AU768904B2 - A method for the prophylaxis and/or treatment of medical disorders - Google Patents

A method for the prophylaxis and/or treatment of medical disorders Download PDF

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AU768904B2
AU768904B2 AU52020/00A AU5202000A AU768904B2 AU 768904 B2 AU768904 B2 AU 768904B2 AU 52020/00 A AU52020/00 A AU 52020/00A AU 5202000 A AU5202000 A AU 5202000A AU 768904 B2 AU768904 B2 AU 768904B2
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nucleic acid
acid molecule
chemical analogue
igf
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Stephanie Ruth Edmondson
George Arthur Werther
Christopher John Wraight
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Murdoch Childrens Research Institute
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Description

WO 00/78341 PCT/AU00/00693 1- A METHOD FOR THE PROPHYLAXIS AND/OR TREATMENT OF MEDICAL DISORDERS FIELD OF THE INVENTION The present invention relates generally to a method for the prophylaxis and/or treatment of medical disorders, and in particular proliferative and/or inflammatory skin disorders, and to genetic molecules useful for same. The present invention is particularly directed to genetic molecules capable of modulating growth factor interaction with its receptor on cells such as epidermal keratinocytes to inhibit, reduce or otherwise decrease stimulation of this layer of cells.
The present invention contemplates, in a particularly preferred embodiment, a method for the prophylaxis and/or treatment of psoriasis or neovascularization conditions such as neovascularization of the retina. The present invention is further directed to the subject genetic molecules in adjunctive therapy for epidermal hyperplasia, such as in combination with UV treatment, and to facilitate apoptosis of cancer cells and in particular cancer cells comprising keratinocytes.
BACKGROUND OF THE INVENTION Bibliographic details of the publications numerically referred to in this specification are collected at the end of the description.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia or any other country.
Psoriasis and other similar conditions are common and often distressing proliferative and/or inflammatory skin disorders affecting or having the potential to affect a significant proportion of the population. The condition arises from over proliferation of basal keratinocytes in the epidermal layer of the skin associated with inflammation in the underlying dermis. Whilst a WO 00/78341 PCT/AU00/00693 -2range of treatments have been developed, none is completely effective and free of adverse side effects. Although the underlying cause of psoriasis remains elusive, there is some consensus of opinion that the condition arises at least in part from over expression of local growth factors and their interaction with their receptors supporting keratinocyte proliferation via keratinocyte receptors which appear to be more abundant during psoriasis.
One important group of growth factors are the dermally-derived insulin-like growth factors (IGFs) which support keratinocyte proliferation. In particular, IGF-I and IGF-II are ubiquitous peptides each with potent mitogenic effects on a broad range of cells. Molecules of the IGF type are also known as "progression factors" promoting "competent" cells through DNA synthesis.
The IGFs act through a common receptor known as the Type I or IGF-I receptor, which is tyrosine kinase linked. They are synthesised in mesenchymal tissues, including the dermis, and act on adjacent cells ofmesodermal, endodermal or ectodermal origin. The regulation of their synthesis involves growth hormone (GH) in the liver, but is poorly defined in most tissues Particular proteins, referred to as IGF binding proteins (IGFBPs), appear to be involved in autocrine/paracrine regulation of tissue IGF availability Six IGFBPs have so far been identified. The exact effects of the IGFBPs is not clear and observed effects in vitro have been inhibitory or stimulatory depending on the experimental method employed There is some evidence, however, that certain IGFBPs are involved in targeting IGF-I to its cell surface receptor.
Skin, comprising epidermis and underlying dermis, has GH receptors on dermal fibroblasts Fibroblasts synthesize IGF-I as well as IGFBPs-3, -5 and -6 which may be involved in targeting IGF-I to adjacent cells as well as to the overlaying epidermis. The major epidermal cell type, the keratinocyte, does not synthesize IGF-I, but possesses IGF-I receptors and is responsive to IGF-I It is apparent, therefore, that IGF-I and other growth promoting molecules, are responsible for or at least participate in a range of skin cell activities. In accordance with the present invention, the inventors have established that aberrations in the normal functioning of these molecules or WO 00/78341 PCT/AU00/00693 -3aberrations in their interaction with their receptors is an important factor in a variety of medical disorders such as proliferative and/or inflammatory skin disorders. It is proposed, therefore, to target these molecules or other molecules which facilitate their functioning or interaction with their receptors to thereby ameliorate the effects of aberrant activity during or leading to skin disease conditions and other medical conditions such as those involving neovascularization.
Furthermore, these molecules may also be used to facilitate apoptosis of target cells and may be useful as adjunctive therapy for epidermal hyperplasia.
SUMMARY OF THE INVENTION Nucleotide and amino acid sequences are referred to by a sequence identifier, i.e. (<400>1), etc. A sequence listing is provided after the claims.
Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.
Accordingly, one aspect of the present invention contemplates a method for ameliorating the effects of a medical disorder such as a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation or a cell otherwise involved in the said medical disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing a growth factor mediated cell proliferation and/or inflammation and/or other medical disorder.
According to this preferred embodiment, there is provided a method for ameliorating the effects of a medical disorder such as a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation or a cell otherwise involved with said medical disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof WO 00/78341 PCT/AU00/00693 -4capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation and/or other medical disorder.
According to this embodiment, there is provided a method for ameliorating the effects of a proliferative and/or inflammatory skin disorder such as psoriasis said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation with effective amounts of UV treatment and a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation.
According to this embodiment, there is provided in a particularly preferred aspect a ribozyme comprising a hybridising region and a catalytic region wherein the hybridising region is capable of hybridising to at least part of a target mRNA sequence transcribed from a genomic gene corresponding to <400>1 or <400>2 wherein said catalytic domain is capable of cleaving said target mRNA sequence to reduce or inhibit IGF-I mediated cell proliferation and/or inflammation and/or other medical disorders.
Yet another aspect of the present invention contemplates co-suppression to reduce expression or to inhibit translation of an endogenous gene encoding, for example, IGF-I, its receptor, or IGFBPs such as IGFBP-2 and/or In co-suppression, a second copy of an endogenous gene or a substantially similar copy or analogue of an endogenous gene is introduced into a cell following topical administration. As with antisense molecules, nucleic acid molecules defining a ribozyme or nucleic acid molecules useful in co-suppression may first be protected such as by using a nonionic backbone.
Another aspect of the present invention contemplates a pharmaceutical composition for topical administration which comprises a nucleic acid molecule capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation such as psoriasis and one or more pharmaceutically acceptable carriers and/or diluents.
WO 00/78341 PCT/AU00/00693 Yet another aspect of the present invention contemplates the use of a nucleic acid molecule in the manufacture of a medicament for the treatment of proliferative and/or inflammatory skin disorders or other medical disorders mediated by a growth factor.
Still a further aspect of the present invention contemplates an agent comprising a nucleic acid molecule as hereinbefore defined useful in the treatment of proliferative and/or inflammatory skin disorders, such as psoriasis or other medical disorder..
The present invention further contemplates the use of the genetic molecules and in particular the antisense molecules to inhibit the anti-apoptotic activity of IGF-I receptor.
WO 00/78341 -6- BRIEF DESCRIPTION OF THE FIGURES PCTAU00/00693 Figure 1 is a representation of the nucleotide sequence of IGFBP-2.
LOCUS
DEFINITION
ACCESSION
KEYWORDS
SOURCE
HSIGFBP2 1433 bp RNA PRI Human mRNA for insulin-like growth factor binding X16302 insulin-like growth factor binding protein.
human 31- JAN -1990 protein (IGFBP-2)
RE
Co
FE
ORGANISM Homo sapiens Eukaryota; Animalia; Metazoa; Chordata; Vertebrata; Mammalia; Theria; Eutheria; Primates; Haplorhili; Catarrhini; Hominidae.
~FERENCE 1 (bases 1 to 1433) AUTHORS Binkert, Landwehr,J., Mary,J.L., Schwander,J. and Heinrich,G.
TITLE Cloning, sequence analysis and expression of a cDNA encoding a novel insulin-like growth factor binding protein (IGFBP-2) JOURNAL EMBO J. 8, 2497-2502 (1989) STANDARD full automatic )MMENT NCBI gi: 33009 1ATURES Location/Qualifiers source 1. .1433 /organism= "Homo sapiens" /dev-stage='lfetalot /tissue-type-'liver' misc feature 1416. .1420 /note=11pot. polyadenylation signal" polyA._site 1433 /note=1"polyademylation st, CDS 118. .1104 /note="precursor polypeptide; (AA -39 to 289); NCBI gi: 33010."1 /codon-Start=1 /translation= "MLPRVGCPALPLPPPPLLPLLPLLLLLLGASGGGGGARAEVLFR
CPPCTPERLAACGPPPVAPPAAVAAVAGGARMPELVREPGCCSVALEGEACG
VYTPRCGQGLRCYPHPGSELPLQALVMGEGTCEKRRDAEYGASPEQVADNGDDHSEGG
LVEHVDST4NMLGGGGSAGRKPLKSGMKELAVFREKVTEQHRQMGKGKHHLGLEEP KKLRPPPARTPCQQELDQVLER ISTMRLPDERGPLEHLYSLIAIPNCDKHGLYNLKQCK
MSLNGQRGECWCNPNTGKLIQGAPTIRGDPECHLFYNEQEACGVHTORMQ"
(-c400>21) CDs 118. .234 /note=1signal peptide; (AA -39 to NOBI gi; 33011."1 /codon-start~l /translation= nMLPRVGCPALPLPPPPLLPLLPLLLLLLGASGGGGGARA' (k400>22) CUs 235. .1101 /note='mature IGFBP-2; (AA 1 to 289); NCBI gi: 33012."1 /codon-start=1 /translation- "EVLFRCPPCTPERLAACGPPPVAPPAAVAAVAGGARMPCAELVR
EPGCGCCSVCARLEGECGVYTPRCGQGLRCYPHPGSELPLQALMGEGTCERRDE
YGASPEQVAflNGDDHSEGGLVENHVDST?NMLGGGGSAGRKPLKSGMKELAVFREV
EQHRQMGKGGKHHLGLEEPKKLRPPPARTPCQOELDQVLERISTMRLPDERGPLEHLY
SLHIPNCDKHGLYNLKQCKMSLNGQRGECWCVNPNTGKL IQGAPTI RGDPECHLFYNE QQEACGVHTQRMQ" (<400>23) ~SE COUNT 239 a 466 c 501 g 227 t
ORIGIN
WO 00/78341 PCT/AU00/00693 HSIGFBP2 Length: 1433 May 11, 1994 10:06 Type: N Check: 6232 Figure 2 is a representation of the nucleotide sequence of IGFBP-3.
LOCUS
DEFINITION
ACCESSION
KEYWORDS
SOURCE
ORGANISM
HUMGFIBPA 2474 bp ss-mRNA PRI 15-JUN-1990 Human growth hormone-dependent insulin-like growth factor-binding protein mRNA, complete cds.
M31159 insulin-like growth factor binding protein.
Human plasma, cDNA to mRNA, clone BP-53.
