6036896, rs6114853, rs714689, rs2424629, rs910236, rs6114854, rs2245957, rs6076261, rs910237, rs910238, rs6049926, rs910239, rs910240, rs6049927, rs6049928, rs6049929, rs2424630, rs2424631, rs4239747, rs4239748,rs4239749,rs7273541,rs2424632,rs2424633,rs8125275,rs2424634,rs8125200, rs7273856,rs2424635,rs2424636,rs2424637,rs8120600,rs6132759,rs6049930,rs8114121, rs7260865,rs2424638,rs2424639,rs2424640,rs2424641,rs8114459,rsόl14855,rs2424642, rs2424643,rs6114856,rs6114857,rs6049931,rs8116150,rs6049932,rs926710,rs926711, rs2424644,rs2424645,rs6114858,rs974647,rs4815303,rs6106939,rs6049933,rs4813530, rs^βl14859,rs2424646,rs8120183,rs971956,rs971957,rs6036897,rs6049934,rs6049935, rs6049936,rs6049937,rsl883922,rs6049938,rs6049939,rs7360533,rs4815304,rs2424647, rs2424648,rs6138357,rs6076264,rs6076265,rs6076266,rs2424651,rs6036898,rs4813531, rs4813532,rs4815305,rs4815306,rs6049940,rs6049941,rs6049942,rs6083602,rs2424652, rs2424653,rs2424654,rs6049943,rs4239750,rs2424655,rs6132761,rs4546069,rs6083603, rs4398330,rs6049944,rs6049945,rs2424656,rs2424657,rs2424658,rs6036899,rs6083604, rs6083605,rs6049946,rsl569756,rsl007136,rsl474776,rs6076269,rs6049947,rs6036900, rs6049948,rs5841039,rsl007135,rs6106942,rs6138360,rs6049949,rs6049950,rs7271933, rs6'l14862,rs2424660,rs6049952,rs2424661,rs2424662,rs2253628,rs2424663,rs2424664, rs2424665,rs2424666,rs2424667,rs6138361,rs6049954,rs4815307,rs2424668,rs3085897, rs6138362,rs6138363,rs6138364,rs2424669,rs6083608,rs7345304,rs6049956,rs4813535, rs8118505,rs2424670,rs6076272,rs2424671,rs7345970,rs6138365,rs8184060,rs8184072, rs2424673,rs2424674,rs6049962,rs2424675,rs6106943,rs2424676,rs7265148,rsβl14863, rs7354663,rs2424677,rs5841040,rsβl14864,rs2424678,rs6036903,rs6106944,«910241, rs8123123,rs910242,rsl535065,rsl535066,rs2424679,rs2424680,rs6049963,rs2892219, rs732829,rs6049964,rs6049965,rs6515532,rs2244284,rs2424681,rs2424682,rs6083610, rs2424683,rs6114865,rs6049966,rs6114866,rs6076274,rs2424684,rs6083612,rs4815308, rs2424685,rs6138369,rs2424686,rs6049967,rs6138370,rs6132762,rs7264110,rs6076275, rs6132763,rs6138371,rs6138372,rs4815309,rs6132764,rs6083615,rs6083616,rs6049968, rs6036904,rs4813536,rs6138373,rs7274381,rs6076276,rs6076277,rs6049969,rs6036905, rs8120681,rs6083617,rs6114867,rs6049970,rs6083618,rs6083619,rsl998153,rsl998154, rs6106945,rsl998155,rsl000044,rsl000043,rsl000042,rs6083620,rs6049971,rs6106946, rs6132765,rs4815311,rs4813537,rs6083621,rs6036906,rs6036907,rs6036908,rs6036909, rs6114868,rs7272507,rs7274081,rs6036910,rs4813538,rs4813539,rs226664,rs226665, rs8123361,rs8116690,rs226666,rs6083622,rs6114869,rs73329,rs7270151,rs7272053, rs6138374,rs6114870,rs226667,rs226668,rs6114871,rs226669,rs226670,rs226671,rs6049972, rs6049973,rs226672,rs911173,rs6049974,rs6049975,rs6114872,rs226674,rs4815312, rs3055823,rs226675,rs4588255,18226676,rs226677,rs226678,rs226679,rs6049976,rs226680, rs2424688andrs2424689.

5. The method of claim 1 , wherein the one or more polymorphic variations are detected at positions selected from the group consisting of rs2223829, rs6515520, rs6515521, rs6076253, rs2064435, rs6049907, rs8117631, rs6049925, rs910237, rs910238, rs2424630, rs2424631, rs2424634, rs8114459, rs974647, rs4813530, rs2424646, rs971957, rsl883922, rs6049941, rs6049944, rs6049945, rsl569756, rs6049948, rs7271933, rs2424661, rs2253628, rs4815307, rs2424669, rs2424670, rs2424671, rs2424675, rs2424678, rs910242, rs2244284, rs6049967, rs6076275, rs6076276, rs6049971, rs6036906, rs4813538, rs4813539, rs226664, rs226665, rs226666, rs226670, rs226672, rs226674, rs226675 andrs4588255.

6. The method of claim 1 , wherein the one or more polymorphic variations are detected in a region spanning positions 15272 to 98014 in SEQ ID NO: 1.

7. The method of claim 1 , wherein the one or more polymorphic variations are detected at one or more positions selected from the group consisting of rs2029892, rs7103192, rs2403370, rs7106206, rs7130566, rs7111238, rs2132518, rs2132519, rs7118054, rs4528318, rs7115107, rs7103582, rs903834, rs4255529, rs7944101, rs7128310, rs3215082, rs7117587, rs4909953, rs3736327, rs4910190, rs7103202, rs3816958, rs2270620, rs2242361, rs2242360, rs7932171, rsl546164, rs7952450, rs7927566, rs3840763, rs7123900, rs7951151, rs2029890, rs2173004, rs2403333, rs4910192, rs7948465, rs7948713, rs6484495, rs7928753, rs7109030, rs7936245, rs7103352, rs7115367, rs7937695, rs963372, rs4910193, rs4910194, rs4910195, rs7106243, rs4910196, rs4910197, rs4910198, rs2132522, rs2132521, rsl603397, rs6416069, rs2403335, rs4367939, rs2403336, rs7119484, rs903836, rs903835, rs7120720, rs7931361, rsl908705, rs6484497, rs4910199, rs7117811, rs7114654, rs7125589, rs7125751, rs2687486, rs7947838, rs2644720, rs7933687, rs2088279, rs2687487, rs771379, rs771378, rs811295, rs811294, rs7950234, rs7939447, rs7950378, rs771374, rs771375, rslO1618O, rs771376, rs771377, rsl 120852, rsl580744, rs7935433, rs2687489, rs2644721, rs903831, rs903832, rs903833, rs755910, rs2644718, rs2644719, rs7931839, rs7925687, rs771371, rs2232929, rs2232928, rs2232927, rs2232926, rs2232925, rs2232924, rs2232923, rs2232922, rs2232921, rs2232920, rs2232919, rs2232918, rs2232917, rs2232916, rsl4229, rsl5752, rs2232915, rs2232914, rs2232913, rs4477433, rs2232912, rs771372, rs771373, rs4397842, rsl980286, rsl980287, rs7106192, rs7109947, rs7126003, rs7950031, rs2403432, rs2091001, rs7125450, rsl047110, rs2403429 and rs2403431.

8. The method of claim 1 , wherein the one or more polymorphic variations are detected at positions selected from the group consisting of rs2403370, rs7103582, rs3215082, rs7117587, rs4910190, rs2270620, rs2242361, rs2242360, rs3840763, rs2173004, rs7109030, rs2132521, rs4367939,rs903835,rsl908705,rs4910199,rs2687486,rs2088279,rs771374,rs771375, rsl016180,rs771376,rs903832 andrs2644718

9. Themethodofclaim 1,whereintheoneormorepolymorphicvariationsaredetectedin aregionspanningpositions2531 to68207inSEQIDNO: 2.