Homo sapiens Eukaryota; Animalia; Chordata; Vertebrata; Mammalia; Theria; Eutheria; Primates; Haplorhini; Catarrhini; Hominidae.
REFERENCE 1 (bases 1 to 2474) AUTHORS Wood,W.I., Cachianes,G., Henzel,W.J., Winslow,G.A., Spencer,S.A., Hellmiss,R., Martin,J.L. and Baxter,R.C.
C<
TITLE Cloning and expression of the growth hormone-dependent insulin-like growth factor-binding protein JOURNAL Mol. Endocrinol. 2, 1176-1185 (1988) STANDARD full automatic 3MMENT NCBI gi: 183115
FEATURES
mRNA
CDS
source BASE COUNT
ORIGIN
Location/Qualifiers .2474 /note="GFIBP mRNA" 110. .985 /gene="IGFBPl" /note="insulin-like growth factor-binding protein; gi: 183116."
NCBI
/codonstart=l /translation="MQRARPTLWAAALTLLVLLRGPPVARAGASSGGLGPVVRCEPCD
ARALAQCAPPPAVCAELVREPGCGCCLTCALSEGQPCGIYTERCGSGLRCQPSPDEAR
PLQALLDGRGLCVNASAVSRLRAYLLPAPPAPGNASESEEDRSAGSVESPSVSSTHRV
SDPKFHPLHSKIIIIKKGHAKDSQRYKVDYESQSTDTQNFSSESKRETEYGPCRREME
DTLNHLKFLNVLSPRGVHIPNCDKKGFYKKKQCRPSKGRKRGFCWCVDKYGQPLPGYT
TKGKEDVHCYSMQSK" (<400>24>) 1. .2474 /organism="Homo sapiens" 597 a 646 c 651 g 580 t HUMGFIBPA Length: 2474 May 11, 1994 10:00 Type: N Check: 9946 Figure 3 is a representation of the nucleotide sequence of IGF-1-receptor.
LOCUS
DEFINITION
ACCESSION
KEYWORDS
HSIGFIRR 4989 bp RNA PRI 28-MAR-1991 Human mRNA for insulin-like growth factor I receptor X04434 M24599 glycoprotein; insulin receptor; insulin-like growth factor I receptor; membrane glycoprotein; receptor; tyrosine kinase.
SOURCE human WO 00/78341 WO 00/834 1PCT/AUOO/00693 -8- ORGANISM Homo sapiens Eukaryota; Animalia; Metazoa; Chordata; Vertebrata; Mammalia; Theria; Eutheria; Primates; Haplorhini; Catarrhini; Hominidae.
REFERENCE 1 (bases 1 to 4989) AUTHORS Ullrich,A., Gray,A., Tam,A.W., Yang-Feng,T., Tsubokawa,M., ColJlins,C., Henzel,W., Bon,T.L., Kathuria,S., Chen,B., Jakobs,S., Francke, Ramachandran, J. and Fuj ita -Yamaguchi, Y.
TITLE Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural dererminants that define 0 functional specificity JOURNAL EMBO J. 5, 2503-2512 (1986) STANDARD full automatic COMMENT NCBI gi: 33058
FEATURES
source sigpeptide matpept ide misc-feature misc-feature misc-feature misc-feature misc-feature misc-feature misc-feature misc-feature misc-feature misc-feature misc-feature misc-feature misc-feature misc feature misc-feature misc-feature misc-feature Location/Qualifiers 1. .4989 /arganism= "Homno sapiens" /tissue_type-'lplacenta"l /clone_lib=" (lamda)gtlO"1 /clone=1"(lambda)IGF-l-R.85, (lambda)IGF-1-R.76" 32. .121 122. .4132 /note=11IGF-I receptor" 122. .2251 /note=1'alpha-subunit (AA 1 710)" 182. .190 /note= "pot. N- linked glycosylation site (AA 21 23)' 335. .343 /note=1'pot .N-1inked 434. .442 /note=1"pot .N-linked 761. .769 /note="pot .N-linked 971. .979 /note="pot .N-linked 1280. .1288 /note= "pot .N'-inked 1343. .1351 /note= "pot .N-linked 1631. .1639 /note="pot .N-linked 1850. .1858 /note= "pot .N-linked 1895. .1903 /note= "pot .N-linked 1949. .1957 glycostlation glycostlation glycostlation glycostlation glycostlation glycosyl at ion glycostl at ion glycosylation glycosylation site site site site site site site site site 72 -74) 105 -107) 214 -216) 284 -286) 387 -389)" 408 -410)" 504 -506)" 577 -579) 592 -594) u /note=11pot.N-linked glycosylation site (AA 610 -612)" 2240. .2251 /note="putative proreceptor processing 710)" 2252. .4132.
/note="beta-subunit (AA 711 1337)" 2270. .2278 /note&'pot .N-linked glycosylation site 2297. .2305 /note="pot .N~-linked glycosylat ion site 2321. .2329 /note="pot .N-linked glycosylat ion site site (AA 707 (AA 717 (AA 726 (AA 734 719] 72B) 736)" WO 00/78341 WO 0078341PCT/AUOO/00693 -9misc-featt misc-featL misc-f eatt misac-f eatt misc-f eatt misc-f eat.
misc-feati misc-f eati
CDS
Ire 2729. .2737 /note="pot.N-linked glycosylation site (AA 870 872)' ire 2768. .2776 /note-Ilpot.N-linked glycosylation site (AA 883 885)" ire 2837. .2908 /note="transmembrane region (AA 906 929)" ire 2918. .2926 /note="pot.N-linked glycosylation site (AA 933 935)" ire 3047. .3049 /note="pot.ATP binding site (AA 976)" ire 3053. .3055 /note-"lpot.ATP binding site (AA 978)" ire 3062. .3064 /note="pot.ATP binding site (AA 981)" ire 3128. .3130 /note="pot.ATP binding site (AA 1003)" 32. .4132 /product="IGF-I receptor" /note&'150 stops when translation attempted, frame 1, code 0" 1216 a 1371 c 1320 g 1082 t BASE COUNT
ORIGIN
HSIGFIRR Length: 4989 May 11, 1994 12:10 Type: N Check: 133 Figure 4A is a photographic representation of a Western ligand blot of HaCaT conditioned medium showing IGFBP-3 secreted in 24 hours after 7 day treatment with phosphorothioate oligonucleotides (BP3AS2, BP3AS3 and BP3S) at 0.5pM and no oligonucleotide added.
Figure 4B is a graphical representation of a scanning imaging desitometry of Western ligand blot (Figure 4A), showing relative band intensities of IGFBP-3 and the 24kDa IGFBP-4 after treatment with phosphorothioate oligonucleotides; no oligonucleotide added.
Figure 5A is a photographic representation of a Western ligand blot of HaCaT conditioned medium showing IGFBP-3 secreted in 24 hours after 7 day treatment with phosophorothioate oligonucleotide BP3AS2 at 0.5[MM compared with several control oligonucleotides at oligonucleotide BP3AS2NS; oligonucleotide BP3AS4; oligonucleotide BP3AS4NS; and (untreated), no oligonucleotide added.
WO 00/78341 PCT/AU00/00693 Figure 5B is a graphical representation of a scanning imaging densitometry of Western ligand blot (Figure 5A), showing relative band intensities of IGFBP-3 after treatment with phosphorothioate oligonucleotides as in Figure 5A, showing IGFBP-3 band intensities expressed as a percentage of the average band intensity from conditioned medium of cells not treated with oligonucleotide.
Figure 6 is a graphical representation showing inhibition of IGF-I binding by antisense oligonucleotides to IGF-I receptor. IGFR.AS: antisense; IGFR.S: sense.
Figure 7 is a graphical representation showing inhibition of IGFBP-3 production in culture medium following initial treatment with antisense oligonucleotides once daily over a 2 day period.
Figure 8 is a graphical representation showing optimization of IGFBP-3 antisense oligonucleotide concentration as determined by relative IGFBP-3 concentration in culture medium.
Figure 9 is a diagramatic representation of a map of IGF-1 Receptor mRNA and position of target ODNs.
Figure 10 is a photographical representation showing Lipid-mediated uptake of oligonucleotide in keratinocytes. HaCaT keratinocytes were incubated for 24 hours in medium (DMEM plus 10% v/v FCS) containing fluorescently labelled ODN (R451, 30 nM) and cytofectin GSV (2 The cells were then transferred to ODN-free medium and fluorescence microscopy and phase contrast images of the cells were obtained.
Figure 11 is a graphical representation of uptake and toxicity of ODN/lipid complexes in keratinocytes. Confluence HaCaT keratinocytes were incubated in DMEM containing fluoresently labelled ODN (R451) plus liposome over 120 hours, viewed using fluorescene microscopy and trypan blue stained and counted.
WO 00/78341 PCT/AU00/00693 11 Figure 12 is a graphical representation of an IGF-1 Receptor mRNA in ODN treated HaCaT cells (2zg/ml GSV). HaCaT keratinocytes were treated for 96 hours with propynyl, dU, dC ODNs complexed with cytofectin GSV. Cells were treated with ODNs complementary to the human IGF-I receptor mRNA (27, 32, 74 and 78), 2 randomised sequence ODNs (R451) and R766), liposome alone (GSV) or were left untreated Total RNA was isolated then analysed for IGF-I receptor mRNA and GAPDH mRNA levels by RNase Protection and Phosphorlmager quantitiation.
Electrophoretic analysis of IGF-I receptor and GAPDH mRNA fragments after RNase Protection. Molecular weight markers are shown on the right hand side. Full length probe is shown on the left hand side (G-probe and I-probe). GAPDH protected fragments are seen at 316 bases and IGF-I receptor protected fragments are seen at 276 bases.
Relative level of IGF-I receptor mRNA following each treatment is shown.
Figure 13 is a graphical representation of an IGF-1 receptor mRNA in ODN treated HaCaT cells (2pg/ml GSV). Summary of IGF-I receptor ODN screening data. HaCaT keratinocytes were treated for 96 hours with C-5 propynyl, dU, dC ODNs complexed with cytofectin GSV. Total RNA was isolated then analysed for IGF-I receptor mRNA and GAPDH mRNA levels by RNase protection and phosphorlmager quantitiation. Relative level of IGF-I receptor mRNA is shown after treatment with ODNs complementary to the human IGF-I receptor mRNA, 4 randomised sequence ODNs and liposome alone. (26-86= IGF-I receptor ODNs; R1, R4, R7 and R9 randomised ODNs (R1 =R121, R4=R451, R7=R766, R9=R961); GSV=liposome alone; UT=untreated). *indicates a significant difference in relative IGF-I receptor mRNA from GSV treated cells (n=4-10, p<0.05).
Figure 14 is a graphical representation of the effect of antisense oligonucleotides on IGF-1 receptor levels on the surface of keratinocytes. HaCaT cells were grown to confluence in 24well plates in DMEM containing 10% v/v FCS. Oligodeoxynucleotide (ODN) and Cytofectin GSV (GSV, Glen Research) were mixed together in serum-free DMEM, incubated at room WO 00/78341 PCT/AU00/00693 -12temperature for 10 minutes before being diluted ten-fold in medium and placed on the cells.