10. Themethodofclaim 1,whereintheoneormorepolymorphicvariationsaredetectedat oneormorepositions selectedfromthegroupconsistingofrs2223795,rs2206993,rs2344472, rs2880867,rs2344471,rs2143790,rs2143791,rs2880866,rs2344470,rs2344469,rs2344468, rs2344466,rs2344465,rs2344464,rs7757684,rs7740570,rs7763133,rs2206994,rs2223797, rs7769108,rs7746260,rs4710287,rs2344462,rs2344461,rs2880864,rs7451281,rsl591554, rs448006,rsl075170,rsl577639,rsl591553,rsl832210,rslll5388,rs2344460,rs450321, rs2206995,rs2206996,rs410069,rs405339,rsl574970,rs432463,rsl932678,rsl932676, rsl77282,rs7452381,rsl855929,rsl77283,rsl577640,rs7740122,rs7769425,rsl336341, rs6927479,rs6927714,rs214140,rs6919904,rs214141,rsl932674,rsl932673,rs2223801, rsl855927,rsl855928,rs214143,rs214146,rs2210875,rs7746503,rs2210874,rsl932672, rsl414816,rsl414815,rsl414814,rsl336354,rs958834,rs4598053,rs4472334,rs4472335, rsl932671,rs6910633,rs4710346,rs7769976,rsl414813,rsl414812,rslO41718,rs6902053, rsl336353,rsl953630,rsl953629,rs3904731,rsl932670,rsl932669,rsl577645,rsl577644, rs6926794,rs6903599,rs6908227,rsl953628,rs7746839,rs7758848,rsl577643,rsl591556, rs4407695,rsl932668,rsl577642,rs7770087,rsl336352,rsl336351,rsl336350,rsl336349, rs4569947,rs7764580,rs7744442,rsl932667,rs6913091,rs6913467,rs6455373,rs7381824, rs6455374,rs7383515,rsl414811,rs4710349,rs4710350,rs4710687,rsl414809,rs4710688, rs4710689,rsl414808,rs4710691,rs6908596,rsl360946,rs7751781,rsl932666,rsl932665, rsl932664,rs3056688,rs6912856,rs6936876,rs6937230,rs6937260,rs6913748,rsl577651, rsl577650,rs7747680,rs6453545,rsl577649,rs6903830,rs6917092,rsl855940,rsl855939, rsl855938,rsl855937,rsl855935,rsl855934,rsl855933,rsl577648,rs6940162,rsl577647, rs4443495,rs2344449,rs3056645,rs3056644,rs6928630,rs6915000,rs6915206,rs6929218, rsl932662,rs7454074,rs4524585,rsl932661,rsl336364,rsl336363,rsl336362,rsl537871, rsl537870,rs7776018,rs7776147,rs6921345 andrs6453584.

11. Themethodofclaim 1,whereintheoneormorepolymorphicvariationsaredetectedat positionsselectedfromthegroupconsistingofrs4710287,rs7451281,rsl577639,rs432463, rsl77282,rs214140,rsl336353,rsl591556,rs4407695,rsl336351,rsl932665,rs6929218and rsl932661.

12. The method of claim 1, wherein the one or more polymorphic variations are detected in a region spanning positions 21348 to 95483 in SEQ ID NO: 3.

13. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in linkage disequilibrium with one or more positions in claim 3, 4, 7 or 10.

14. The method of claim 1, wherein detecting the presence or absence of the one or more polymorphic variations comprises: hybridizing an oligonucleotide to the nucleic acid sample, wherein the oligonucleotide is complementary to a nucleotide sequence in the nucleic acid and hybridizes to a region adjacent to the polymorphic variation; extending the oligonucleotide in the presence of one or more nucleotides, yielding extension products; and detecting the presence or absence of a polymorphic variation in the extension products.

15. The method of claim 1, wherein the subject is a human.

16. A method for identifying a polymorphic variation associated with type II diabetes proximal to an incident polymorphic variation associated with type II diabetes, which comprises: identifying a polymorphic variation proximal to the incident polymorphic variation associated with type II diabetes, wherein the polymorphic variation is detected in a nucleotide sequence referenced in Table 1 or SEQ E) NO: 1-6, a substantially identical sequence thereof or a fragment of the foregoing; and determining the presence or absence of an association of the¹ proximal polymorphic variant with type II diabetes.

17. The method of claim 16, wherein the incident polymorphic variation is at a position in claim 3, 4, 7 or 10.

18. The method of claim 16, wherein the proximal polymorphic variation is within a region between about 5 kb 5' of the incident polymorphic variation and about 5 kb 3' of the incident polymorphic variation.

19. The method of claim 16, which further comprises determining whether the proximal polymorphic variation is in linkage disequilibrium with the incident polymorphic variation.

20. The method of claim 16, which further comprises identifying a second polymorphic variation proximal to the identified proximal polymorphic variation associated with type II diabetes and determining if the second proximal polymorphic variation is associated with type II diabetes.

21. The method of claim 20, wherein the second proximal polymorphic variant is within a region between about-5 kb 5' of the incident polymorphic variation and about 5 kb 3' of the proximal polymorphic variation associated with type II diabetes.

22. A method for identifying a candidate molecule that increases glucose uptake in a cell, which comprises:

(a) introducing a test molecule to a system which comprises a nucleic acid comprising a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6, a substantially identical sequence thereof or a fragment of the foregoing, or introducing a test molecule to a system which comprises a protein encoded by a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6, a substantially identical sequence thereof or a fragment of the foregoing; and

(b) determining the presence or absence of an interaction between the test molecule and the nucleic acid or protein, whereby the presence of an interaction between the test molecule and the nucleic acid or protein identifies the test molecule as a candidate molecule that increases glucose uptake in a cell.

23. The method of claim 22, wherein the system is an animal.

24. The method of claim 22, wherein the system is a cell.

25. The method of claim 22, wherein the nucleotide sequence comprises one or more polymorphic variations associated with type II diabetes.

26. The method of claim 22, wherein the one or more positions is claim 3, 4, 7 or 10.

27. A method for treating type II diabetes in a subject, which comprises administering a candidate molecule identified by the method of claim 22 to a subject in need thereof, whereby the candidate molecule treats type II diabetes in the subject.

28. A method for identifying a candidate therapeutic for treating type II diabetes, which comprises: (a) introducing a test molecule to a system which comprises a nucleic acid comprising a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6, a substantially identical sequence thereof or a fragment of the foregoing, or introducing a test molecule to a system which comprises a protein encoded by a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6, a substantially identical sequence thereof or a fragment of the foregoing; and

(b) determining the presence or absence of an interaction between the test molecule and the nucleic acid or protein, whereby the presence of an interaction between the test molecule and the nucleic acid or protein identifies the test molecule as a candidate therapeutic for treating type II diabetes.

29. A method for treating type II diabetes in a subject, which comprises contacting one or more cells of a subject in need thereof with a nucleic acid, wherein the nucleic acid comprises a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6, a substantially identical sequence thereof, a fragment of the foregoing or a complementary nucleotide sequence of the foregoing, whereby contacting the one or more cells of the subject with the nucleic acid treats type II diabetes in the subject.

30. The method of claim 29, wherein the nucleic acid is RNA or PNA.

31. The method of claim 29, wherein the nucleic acid is duplex RNA.

32. A method for treating type II diabetes in a subject, which comprises contacting one or more cells of a subject in need thereof with a protein, wherein the protein is encoded by a nucleotide sequence which comprises a polynucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6, a substantially identical sequence thereof or a fragment of the foregoing, whereby contacting the one or more cells of the subject with the protein treats type II diabetes in the subject.