Cells were incubated for 72 hours with 30 nM random sequence or antisense ODN and 2 zgg/ml GSV or with GSV alone in DMEM containing 10% v/v FCS with solutions replaced every 24 hours. This was followed by incubation with ODN/GSV in serum-free DMEM for 48 hours. All incubations were performed at 37 0 C. Wells were washed twice with 1 ml cold PBS. Serum-free DMEM containing 10-M 2 I-IGF-I was added with or without the IGF-I analogue, des IGF-I, at 10- 0 M to 10-M. Cells were incubated at 4°C for 17 hours with gentle shaking then washed three times with 1 ml cold PBS and lysed in 250 pl NaOH/0.1% v/v Triton X-100 at room temperature for 4 hours. Specific binding of the solubilised cell extract was measured using a y counter.
Figure 15 is a graphical representation of the effect of antisense oligonucleotides on IGF-1 receptor levels on the surface of keratinocytes.
Figure 16 is a photographical representation of H E stained sections of psoriatic skin biopsy prior to grafting and 49 day old psoriatic skin graft using skin from the same donor.
Figure 17 is a photographical representation of uptake of oligonucleotide after intradermal injection into psoriatic skin graft on a nude mouse. Psoriatic skin graft was intradermally injected with ODN (R451, 50 gl, 10 The graft was removed and sectioned after 24 hours, then viewed using confocal microscopy.
Figure 18(a) is a photographical representation of Pregraft, Donor JH, Donor JH, PBS treated, 50ul, Donor JH, #50 treated, 5 0/l, Figure 18(b) is a photographical representation of Donor LB, pregraft, Donor LB, PBS treated (50 1 zl), Donor LB, #74 treated (50 1 l, WO 00/78341 PCT/AU00/00693 13- Figure 18(c) is a photographical representation of Donor PW, pregraft, Donor PW, R451 treated (501l, 10M), Donor LB, #74 treated (50,1, Figure 18(d) is a photographical representation of Donor GM, pregraft, Donor GB, R451 treated (50l, 10uM), Donor GM, #27 treated (501l, Figure 19(a) is a photographical representation showing Donor JH pregraft, Donor JH PBS treated 50Al, Donor JH #50 treated 5 01l, Figure 19(b) is a photographical representation Donor LB pregraft, Donor LB PBS treated 501l, Donor LB #74 treated 5 0/l1, Figure 19(c) is a photographical representational showing Donor PW pregraft, Donor PW r451 treated 50y1, 10pM, Donor PW #74 treated 501, Figure 19(d) is a photographical representation showing Donor GM pregraft, Donor GM R451 treated 501p, 10MM, Donor #27 treated 5 0ul, Figure 20 is a graphical representation showing suppression of psoriasis after treatment with oligonucleotide (quantification). Oligonucleotide (50 ul, 10k.M) was injected every two days for 20 days, as were control treatments. Skin thickness was measured by removing the skin and using computer software (MCID analysis) to measure the exact thickness of each graft.
N=3-4 for each treatment. *indicates a significant difference from the pregraft value (ANOVA, P<0.05) Figure 21 is a photographic representation of chKi-67 imunobiological binding.
Figure 22 is a photographical representation showing penetration of oligonucleotide into human skin after topical treatment. Fluorescently labelled oligonucleotide (10 zM R451) was WO 00/78341 PCT/AU00/00693 -14applied topically after formulation with cytofectin GSV (10 4g/ml) and viewed using confocal microscopy.
Figure 23 is a photographical representation showing penetration of oligonucleotide into human skin after application of topical gel formation. Fluorescently labelled oligonucleotide gM R451) was applied topically after complexing with cytofectin GSV (10 pg/ml) and formulation into 3% methylcellulose gel. Image was obtained using confocal microscopy.
Figure 24 is a graphical representation showing IGFBP-3 mRNA.
Figure 25(a) is a graphical representation showing IGFBP-3 mRNA in AON treated (100nM) HaCaT cells 2 mg/ml GSV).
Figure 25(b) is a graphical representation showing IGFBP-3 mRNA levels of AON treated (100nm) HaCaT cells (2/g/ml GSV).
Figure 25(c) is a graphical representation showing IGFBP-3 mRNA in AON treated HaCaT cells (2bzg/ml GSV).
Figure 25(d) is a graphical representation showing IGFBP-3 mRNA in AON treated HaCaT cells (2/g/ml GSV).
Figure 26(a) is a graphical representation showing IGFBP-3 mRNA in ODN treated HaCaT cells (2pg/ml). HaCaT keratinocytes were treated for 51 hours with C-5 propynl, dU, dC ODNs complexed with cytofectin GSV. Total RNA was isolated then analysed for IGFBP- 3 mRNA and GAPDH mRNA levels by Northern analysis and phosphorimager quantitation.
Relative level of IGFBP-3 mRNA is shown after treatment with ODNs complementary to the human IGFBP-3 mRNA, 4 randomised sequence ODNs and lipsome alone. (1-24 =IGFBP-3 ODNs; R1, R4, R7 and R9=randomised ODNs (R1=R121, R4=R451, R7=R766, R9 R961); GS=liposome alone; UT=untreated). *indicates a significant different in relative WO 00/78341 PCT/AU00/00693 IGFBP-3 mRNA from GSV treated cells 5-8, p<0.01), **indicates a significant difference in relative IGFBP-3 mRNA from GSV treated cells 5-8, p <0.05).
Figure 26(b) is a graphical representation showing IGFBP-3 mRNA in ODN treated (100nM) HaCaT cells (2g/ml GSV). HaCaT keratinocytes were treated for 51 hours with propynl, dU, dC ODNs complexed with cytofectin GSV. Total RNA was isolated then analysed for IGFBP-3 mRNA and GAPDH mRNA levels by Northern analysis and phosphorimager quantitation. Relative level of IGFBP-3 mRNA is shown after treatment with ODNs complementary to the human IGFBP-3 mRNA, 4 randomised sequence ODNs and liposome alone. (1-24=IGFBP-3 ODNs; RI, R4, R7 and R9 randomised ODNs (R1-R121, R4=R451, R7=R766, R9-R961), GS=lipsome alone; UT=untreated). *indicates a significant difference in relative IGFBP-3 mRNA from GSV treated cells 6-8, p<0.01).
Figure 27 is a representation showing a reduction in IGF-I receptor mRNA in HaCaT cells following treatment with antisense oligonucleotides. Confluent HaCaT cells were treated every 24 h for 4 days with 2 gg/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I receptor specific oligonucleotides (#26 to #86) or random sequence oligonucleotides (R121, R451 and R766). Total RNA was isolated and analysed for IGF-I receptor and GAPDH mRNA by RNase protection assay. Representative RNase protection assay gel showing IGF-I receptor (IGFR) and GAPDH mRNA in untreated or treated HaCaT cells. In this example, a reduction in IGFR band intensity relative to GAPDH can be seen with AON #27 and #78, but not with #32, #74 or the controls (R4, R7, random oligonucleotides R451 and R766, respectively; G, GSV lipid; UT, untreated).
Densitometric quantitation of IGF-I receptor mRNA (normalised to GAPDH mRNA) in HaCaT cells following treatment with IGF-I receptor specific oligonucleotides (solid black), random sequence oligonucleotides (horizontal striped bar) or GSV alone (shaded bar) compared to untreated cells (UT, vertical striped bar). Each oligonucleotide was assayed in duplicate in at least two separate experiments.
WO 00/78341 PCT/AU00/00693 -16- Results are presented as mean SEM. A one-way ANOVA followed by Tukey's test was performed; A indicates a significant difference between cells treated with IGF-I receptor specific AONs and all of the control treatments n=4 except for #27 and #32 #28 and #68 R766 and R451, GSV and untreated Figure 28 is a representation showing a reduction in total cellular IGF-I receptor protein following antisense oligonucleotide treatment. Confluent HaCaT cells were treated every 24 h for 4 days with 2 ,g/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I receptor specific AONs #50 and #64) or the random sequence oligonucleotide, R451. Total cellular protein was isolated and analysed for IGF-I receptor by SDS PAGE followed by western blotting with an antibody specific for the human IGF-I receptor. Duplicate treated cellular extracts showing the IGF-I receptor at the predicted size of 110 kD Densitometric quantitation of IGF-I receptor protein. Results are presented as mean SEM of four different experiments each performed in duplicate. A one-way ANOVA followed by a Dunnett's test was performed; indicates a significant difference from GSV treated cells GSV, GSV lipid alone; UT, untreated; R451, random sequence oligonucleotide; 64, 50, 27, IGF-I receptor-specific AONs.
Figure 29 is a representation showing a reduction in IGF-I receptor numbers on the keratinocyte cell surface after antisense oligonucleotide treatment. HaCaT cells were transfected with IGF-I receptor specific AONs #27 #50 #64 a random sequence oligonucleotide R451 or treated with GSV lipid alone every 24 h for four days (untreated cells, Competition binding assays using "I-IGF-I and the receptor-specific analogue, des(1-3)IGF-I, were performed (inset); plotted values are means standard error. The mean values were then subjected to Scatchard analysis.
Figure 30 is a representation showing a reduction in keratinocyte cell number following antisense oligonucleotide treatment. HaCaT cells, initially at 40% confluence, were transfected with the IGF-I receptor specific AON #64, control sequences R451 and 6416, or WO 00/78341 PCT/AU00/00693 -17treated with GSV lipid alone every 24 h for 2 days (UT, untreated cells). Cell number was measured in the culture wells using a dye binding assay (Experimental protocol). Results are presented as mean SD. A one-way ANOVA was performed, followed by a Tukey's multiple comparison test. A indicates a significant difference between cells treated with AON #64 and all of the control treatments (p <0.001).
Figure 31 is a representation showing a reversal of epidermal hyperplasia in psoriatic human skin grafts on nude mice following intradermal injection with antisense oligonucleotides Grafted psoriasis lesions were injected with IGF-I receptor specific AONs, a random sequence oligonucleotide in PBS, or with PBS alone, every 2 days for 20 days, then analysed histologically. Donor A graft treated with AON #50 showing epidermal thinning compared with pregraft and control (PBS) treated graft, and Donor B graft treated with AON #27 showing epidermal thinning compared with pregraft and control (R451) treated graft. E, epidermis; Scale bar, 400 mm; all pictures are at the same magnification. Mean epidermal cross-sectional area over the full width of grafts was determined by digital image analysis.
Results are presented as mean SEM. Shaded bars, control treatments: R451, random oligonucleotide sequence; solid bars, treatments with oligonucleotides that inhibited IGF-I receptor expression in vitro. indicates a significant difference from the vehicle treated graft (p<0.01, indicates a significant difference from the random sequence (R451) treated graft (p<0.01, Parakeratosis (arrow) was absent in grafts treated with IGF-I receptor AONs (AON #50) but persisted in pregraft and control (PBS) treated graft.
Scale bar, 100 mm.
Figure 32 is a representation showing a reversal of epidermal hyperplasia correlates with reduced IGF-I receptor mRNA in grafted psoriasis lesions treated with antisense oligonucleotides A psoriasis lesion prior to grafting, and after grafting and treatment with IGF-I receptor specific oligonucleotide #27 (AON #27) or random sequence (R451) was immunostained with antibodies to Ki67 to identify proliferating cells. Proliferating cells are indicated by a dark brown nucleus (arrows). Scale bar, 250 mm; all pictures are at the same WO 00/78341 PCT/AU00/00693 18magnification. The same lesion prior to grafting and after oligonucleotide treatment as in was subjected to in situ hybridisation with a "S-labeled cRNA probe complementary to the human IGF-I receptor mRNA. The presence of IGF-I receptor mRNA is indicated by silver grains (tiny black speckles), which are almost eliminated in the epidermis of the lesion treated with the IGF-I receptor-specific oligonucleotide #27 (AON Arrows indicate the basal layer of the epidermis with dermis underneath. Scale bar, 50 /am.
Figure 33 is a representation showing a reduction in IGF-I receptor mRNA in HaCaT keratinocytes following treatment with oligonucleotides. HaCaT cell monolayers grown to 90% confluence in DMEM contianing 10% v/v fetal calf serum were treated with 24 h for two days with 2 ILg/ml GSV lipid alone (GSV) or complexed with 30 nM oligonucleotide.
Total RNA was isolated and analysed for IGF-I receptor and GAPDH mRNA using a commercially availble ribonuclease protection assay kit (RPAII, Ambicon Inc, Austin, Texas).
Band intensity was quantified using ImageQuant software (Molecular Dynamics, Sunnyvale, California).
Figure 34 is a representation showing a reduction in IGF-I receptor protein in HaCaT keratinocytes following treatment with oligonucleotides. HaCaT cell monolayers grown to confluence in DMEM containing 10% v/v fetal calf serum were treated every 24 h for four days with 2 /g/ml GSV lipid alone (GSV) or complexed with 30 nM oligonucleotide.
Cells were lyased in a buffer containing 50 mM HEPES, 150 mM NaCI, 10% v/v gycerol, 1% v/v Triton X-100 and 100 pg/ml aprotinin on ice for 30 mins, then 30 pg of lysate was loaded onto a denaturing 7% w/v polyacrylamide gel followed by transfer onto an Immobilon- P membrane (Millipore, Bedford, Massachusetts). Membranes were incubated with the anti- IGF-I receptor antibody C20 (Sanra Cruz Biotechnology Inc., Santa Cruz, California, ng/ml in 150 mM NaC1, 10 mM Tris-HCI, pH 7.4, 0.1% v/v Tween 20) for 1 h at room temperature and developed using the Vistra ECF western blotting kit (Amersham, Buckinghamshire, England). Band intensity was quantified using ImageQuant software (Molecular Dynamics, Sunnyvale, California).
WO 00/78341 PCT/AU00/00693 -19- Figure 35 is a representation showing a reduction in HaCaT keratinocyte cell number following treatment with oligonucleotides. HaCaT cell monolayers grown to 40% confluence in DMEM containing 10% fetal calf serum were treated every 24 h for three days with 2 ,ug/ml GSV lipid alone (GSV) or complexed with 15 nM oligonucleotide. Cell number was measured every 24 h using the amido black dye binding assay [32].
WO 00/78341 PCT/AU00/00693 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is predicated in part on the use of molecules and in particular genetic molecules and more particularly antisense molecules to down-regulate a growth factor, its receptor and/or growth factor expression facilitating sequences.
Accordingly, one aspect of the present invention contemplates a method for ameliorating the effects of a medical disorder such as a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation or a cell otherwise involved in the said medical disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing a growth factor mediated cell proliferation and/or inflammation and/or other medical disorder.
Growth factor mediated cell proliferation and inflammation are also referred to as epidermal hyperplasias and these and other medical disorders may be mediated by any number of molecules such as but not limited to IGF-I, keratinocyte growth factor (KGF), transforming growth factor-a (TGFa), tumour necrosis factor-a (TNFa), interleukin-l, -6 and 8 (IL-1, IL-4, IL-6 and IL-8, respectively), basic fibroblast growth factor (bFGF) or a combination of one or more of the above. The present invention is particularly described and exemplified with reference to IGF-I and its receptor (IGF-I receptor) and to IGF-I facilitating molecules, IGFBPs, since targeting these molecules according to the methods contemplated herein provides the best results to date. This is done, however, with the understanding that the present invention extends to any growth factor or cytokine-like molecule, a receptor thereof or a facilitating molecule like the IGFBPs involved in skin cell proliferation such as those molecules contemplated above and/or their receptors and/or facilitating molecules therefor.
According to this preferred embodiment, there is provided a method for ameliorating the effects of a medical disorder such as a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin WO 00/78341 PCT/AU00/00693 -21capable of proliferation and/or inflammation or a cell otherwise involved with said medical disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation and/or other medical disorder.
The present invention is particularly described by psoriasis as the proliferative skin disorder.
However, the subject invention extends to a range of proliferative and/or inflammatory skin disorders or epidermal hyperplasias such as but not limited to psoriasis, ichthyosis, pityriasis rubra pilaris seborrhoea, keloids, keratoses, neoplasias and scleroderma, warts, benign growths and cancers of the skin. The present invention extends to a range of other disorders such as neovascularization conditions such as but not limited to hyperneovasularization such as neovascularization of the retina, lining of the brain, skin, hyperproliferation of the inside of blood vessels, kidney disease, atherosclerotic disease, hyperplasias of the gut epithelium or growth factor mediated malignancies such as IGF1mediated malignancies.
Furthermore, down-regulation of IGF-I receptor is useful as adjunctive therapy for epidermal hyperplasia. In accordance with this aspect of the present invention it is known that IGF-I receptor elicits separate intracellular signals which prevent apoptosis In keratinocytes, IGF-I receptor activation has been shown to protect UV-irradiated cells from apoptosis In another cell type, a number of IGF-I receptors expressed by the cells correlated with tumorigenicity and apoptotic resistance Consequently, in accordance with the present invention, by inactivating IGF-I receptor on cells such as epidermal keratinocytes will achieve three important outcomes: Acute epidermal hyperplasia following UV has been suggested to increase the risk of keratinocyte carcinogenic transformation By reducing IGF-I receptor expression in the epidermis, the incidence of epidermal hyperplasia following UV exposure is likely to be reduced leading to an overall acceleration in normalization of the lesion and reduced carcinogenic risk.
WO 00/78341 PCT/AU00/00693 -22- (ii) Inhibition of anti-apoptotic action of IGF-I receptor will enhance the reversal of epidermal thickening and accelerate normalization of differentiation. Topical or injected IGF-I receptor antisense as adjunctive treatment will increase apoptosis in the epidermal layer thereby enhancing the reduction in acanthosis observed in UV treatments.
(iii) Survival of keratinocytes, ie. those which evade apoptosis is likely to occur when cells have damaged DNA. Such mutations may be in the tumor suppressor region.
Consequently, the use of antisense therapy will result in less frequent selection of mutated keratinocytes and therefore reduced incidence of basal cell carcinomas and squamous.
According to this embodiment, there is provided a method for ameliorating the effects of a proliferative and/or inflammatory skin disorder such as psoriasis said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation with effective amounts of UV treatment and a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation.
The UV treatment and nucleic acid molecule or its chemical analogue may be administered in any order or may be done simultaneously. This method is particularly useful in treating psoriasis by combination of UV and antisense therapy. Preferably the antisense therapy is directed to the IGF-I receptor.
In a preferred embodiment, the present invention is directed to a method for ameliorating the effects of psoriasis or other medical disorder, said method comprising contacting proliferating skin or skin capable of proliferation or cells associated with said disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation or ameliorating the medical disorder.
WO 00/78341 PCT/AU00/00693 -23- The present invention extends to any mammal such as but not limited to humans, livestock animals horses, sheep, cows, goats, pigs, donkeys), laboratory test animals rabbits, mice, guinea pigs), companion animals cats, dogs) and captive wild animals. However, the instant invention is particularly directed to proliferative and/or inflammatory skin disorders such as psoriasis in humans as well as medical disorders contemplated above.
The aspects of the subject invention instantly contemplated are particularly directed to the topical application of one or more suitable nucleic molecules capable of inhibiting, reducing or otherwise interfering with IGF-mediated cell proliferation and/or inflammation. More particularly, the nucleic acid molecule targets IGF-I interaction with its receptor.
Conveniently, therefore, the nucleic acid molecule is an antagonist of IGF-I interaction with its receptor. Most conveniently, the nucleic acid molecule antagonist is an antisense molecule to the IGF-I receptor, to IGF-I itself or to a molecule capable of facilitating IGF-I interaction with its receptor such as but not limited to an IGFBP.
Insofar as the invention relates to IGFBPs, the preferred molecules are IGFBP-2, -4, and The most preferred molecules are IGFBP-2 and IGFBP-3.
The nucleotide sequences of IGFBP-2 and IGFBP-3 are set forth in Figures 1 (<400> 1) and 2 respectively. According to a particularly preferred aspect of the present invention, there is provided a nucleic acid molecule comprising at least about ten nucleotides capable of hybridising to, forming a heteroduplex or otherwise interacting with an mRNA molecule directed from a gene corresponding to a genomic form of <400> 1 and/or <400>2 and which thereby reduces or inhibits translation of said mRNA molecule.
Preferably, the nucleic acid molecule is at least about 15 nucleotides in length and more preferably at least about 20-25 nucleotides in length. However, the instant invention extends to any length nucleic acid molecule including a molecule of 100-200 nucleotides in length to correspond to the full length of or near full length of the subject genes.
WO 00/78341 PCT/AU00/00693 -24- The nucleotide sequence of the antisense molecules may correspond exactly to a region or portion of <400>1 or <400>2 or may differ by one or more nucleotide substitutions, deletions and/or additions. It is a requirement, however, that the nucleic acid molecule interact with an mRNA molecule to thereby reduce its translation into active protein.
Examples of potential antisense molecules for IGFBP-2 and IGFBP-3 are those capable of interacting with sequences selected from the lists in Examples 6 and 7, respectively.
The nucleic acid molecules in the form of an antisense molecule may be linear or covalently closed circular and single stranded or partially double stranded. A double stranded molecule may form a triplex with target mRNA or a target gene. The molecule may also be protected from, for example, nucleases, by any number of means such as using a nonionic backbone or a phosphorothioate linkage. A convenient nonionic backbone contemplated herein is ethylphosphotriester linkage or a 2'-O-methylribosyl derivative. A particularly useful modification modifies the DNA backbone by introducing phosphorothioate internucleotide linkages. Alternatively or in addition to the pyrimidine bases are modified by inclusion of a propyne substitution which modification is proposed to enhance duplex stability The present invention extends to any chemical modification to the bases and/or RNA or DNA backbone. Reference to a "chemical analogue" of a nucleic acid molecule includes reference to a modified base, nucleotide, nucleoside or phosphate backbone.
Examples of suitable oligonucleotide analogues are conveniently described in Ts'O et al Further suitable examples of oligonucleotide analogues and chemical modifications are described in references 25 to 31.