33. A method for treating type II diabetes in a subject, which comprises: detecting the presence or absence of one or more polymorphic variations associated with type II diabetes in a nucleic acid sample from a subject, wherein the one or more polymorphic variation are detected in a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6, a substantially identical sequence thereof or a fragment of the foregoing; and administering a type II diabetes treatment to a subject in need thereof based upon the presence or absence of the one or more polymorphic variations in the nucleic acid sample.

34. The method of claim 33, wherein the chromosome positions are claim 3, 4, 7 or 10.

35. The method of claim 33, which further comprises determining blood glucose levels in the subject.

36. The method of claim 33, wherein the treatment is selected from the group consisting of administering insulin, a hypoglycemic, a starch blocker, a liver glucose regulating agent, an insulin sensitizer, a glucose level monitoring regimen, dietary counseling, a dietary regimen for managing blood glucose levels, and combinations of the foregoing.

37. A method for detecting or preventing type II diabetes in a subject, which comprises: detecting the presence or absence of one or more polymorphic variations associated with type II diabetes in a nucleic acid sample from a subject, wherein the polymorphic variation is detected in a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6, a substantially identical sequence thereof or a fragment of the foregoing; and administering a type II diabetes treatment or detection procedure to a subject in need thereof based upon the presence or absence of the one or more polymorphic variations in the nucleic acid sample.

38. The method of claim 37, wherein the one or more polymorphic variations are detected at one or more positions in claim 3, 4, 7 or 10.

39. The method of claim 37, wherein the type II diabetes treatment is selected from the group consisting of administering insulin, a hypoglycemic, a starch blocker, a liver glucose regulating agent, an insulin sensitizer, a glucose level monitoring regimen, dietary counseling, a dietary regimen for managing blood glucose levels, and combinations of the foregoing.

40. A method of targeting information for preventing or treating type II diabetes to a subject in need thereof, which comprises: detecting the presence or absence of one or more polymorphic variations associated with type II diabetes in a nucleic acid sample from a subject, wherein the polymorphic variation is detected in a nucleotide sequence referenced in Table 1 or SEQ ID NO: 1-6, a substantially identical sequence thereof or a fragment of the foregoing; and directing information for preventing or treating type II diabetes to a subject in need thereof based upon the presence or absence of the one or more polymorphic variations in the nucleic acid sample.

41. The method of claim 40, wherein the one or more polymorphic variations are detected at one or more positions in claim 3, 4, 7 or 10.

42. The method of claim 40, wherein the information comprises a description of a type II diabetes detection procedure or treatment.

43. The method of claim 42, wherein the treatment is selected from the group consisting of administering insulin, a hypoglycemic, a starch blocker, a liver glucose regulating agent, an insulin sensitizer, a glucose level monitoring regimen, dietary counseling, a dietary regimen for managing blood glucose levels, and combinations of the foregoing.

44. A composition comprising a cell from a subject having type II diabetes or at risk of type II diabetes and an antibody that specifically binds to a protein, polypeptide or peptide encoded by a nucleotide sequence identical to or 90% or more identical to a nucleotide sequence in Table 1 or SEQ ID NO: 1-6.

45. The composition of claim 44, wherein the antibody specifically binds to an epitope that comprises a valine at position 580 in a PIGR polypeptide, a valine at position 264 in a LOC166350/DNAJBU polypeptide, a threonine at position 247 in a KIAA0141 polypeptide, a glutamic acid at position 652 in a Fl 3Al polypeptide, an aspartic acid at position 905 in a PPP1R3A polypeptide, a threonine at position 435 in a C14orfl31 polypeptide, or a threonine at position 117 in a COPE polypeptide.

46. A composition comprising a cell from a subject having type II diabetes or at risk of type II diabetes and a RNA, DNA, PNA or ribozyme molecule comprising a nucleotide sequence identical to or 90% or more identical to a portion of a nucleotide sequence in Table 1 or SEQ ID NO: 1-6 or a complementary nucleotide sequence of the foregoing.

47. The composition¹ of claim 46, wherein the RNA molecule is a short inhibitory RNA molecule.