Alternatively, the antisense molecules of the present invention may target the IGF-I gene itself or its receptor or a multivalent antisense molecule may be constructed or separate molecules administered which target at least two or an IGFBP, IGF-I and/or IGF-I-receptor. Examples of suitable antisense molecules capable of targetting the IGF-I receptor are those capable of WO 00/78341 PCT/AU00/00693 interacting with sequences selected from the list in Example 8. One particularly useful antisense molecule is ATCTCTCCGCTTCCTTTC (<400> Other particularly useful antisense molecules are: #27 UCCGGAGCCAGACUU #64 CACAGUUGCUGCAAG #78 UCUCCGCUUCCUUUC #28 AGCCCCCACAGCGAG #32 GCCUUGGAGAUGAGC #40 UAACAGAGGUCAGCA #42 GGAUCAGGGACCAGU #46 CGGCAAGCUACACAG
GGCAGGCAGGCACAC
Particularly useful molecules are selected from #27, #64 and #78. In a preferred embodiment these molecules comprise a C-5 propynyl dU, dC phosphorothioate modification.
A particularly preferred embodiment of the present invention contemplates a method of ameliorating the effects of psoriasis or other medical disorder, said method comprising contacting proliferating skin or skin capable of proliferation or cells associated with said medical disorder with an effective amount of one or more nucleic acid molecules or chemical analogues thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation or ameliorating the medical disorder wherein said one or more molecules comprises a polynucleotide capable of interacting with mRNA directed from an IGF-I gene, an IGF-I receptor gene or a gene encoding an IGFBP such as IGFBP-2 and/or IGFBP-3.
Preferably, the nucleic acid molecule are antisense molecules. Particularly useful antisense molecules are: #27 UCCGGAGCCAGACUU #64 CACAGUUGCUGCAAG WO 00/78341 PCT/AU00/00693 -26- #78 UCUCCGCUUCCUUUC #28 AGCCCCCACAGCGAG #32 GCCUUGGAGAUGAGC
UAACAGAGGUCAGCA
#42 GGAUCAGGGACCAGU #46 CGGCAAGCUACACAG
GGCAGGCAGGCACAC
Even more particularly useful molecules are selected from #27, #64 and #78.
In accordance with one aspect of the present invention the nucleic acid molecule is topically applied in aqueous solution or in conjunction with a cream, ointment, oil or other suitable carrier and/or diluent. A single application may be sufficient depending on the severity or exigencies of the condition although more commonly, multiple applications are required ranging from hourly, multi-hourly, daily, multi-daily, weekly or monthly, or in some other suitable time interval. The treatment might comprise solely the application of the nucleic acid molecule or this may be applied in conjunction with other treatments for the skin proliferation and/or inflammatory disorder being treated or for other associated conditions including microbial infection, bleeding and the formation of a variety of rashes.
As an alternative to or in conjunction with antisense therapy, the subject invention extends to the nucleic acid molecule as, or incorporating, a ribozyme including a minizyme to, for example, IGF-I, its receptor or to molecules such as IGFBPs and in particular IGFBP-2 and -3.
Ribozymes are synthetic nucleic acid molecules which possess highly specific endoribonuclease activity. In particular, they comprise a hybridising region which is complementary in nucleotide sequence to at least part of a target RNA. Ribozymes are well described by Haseloff and Gerlach and in International Patent Application No. WO 89/05852. The present invention extends to ribozymes which target mRNA specified by genes encoding IGF-I, its receptor or one or more IGFBPs such as IGFBP-2 and/or IGFBP-3.
WO 00/78341 PCT/AU00/00693 -27- According to this embodiment, there is provided in a particularly preferred aspect a ribozyme comprising a hybridising region and a catalytic region wherein the hybridising region is capable of hybridising to at least part of a target mRNA sequence transcribed from a genomic gene corresponding to (<400>1) or (<400>2) wherein said catalytic domain is capable of cleaving said target mRNA sequence to reduce or inhibit IGF-I mediated cell proliferation and/or inflammation and/or other medical disorders.
Yet another aspect of the present invention contemplates co-suppression to reduce expression or to inhibit translation of an endogenous gene encoding, for example, IGF-I, its receptor, or IGFBPs such as IGFBP-2 and/or In co-suppression, a second copy of an endogenous gene or a substantially similar copy or analogue of an endogenous gene is introduced into a cell following topical administration. As with antisense molecules, nucleic acid molecules defining a ribozyme or nucleic acid molecules useful in co-suppression may first be protected such as by using a nonionic backbone.
The efficacy of the nucleic acid molecules of the present invention can be conveniently tested and screened using an in vitro system comprising a basal keratinocyte cell line. A particularly useful system comprises the HaCaT cell line described by Boukamp et al In one assay, IGF-I is added to an oligonucleotide treated HaCaT cell line. Alternatively, growth of oligonucleotide treated HaCaT cells is observed on a feeder layer of irradiated 3T3 fibroblasts.
Using such in vitro assays, it is observed that antisense oligonucleotides to IGFBP-3, for example, inhibit production of IGFBP-3 by HaCaT cells. Other suitable animal models include the nude mouse/human skin graft model (15; 16) and the "flaky skin" mouse model (17; 18). In the nude mouse model, microdermatome biopsies of psoriasis lesions are taken under local anaesthetic from volunteers then transplanted to congenital athymic (nude) mice. These transplanted human skin grafts maintain the characteristic hyperproliferating epidermis for 6-8 weeks. They are an established model for testing the efficacy of topically applied therapies for psoriasis. In the "flaky skin" mouse model, the fsn/fsn mutation produces mice with skin resembling human psoriasis. This mouse, or another mutant mouse with a similar phenotype is a further in vivo model to test the efficacy of topically applied therapies for psoriasis.
WO 00/78341 PCT/AU00/00693 -28- Another aspect of the present invention contemplates a pharmaceutical composition for topical administration which comprises a nucleic acid molecule capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation such as psoriasis and one or more pharmaceutically acceptable carriers and/or diluents. Preferably, the nucleic acid molecule is an antisense molecule to IGF-I, the IGF-I receptor or an IGFBP such as IGFBP-2 and/or IGFBP-3 or comprises a ribozyme to one or more of these targets or is a molecule suitable for cosuppression of one or more of these targets. The composition may comprise a single species of a nucleic acid molecule capable of targeting one of IGF-I, its receptor or an IGFBP, such as IGFBP-2 or IGFBP-3 or may be a multi-valent molecule capable of targeting two or more of IGF-I, its receptor or an IGFBP, such as IGFBP-2 and/or IGFBP-3.
The nucleic acid molecules may be administered in dispersions prepared in creams, ointments, oil or other suitable carrier and/or diluent such as glycerol, liquid polyethylene glycols and/or mixtures thereof. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for topical use include sterile aqueous solutions (where water soluble) or dispersions and powders for the extemporaneous preparation of topical solutions or dispersions. In all cases, the form is preferably sterile although this is not an absolute requirement and is stable under the conditions of manufacture and storage. 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), suitable mixtures thereof and vegetable oils. 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 ofsuperfactants. The prevention of the action of microorganism can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.
WO 00/78341 PCT/AU00/00693 -29- Topical solutions are prepared by incorporating the nucleic acid molecule compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by where necessary filter sterilization.
The active agent may alternatively be administered by intravenous, subcutaneous, nasal drip, suppository, implant means amongst other suitable routes of administration including intraperitoneal, intramuscular, absorption through epithelial or mucocutaneous linings for example via nasal, oral, vaginal, rectal or gastrointestinal administration. Reference may conveniently be made to reference 24.
As used herein "pharmaceutically acceptable carriers and/or diluents" include any and all solvents, dispersion media, aqueous solutions, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. Conveniently, the nucleic acid molecules of the present invention are stored in freeze-dried form and are reconstituted prior to use.
Yet another aspect of the present invention contemplates the use of a nucleic acid molecule in the manufacture of a medicament for the treatment of proliferative and/or inflammatory skin disorders or other medical disorders mediated by a growth factor. The proliferative and/or inflammatory skin disorder is generally psoriasis or other medical disorders as described above and the nucleic acid molecule targets IGF-I, the IGF-I receptor and/or an IGFBP such as IGFBP- 2 and/or IGFBP-3.
Still a further aspect of the present invention contemplates an agent comprising a nucleic acid molecule as hereinbefore defined useful in the treatment of proliferative and/or inflammatory skin disorders, such as psoriasis or other medical disorder..
WO 00/78341 PCT/AU00/00693 The present invention further contemplates the use of the genetic molecules and in particular the antisense molecules to inhibit the anti-apoptotic activity of IGF-I receptor. Such a use is appropriate for the treatment of certain cancers and as adjunct therapy for epidermal hyperplasia such as in combination with UV treatment.
The present invention is further described by the following non-limiting Examples.
WO 00/78341 PCT/AU00/00693 -31 EXAMPLE 1 The differentiated human keratinocyte cell line, HaCaT was used in the in vitro assay. Cells at passage numbers 33 to 36 were maintained as monolayer cultures in 5% v/v CO 2 at 37"C in Keratinocyte-SFM (Gibco) containing EGF and bovine pituitary extract as supplied. Media containing foetal calf serum were avoided because of the high content ofIGF-I binding proteins in serum.
Feeder layer plates of lethally irradiated 3T3 fibroblasts were prepared exactly as described by Rheinwald and Green EXAMPLE 2 Cells were grown to 4 days post confluence in 2cm 2 wells with daily medium changes of Keratinocyte-SFM, then the medium was changed to DMEM (Cytosystems, Australia), with the following additions: 25mM Hepes, 0.19% w/v, sodium bicarbonate, 0.03% w/v glutamine (Sigma Chemical Co, USA), 50IU/ml penicillin and 50pg/ml streptomycin (Flow Laboratories).
After 24 hours, IGF-I or tlGF-I was added to triplicate wells, at the concentrations indicated, in fresh DMEM containing 0.02% v/v bovine serum albumin (Sigma molecular biology grade) and incubated for a further 21 hours. ['H]-Thymidine (0.1 gCi/well) was then added and the cells incubated for a further 3 hours. The medium was then aspirated and the cells washed once with ice-cold PBS and twice with ice-cold 10% v/v TCA. The TCA-precipitated monolayers were then solubilized with 0.25M NaOH (200pl/well), transferred to scintillation vials and radioactivity determined by liquid scintillation counting (Pharmacia Wallac 1410 liquid scintillation counter).
EXAMPLE 3 HaCaT conditioned medium (250tl) was concentrated by adding 750tl cold ethanol, incubating at -20°C for 2 hours and centrifuging at 16,000g for 20 min at 4°C. The resulting pellet was air dried, resuspended thoroughly in non-reducing Laemmli sample buffer, heated to 90 0 C for minutes and separated on 12% w/v SDS-PAGE according to the method of Laemmli (1970).
Separated proteins were electrophoretically transferred to nitrocellulose membrane (0.45mm, Schleicher and Schuell, Dassel, Germany) in a buffer containing 25mM Tris, 192mM glycine WO 00/78341 PCT/AU00/00693 -32and 20% v/v methanol. IGFBPs were then visualised by the procedure ofHossenlopp et al [11], using 12 sI]-IGF-I, followed by autoradiography. Autoradiographs were scanned in a BioRad Model GS-670 Imaging Densitometer and band densities were determined using the Molecular Analyst program.
EXAMPLE 4 Phosphorothioate oligodeoxynucleotides were synthesised by Bresatec, Adelaide, South Australia, Australia. The following antisense sequences were used: BP3AS2, GCG CCC GCT GCA TGA CGC CTG CAA C a 25mer complementary to the start codon region of the human IGFBP-3 mRNA; BP3AS3, CGG GCG GCT CAC CTG GAG CTG GCG a 24mer complementary to the exon 1/intron 1 splice site; BP3AS4, AGG CGG CTG ACG GCA CTA an 18mer complementary to a region of the coding sequence lacking RNA secondary structure and oligonucleotide-dimer formation (using the computer software "OLIGO for Since BP3AS4 was found to be ineffective at inhibiting IGFBP-3 synthesis, it was used as a control. The following additional control oligonucleotide sequences were used: BP3S, CAG GCG TCA TGC AGC GGG C -3' an 18mer sense control sequence equivalent to the start codon region; BP3AS2NS, CGG AGA TGC CGC ATG CCA GCG CAG G a 25mer randomised sequence with the same GC content as BP3AS2; BP3AS4NS, GAC AGC GTC GGA GCG ATC an 18mer randomised sequence with the same GC content as BP3AS4NS.
Design of the oligonucleotides was based on the human IGFBP-3 cDNA sequence of Spratt et al[12].
Cells were grown to one day post confluence in 2cm 2 wells with daily medium changes of Keratinocyte-SFM, then subjected to daily medium changes of Keratinocyte-SFM for a further 4 days. Daily additions of 0.5ml fresh Keratinocyte-SFM were then continued for a further 7 days, except that at the time of medium addition, 51l oligonucleotide in PBS was added to give the final concentrations indicated, then the wells were shaken to mix the oligonucleotide. After the final addition, cells were incubated for 24 hours and the medium collected for assay of IGFBPs. Cells were then counted after trypsinisation in a Coulter Industrial D Counter, Coulter Bedfordshire, UK. Cell numbers after oligonucleotide treatment differed by less than WO 00/78341 PCT/AU00/00693 -33- EXAMPLE HaCaT cells secrete mainly IGFBP-3 with the only other IGFBP detectable in HaCaT conditioned medium being IGFBP-4 The effect on IGFBP-3 and IGFBP-4 synthesis of antisense oligonucleotides at two concentrations, 5gM and 0.5pM, was tested. Two oligonucleotides were used, BP3AS2 and BP3AS3, directed against the start site and the intron 1/exon 1 splice site, respectively of the IGFBP-3 mRNA. As a control, a sense oligonucleotide corresponding to the start site was used. As shown in Figures 4A and 4B, all oligonucleotides at 5pM caused a significant reduction of IGFBP-3 synthesis compared with untreated cells, however, the two antisense oligonucleotides inhibited IGFBP-3 synthesis of approximately compared to the sense control (Figure 4B). The antisense oligonucleotide directed to the start codon appeared to be more effective of the two, the difference being more apparent at the lower concentration of 0.5pM. The cells of IGFBP-4 secreted by the HaCaT cells make photographic reproduction of the bands on Western ligand blots difficult, however densitometry measurements provide adequate relative quantitation. This resulted in the significant observation that IGFBP-4 levels were unaffected by oligonucleotide addition to the cells, suggesting that the observed inhibitory effects on IGFBP-3 are specific.
To further investigate the inhibitory effects of the more effective of the two antisense oligonucleotides, BP3AS2, inhibition by this oligonucleotide at 0.5pM was compared with a number of control oligonucleotides, including one antisense oligonucleotide to IGFBP-3 that had proved to be ineffective at 0.5pM. As shown in Figures 5A and 5B, BP3AS2 was again inhibitory, resulting in levels of IGFBP-3 of approximately 50% of the most non-specifically inhibitory control oligonucleotide, the randomised equivalent of BP3AS2. The other control oligonucleotides caused no reduction in IGFBP-3 levels at 0.5uM, compared to untreated cells.
Of possible significance is the fact that this control oligonucleotide, BP3AS2NS, like BP3AS2 itself, has the highest potential Tm of the three control oligonucleotides used in this experiment, enhancing the probability of non-specific base pairing with non-target mRNAs. However, the lack of inhibition of IGFBP-4 secretion by BP3AS2 suggests that this oligonucleotide is selective even compared with the most closely related protein likely to be present in this cell line.
WO 00/78341 WO 0078341PCT/AUOO/00693 34 EXAMPLE 6 Antisense oligonucleotides to IGFBP2 may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides:
ATTCGGGGCGAGGGA
TTCGGGGCGAGGGAG
TCGGGGCGAGGOAGG
CGGGGCGAGGGAGGA
GGGGCGAGGGAGGAG
GGGCGAGGGAGGAGG
GGCGAGGGAGGAGGA
GCGAGGGAGGAGGAA
CGAGGGAGGAGGAAG
GAGGGAGGAGGAAGA
AGGGAGGAGGAAGAA
GGGAGGAGGAAGAAG
GGAGGAGGAAGAAGC
GAGGAGGAAGAAGCG
AGGAGGAAGAAGCGG
GGAGGAAGAAGCGGA
GAGGAAGAAGCGGAG
AGGAAGAAGCGGAGG
GGAAGAAGCGGAGGA
GAAGAAGCGGAGGAG
AAGAAGCGGAGGAGG
AGAAGCGGAGGAGGC
GAAGCGGAGGAGGCG
AAGCGGAGGAGGCGG
AGCGGAGGAGGCGGC
GCGGAGGAGGCGGCT
CGGAGGAGGCGGCTC
GGAGGAGGCGGCTCC
GAGGAGGCGGCTCCC
AGGAGGCGGCTCCCG
GGAGGCGGCTCCCGC
GAGGCGGCTCCCGCT
AGGCGGCTCCCGCTC
GGCGGCTCCCGCTCG
GCGGCTCCCGCTCGC
CGGCTCCCGCTCGCA
GGCTCCCGCTCGCAG
GCTCCCGCTCGCAGG
CTCCCGCTCGCAGGG
TCCCGCTCGCAGGGC
CCCGCTCGCAGGGCC
CCGCTCGCAGGGCCG
CGCTCGCAGGGCCGT
GCTCGCAGGGCCGTG
CTCGCAGGGCCGTGC
TCGCAGGGCCGTGCA
CGCAGGGCCGTGCAC
GCAGGGCCGTGCACC
CAGGGCCGTGCACCT
AGGGCCGTGCACCTG
GGGCCGTGCACCTGC
GGCCGTGCACCTGCC
GCCGTGCACCTGCCC
CCGTGCACCTGCCCG
CGTGCACCTGCCCGC
GTGCACCTGCCCGCC
TGCA CCTGCCCGCCC
GCACCTGCCCGCCCG
CACCTGCCCGCCCGC
ACCTGCCCGCCCGCC
CCTGCCCGCCCGCCC
CTGCCCGCCCGCCCG
TGCCCGCCCGCCCGC
GCCCGCCCGCCCGCT
CCCGCCCGCCCGCTC
CCGCCCGCCCGCTCG
CGCCCGCCCGCTCGC
GCCCGCCCGCTCGCT
CCCGCCCGCTCGCTC
CCGCCCGCTCGCTCG
CGCCCGCTCGCTCGC
GCCCGCTCGCTCGCT
CCCGCTCGCTCGCTC
CCGCTCGCTCGCTCG
CGCTCGCTCGCTCGC
GCTCGCTCGCTCGCC
CTCGCTCGCTCGCCC
TCGCTCGCTCGCCCG
CGCTCGCTCGCCCGC
GCTCGCTCGCCCGCC
CTCGCTCGCCCGCCG
TCGCTCGCCCGCCGC
CGCTCGCCCGCCGCG
GCTCGCCCGCCGCGC
CTCGCCCGCCGCGCC
TCGCCCGCCGCGCCG
CGCCCGCCGCGCCGC
GCCCGCCGCGCCGCG
CCCGCCGCGCCGCGC
CCGCCGCGCCGCGCT
CGCCGCGCCGCGCTG
GCCGCGCCGCGCTGC
CCGCGCCGCGCTGCC
CGCGCCGCGCTGCCG
GCGCCGCGCTGCCGA
CGCCGCGCTGCCGAC
GCCGCGCTGCCGACC
CCGCGCTGCCGACCG
CGCGCTGCCGACCGC
GCGCTGCCGACCGCC
CGCTGCCGACCGCCA
GCTGCCGACCGCCAG
CTGCCGACCGCCAGC
TGCCGACCGCCAGCA
GCCGACCGCCAGCAT
CCGACCGCCAGCATG
CGACCGCCAGCATGC
GACCGCCAGCATGCT
ACCGCCAGCATGCTG
CCGCCAGCATGCTGC
CGCCAGCATGCTGCC
GCCAGCATGCTGCCG
C CAGCATGCTGC CGA
CAGCATGCTGCCGAG
AGCATGCTGCCGAGA
GCATGCTGCCGAGAG
CATGCTGCCGAGAGT
ATGCTGCCGAGAGTG
TGCTGCCGAGAGTGG
GCTGCCGAGAGTGGG
CTGCCGAGAGTGGGC
TGCCGAGAGTGGGCT
GCCGAGAGTGGGCTG
CCGAGAGTGGGCTGC
CGAGAGTGGGCTGCC
GAGAGTGGGCTGCCC
AGAGTGGGCTGCCCC
GAGTGGGCTGCCCCG
AGTGGGCTGCCCCGC
GTGGGCTGCCCCGCG
TGGGCTGCCCCGCGC
GGGCTGCCCCGCGCT
GGCTGCCCCGCGCTG
GCTGCCCCGCGCTGC
CTGCCCCGCGCTGCC
TGCCCCGCGCTGCCG
GCCCCGCGCTGCCGC
CCCCGCGCTGCCGCT
WO 00/78341 WO 00/834 1PCT/AUOO/00693
CCCGCGCTGCCGCTG
CCGCGCTGCCGCTGC
CGCGCTGCCGCTGCC
GCGCTGCCGCTGCCG
CGCTGCCGCTGCCGC
GCTGCCGCTGCCGCC
CTGCCGCTGCCGCCG
TGCCGCTGCCGCCGC
GCCGCTGCCGCCGCC
CCGCTGCCGCCGCCG
CGCTGCCGCCGCCGC
GCTGCCGCCGCCGCC
CTGCCGCCGCCGCCG
TGCCGCCGCCGCCGC
GCCGCCGCCGCCGCT
CCGCCGCCGCCGCTG
CGCCGCCGCCGCTGC
GCCGCCGCCGCTGCT
CCGCCGCCGCTGCTG
CGCCGCCGCTGCTGC
GCCGCCGCTGCTGCC
CCGCCGCTGCTGCCG
CGCCGCTGCTGCCGC
GCCGCTGCTGCCGCT
CCGCTGCTGCCGCTG
CGCTGCTGCCGCTGC
GCTGCTGCCGCTGCT
CTGCTGCCGCTGCTG
TGCTGCCGCTGCTGC
GCTGCCGCTGCTGCC
CTGCCGCTGCTGCCG
TGCCGCTGCTGCCGC
GCCGCTGCTGCCGCT
CCGCTGCTGCCGCTG
CGCTGCTGCCGCTGC
GCTGCTGCCGCTGCT
CTGCTGCCGCTGCTG
TGCTGCCGCTGCTGC
GCTGCCGCTGCTGCT
CTGCCGCTGCTGCTG
TGCCGCTGCTGCTGC
GCCGCTGCTGCTGCT
CCGCTGCTGCTGCTG
CGCTGCTGCTGCTGC
GCTGCTGCTGCTGCT
CTGCTGCTGCTGCTA
TGCTGCTGCTGCTAC
GCTGCTGCTGCTACT
CTGCTGCTGCTACTG
TGCTGCTGCTACTGG
GCTGCTGCTACTGGG
CTGCTGCTACTGGGC
TGCTGCTACTGGGCG
GCTGCTACTGGGCGC
CTGCTACTGGGCGCG
TGCTACTGGGCGCGA
GCTACTGGGCGCGAG
CTACTGGGCGCGAGT
TACTGGGCGCGAGTG
ACTGGGCGCGAGTGG
CTGGGCGCGAGTGGC
TGGGCGCGAGTGGCG
GGGCGCGAGTGGCGG
GGCGCGAGTGGCGGC
GCGCGAGTGGCGGCG
CGCGAGTGGCGGCGG
GCGAGTGGCGGCGGC
CGAGTGGCGGCGGCG
GAGTGGCGGCGGCGG
AGTGGCGGCGGCGGC
GTGGCGGCGGCGGCG
TGGCGGCGGCGGCGG
GGCGGCGGCGGCGGG
GCGGCGGCGGCGGGG
CGGCGGCGGCGGGGC
GGCGGCGGCGGGGCG
GCGGCGGCGGGGCGC
CGGCGGCGGQCGCG
GGCGGCGGGGCGCGC
GCGGCGGGGCGCGCG
CGGCGGGGCGCGCGC
GGCGGGGCGCGCGCG
GCGGGGCGCGCGCGG
CGGGGCGCGCGCGGA
GGGGCGCGCGCGGAG
GGGCGCGCGCGGAGG
GGCGCGCGCGGAGGT
GCGCGCGCGGAGGTG
CGCGCGCGGAGGTGC
GCGCGCGGAGGTGCT
CGCGCGGAGGTGCTG
GCGCGGAGGTGCTGT
CGCGGAGGTGCTGTT
GCGGAGGTGCTGTTC
CGGAGGTGCTGTTCC
GGAGGTGCTGTTCCG
GAGGTGCTGTTCCGC
AGGTGCTGTTCCGCT
GGTGCTGTTCCGCTG
GTGCTGTTCCGCTGC
TGCTGTTCCGCTGCC
GCTGTTCCGCTGCCC
CTGTTCCGCTGCCCG
TGTTCCGCTGCCCC
GTTCCGCTGCCCGCC
TTCCGCTGCCCGCCC
TCCGCTGCCCGCCCT
CCGCTGCCCGCCCTG
CGCTGCCCGCCCTGC
GCTGCCCGCCCTGCA
CTGCCCGCCCTGCAC
TGCCCGCCCTGCACA
GCCCGCCCTGCACAC
CCCGCCCTGCACACC
CCGCCCTGCACACCC
CGCCCTGCACACCCG
GCCCTGCACACCCGA
CCCTGCACACCCGAG
CCTGCACACCCGAGC
CTGCACACCCGAGCG
TGCACACCCGAGCGC
GCACACCCGAGCGCC
CACACCCGAGCGCCT
ACACCCGAGCGCCTG
CACCCGAGCGCCTGG
ACCCGAGCGCCTGGC
CCCGAGCGCCTGGCC
CCGAGCGCCTGGCCG
CGAGCGCCTGGCCGC
GAGCGCCTGGCCGCC
AGCGCCTGGCCGCCT
GCGCCTGGCCGCCTG
CGCCTGGCCGCCTGC
GCCTGGCCGCCTGCG
CCTGGCCGCCTGCGG
CTGGCCGCCTGCGGG
TGGCCGCCTGCGGGC
GGCCGCCTGCGGGCC
GCCGCCTGCGGGCCC
CCGCCTGCGGGCCCC
CGCCTGCGGGCCCCC
GCCTGCGGGCCCCCG
CCTGCGGGCCCCCGC
CTGCGGGCCCCCGCC
TGCGGGCCCCCGCCG
GCGGGCCCCCGCCGG
CGGGCCCCCGCCGGT
GGGCCCCCGCCGGTT
GGCCCCCGCCGGTTG
GCCCCCGCCGGTTGC
CCCCCCCCGGTTGCG
CCCCGCCGGTTGCGC
CCCGCCGGTTGCGCC
WO 00/78341 WO 0078341PCT/AUOO/00693 -36-
CCGCCGGTTGCGCCG
CGCCGGTTGCGCCGC
GCCGGTTGCGCCGCC
CCGGTTGCGCCGCCC
CGGTTGCGCCGCCCG
GGTTGCGCCGCCCGC
GTTGCGCCGCCCGCC
TTGCGCCGCCCGCCG
TGCGCCGCCCGCCGC
GCGCCGCCCGCCGCG
CGCCGCCCGCCGCGG
GCCGCCCGCCGCGGT
CCGCCCGCCGCGGTG
CGCCCGCCGCGGTGG
GCCCGCCGCGGTGGC
CCCGCCGCGGTGGCC
CCGCCGCGGTGGCCG
CGCCGCGGTGGCCGC
GCCGCGGTGGCCGCA
CCGCGGTGGCCGCAG
CGCGGTGGCCGCAGT
GCGGTGGCCGCAGTG
CGGTGGCCGCAGTGG
GGTGGCCGCAGTGGC
GTGGCCGCAGTGGCC
TGGCCGCAGTGGCCG
GGCCGCAGTGGCCGG
GCCGCAGTGGCCGGA
CCGCAGTGGCCGGAG
CGCAGTGGCCGGAGG
GCAGTGGCCGGAGGC
CAGTGGCCGGAGGCG
AGTGGCCGGAGGCGC
GTGGCCGGAGGCGCC
TGGCCGGAGGCGCCC
GGCCGGAGGCGCCCG
GCCGGAGGCGCCCGC
CCGGAGGCGCCCGCA
CGGAGGCGCCCGCAT
GGAGGCGCCCGCATG
GAGGCGCCCGCATGC
AGGCGCCCGCATGCC
GGCGCCCGCATGCCA
GCGCCCGCATGCCAT
CGCCCGCATGCCATG
GCCCGCATGCCATGC
CCCGCATGCCATGCG
CCGCATGCCATGCGC
CGCATGCCATGCGCG-
GCATGCCATGCGCGG
CATGCCATGCGCGGA
ATGCCATGCGCGGAG
TGCCATGCGCGGAGC
GCCATGCGCGGAGCT
CCATGCGCGGAGCTC
CATGCGCGGAGCTCG
ATGCGCGGAGCTCGT
TGCGCGGAGCTCGTC
GCGCGGAGCTCGTCC
CGCGGAG CTCGTCCG
GCGGAGCTCGTCCGG
CGGAGCTCGTCCGGG
GGAGCTCGTCCGGGA
GAGCTCGTCCGGGAG
AGCTCGTCCGGGAGC
GCTCGTCCGGGAGCC
CTCGTCCGGGAGCCG
TCGTCCGGGAGCCGG
CGTCCGGGAGCCGGG
GTCCGGGAGCCGGGC
TCCGGGAGCCGGGCT
CCGGGAGCCGGGCTG
CGGGAGCCGGGCTGC
GGGAGCCGGGCTGCG
GGAGCCGGGCTGCGG
GAGCCGGGCTGCGGC
AGCCGGGCTGCGGCT
GCCGGGCTGCGGCTC
CCGGGCTGCGGCTGC
CGGGCTGCGGCTGCT
GGGCTGCGGCTGCTG
GGCTGCGGCTGCTGC
GCTGCGGCTGCTGCT
CTGCGGCTGCTGCTC
TGCGGCTGCTGCTCG
GCGGCTGCTGCTCGG
CGGCTGCTGCTCGGT
GGCTGCTGCTCGGTG
GCTGCTGCTCGGTGT
CTGCTGCTCGGTGTG
TGCTGCTCGGTGTGC
GCTGCTCGGTGTGCG
CTGCTCGGTGTGCGC
TGCTCGGTGTGCGCC
GCTCGGTGTGCGCCC
CTCGGTGTGCGCCCG
TCGGTGTGCGCCCGG
CGGTGTGCGCCCGGC
GGTGTGCGCCCGGCT
GTGTGCGCCCGGCTG
TGTGCGCCCGGCTGG
GTGCGCCCGGCTGGA
TGCGCCCGGCTGGAG
GCGCCCGGCTGGAGG
CGCCCGGCTGGAGGG
GCCCGGCTGGAGGGC
CCCGGCTGGAGGGCG
CCGGCTGGAGGGCGA
CGGCTGGAGGGCGAG
GGCTGGAGGGCGAGG
GCTGGAGGGCGAGGC
CTGGAGGGCGAGGCG
TGGAGGGCGAGGCGT
GGAGGGCGAGGCGTG
GAGGGCGAGGCGTGC
AGGGCGAGGCGTGCG
GGGCGAGGCGTGCGG
GGCGAGGCGTGCGGC
GCGAGGCGTGCGGCG
CGAGGCGTGCGGCGT
GAGGCGTGCGGCGTC
AGGCGTGCGGCGTCT
GGCGTGCGGCGTCTA
GCGTGCGGCGTCTAC
CGTGCGGCGTCTACA
GTGCGGCGTCTACAC
TGCGGCGTCTACACC
GCGGCGTCTACACCC
CGGCGTCTACACCCC
GGCGTCTACACCCCG
GCGTCTACACCCCGC
CGTCTACACCCCGCG
GTCTACACCCCGCGC
TCTACACCCCGCGCT
CTACACCCCGCGCTG
TACACCCCGCGCTGC
ACACCCCGCGCTGCG
CACCCCGCGCTGCGG
ACCCCGCGCTGCGGC
CCCCGCGCTGCGGCC
CCCGCGCTGCGGCCA
CCGCGCTGCGGCCAG
CGCGCTGCGGCCAGG
GCGCTGCGGCCAGGG
CGCTGCGGCCAGGGG
GCTGCGGCCAGGGGC
CTGCGGCCAGGGGCT
TGCGGCCAGGGGCTG
GCGGCCAGGGGCTGC
CGGCCAGGGGCTGCG
GGCCAGGGCCTGCGC
GCCAGGGGCTGCGCT
CCAGGGGCTGCGCTG
WO 00/78341 WO 0078341PCT/AUOO/00693 -37-
CAGGGGCTGCGCTGC
AGGGGCTGCGCTGCT
GGGGCTGCGCTGCTA
GGGCTGCGCTGCTAT
GGCTGCGCTGCTATC
GCTGCGCTGCTATCC
CTGCGCTGCTATCCC
TGCGCTGCTATCCCC
GCGCTGCTATCCCCA
CGCTGCTATCCCCAC
GCTGCTATCCCCACC
CTGCTATCCCCACCC
TGCTATCCCCACCCG
GCTATCCCCACCCGG
CTATCCCCACCCGGG
TATCCCCACCCGGGC
ATCCCCACCCGGGCT
TCCCCACCCGGGCTC
CCCCACCCGGGCTCC
CCCACCCGGGCTCCG
CCACCCGGGCTCCGA
CACCCGGGCTCCGAG
ACCCGGGCTCCGAGC
CCCGGGCTCCGAGCT
CCGGGCTCCGAGCTG
CGGGCTCCGAGCTGC
GGGCTCCGAGCTGCC
GGCTCCGAGCTGCCC
GCTCCGAGCTGCCCC
CTCCGAGCTGCCCCT
TCCGAGCTGCCCCTG
CCGAGCTGCCCCTGC
CGAGCTGCCCCTGCA
GAGCTGCCCCTGCAG
AGCTGCCCCTGCAGG
GCTGCCCCTGCAGGC
CTGCCCCTGCAGGCG
TGCCCCTGCAGGCGC
GCCCCTGCAGGCGCT
CCCCTGCAGGCGCTG
CCCTGCAGGCGCTGG
CCTGCAGGCGCTGGT
CTGCAGGCGCTGGTC
TGCAGGCGCTGGTCA
GCAGGCGCTGGTCAT
CAGGCGCTGGTCATG
AGGCGCTGGTCATGG
GGCGCTGGTCATGGG
GCGCTGGTCATGGGC
CGCTGGTCATGGGCG
GCTGGTCATGGGCGA
CTGGTCATGGGCGAG
TGGTCATGGGCGAGG
GGTCATGGGCGAGGG
GTCATGGGCGAGGGC
TCATGGGCGAGGGCA
CATGGGCGAGGGCAC
ATGGGCGAGGGCACT
TGGGCGAGGGCACTT
GGGCGAGGGCACTTG
GGCGAGGGCACTTGT
GCGAGGGCACTTGTG
CGAGGGCACTTGTGA
GAGGGCACTTGTGAG
AGGGCACTTGTGAGA
GGGCACTTGTGAGAA
GGCACTTGTGAGAAG
GCACTTGTGAGAAGC
CACTTGTGAGAAGCG
ACTTGTGAGAAGCGC
CTTGTGAGAAGCGCC
TTGTGAGAAGCGCCG
TGTGAGAAGCGCCGG
GTGAGAAGCGCCGGG
TGAGAAGCGCCGGGA
GAGAAGCGCCGGGAC
AGAAGCGCCGGGACG
GAAGCGCCGGGACGC
AAGCGCCGGGACGCC
AGCGCCGGGACGCCG
GCGCCGGGACGCCGA
CGCCGGGACGCCGAG
GCCGGGACGCCGAGT
CCGGOACGCCGAGTA
CGGGACGCCGAGTAT
GGGACGCCGAGTATG
GGACGCCGAGTATGG
GACGCCGAGTATGGC
ACGCCGAGTATGGCG
CGCCGAGTATGGCGC
GCCGAGTATGGCGCC
CCGAGTATGGCGCCA
CGAGTATGGCGCCAG
GAGTATGGCGCCAGC
AGTATGGCGCCAGCC
GTATGGCGCCAGCCC
TATGGCGCCAGCCCG
ATGGCGCCAGCCCGG
TGGCGCCAGCCCGGA
GGCGCCAGCCCGGAG
GCGCCAGCCCGGAGC
CGCCAGCCCGGAGCA
GCCAGCCCGGAGCAG
CCAGCCCGGAGCAGG
CAGCCCGGAGCAGGT
AGCCCGGAGCAGGTT
GCCCGGAGCAGGTTG
CCCGGAGCAGGTTGC
CCGGAGCAGGTTGCA
CGGAGCAGGTTGCAG
GGAGCAGGTTGCAGA
GAGCAGGTTGCAGAC
AGCAGGTTGCAGACA
GCAGGTTGCAGACAA
CAGGTTGCAGACAAT
AGGTTGCAGACAATG
GGTTGCAGACAATGG
GTTGCAGACAATGGC
TTGCAGACAATGGCG
TGCAGACAATGGCGA
GCAGACAATGGCGAT
CAGACAATGGCGATG
AGACAATGGCGATGA
GACAATGGCGATGAC
ACAATGGCGATGACC
CAATGGCGATGACCA
AATGGCGATGACCAC
ATGGCGATGACCACT
TGGCGATGACCACTC
GGCGATGACCACTCA
GCGATGACCACTCAG
CGATGACCACTCAGA
GATGACCACTCAGAA
ATGACCACTCAGAAG
TGACCACTCAGAAGG
GACCACTCAGAAGGA
ACCACTCAGAAGGAG
CCACTCAGAAGGAGG
CACTCAGAAGGAGGC
ACTCAGAAGGAGGCC
CTCAGAAGGAGGCCT
TCAGAAGGAGGCCTG
CAGAAGGAGGCCTGG
AGAAGGAGGCCTGGT
GAAGGAGGCCTGGTG
AAGGAGGCCTGGTGG
AGGAGGCCTGGTGGA
GGAGGCCTGGTGGAG
GAGGCCTGGTGGAGA
AGGCCTGGTGGAGAA
GGCCTGGTGGAGAAC
GCCTGGTGGAGAACC
CCTGGTGGAGAACCA
WO 00/78341 WO 0078341PCT/AUOO/00693 38
CTGGTGGAGAACCAC
TGGTGGAGAACCACG
GGTGGAGAACCACGT
GTGGAGAACCACGTG
TGGAGAACCACGTGG
GGAGAACCACGTGGA
GAGAACCACGTGGAC
AGAACCACGTGGACA
GAACCACGTGGACAG
AACCACGTGGACAGC
ACCACGTGGACAGCA
CCACGTGGACAGCAC
CACGTGGACAGCACC
ACGTGGACAGCACCA
CGTGGACAGCACCAT
GTGGACAGCACCATG
TGGACAGCACCATGA
GGACAGCACCATGAA
GACAGCACCATGAAC
ACAGCACCATGAACA
CAGCACCATGAACAT
AGCACCATGAACATG
GCACCATGAACATGT
CACCATGAACATGTT
ACCATGAACATGTTG
CCATGAACATGTTGG
CATGAACATGTTGGG
ATGAACATGTTGGGC
TGAACATGTTGGGCG
GAACATGTTGGGCGG
AACATGTTGGGCGGG
ACATGTTGGGCGGGG
CATGTTGGGCCGGGGG
ATGTTGGGCGGGGGA
TGTTGGGCGGGGGAG
GTTGGGCGGGGGAGG
TTGGGCGGGGGAGGC
TGGGCGGGGGAGGCA
GGGCGGGGGAGGCAG
GGCGGGGGAGGCAGT
GCGGGGGAGGCAGTG
CGGGGGAGGCAGTGC
GGGGGAGGCAGTGCT
GGGGAGGCAGTGCTG
GGGAGGCAGTGCTGG
GGAGGCAGTGCTGGC
GAGGCAGTGCTGGCC
AGGCAGTGCTGGCCG
GGCAGTGCTGGCCGG
GCAGTGCTGGCCGGA
CAGTGCTGGCCGGAA
AGTGCTGGCCGGAAG
GTGCTGGCCGGAAGC
TGCTGGCCGGAAGCC
GCTGGCCGGAAGCCC
CTGGCCGGAAGCCCC
TGGCCGGAAGCCCCT
GGCCGGAAGCCCCTC
GCCGGAAGCCCCTCA
CCGGAAGCCCCTCAA
CGGAAGCCCCTCAAG
GGAAGCCCCTCAAGT
GAAGCCCCTCAAGTC
AAGCCCCTCAAGTCG
AGCCCCTCAAGTCGG
GCCCCTCAAGTCGGG
CCCCTCAAGTCGGGT
CCCTCAAGTCGGGTA
CCTCAAGTCGGGTAT
CTCAAGTCGGGTATG
TCAAGTCGGGTATGA
CAAGTCGGGTATGAA
AAGTCGGGTATGAAG
AGTCGGGTATGAAGG
GTCGGGTATGAAGGA
TCGGGTATGAAGGAG
CGGGTATGAAGGAGC
GGGTATGAAGGAGCT
GGTATGAAGGAGCTG
GTATGAAGGAGCTGG
TATGAAGGAGCTGGC
ATGAAGGAGCTGGCC
TGAAGGAGCTGGCCG
GAAGGAGCTGGCCGT
AAGGAGCTGGCCGTG
AGGAGCTGGCCGTGT
GGAGCTGGCCGTGTT
GAGCTGGCCGTGTTC
AGCTGGCCGTGTTCC
GCTGGCCGTGTTCCG
CTGGCCGTGTTCCGG
TGGCCGTGTTCCGGG
GGCCGTGTTCCGGGA
GCCGTGTTCCGGGAG
CCGTGTTCCGGGAGA
CGTGTTCCGGGAGAA
GTGTTCCGGGAGAAG
TGTTCCGGGAGAAGG
GTTCCGGGAGAAGGT
TTCCGGGAGAAGGTC
TCCGGGAGAAGGTCA
CCGGGAGAAGGTCAC
CGGGAGAAGGTCACT
GGGAGAAGGTCACTG
GGAGAAGGTCACTGA
GAGAAGGTCACTGAG
AGAAGGTCACTGAGC
GAAGGTCACTGAGCA
AAGGTCACTGAGCAG
AGGTCACTGAGCAGC
GGTCACTGAGCAGCA
GTCACTGAGCAGCAC
TCACTGAGCAGCACC
CACTGAGCAGCACCG
ACTGAGCAGCACCGG
CTGAGCAGCACCGGC
TGAGCAGCACCGGCA
GAGCAGCACCGGCAG
AGCAGCACCGGCAGA
GCAGCACCGGCAGAT
CAGCACCGGCAGATG
AGCACCGGCAGATGG
GCACCGGCAGATGGG
CACCGGCAGATGGGC
ACCGGCAGATGGGCA
CCGGCAGATGGGCAA
CGGCAGATGGGCAAG
GGCAGATGGGCAAGG
GCAGATGGGCAAGGG
CAGATGGGCAAGGGT
AGATGGGCAAGGGTG
GATGGGCAAGGGTGG
ATGGGCAAGGGTGGC
TGGGCAAGGGTGGCA
GGGCAAGGGTGGCAA
GGCAAGGGTGGCAAG
GCAAGGGTGGCAAGC
CAAGGGTGGCAAGCA
AAGGGTGGCAAGCAT
AGGGTGGCAAGCATC
GGGTGGCAAGCATCA
GGTGGCAAGCATCAC
GTGGCAAGCATCACC
TGGCAAGCATCACCT
GGCAAGCATCACCTT
GCAAGCATCACCTTG
CAAGCATCACCTTGG
AAGCATCACCTTGGC
AGCATCACCTTGGCC
GCATCACCTTGGCCT
CATCACCTTGGCCTG
ATCACCTTGGCCTGG
TCACCTTGGCCTGGA
WO 00/78341 WO 0/784 1PCT/AIUOO/00693 39
CACCTTGGCCTGGAG
ACCTTGGCCTGGAGG
CCTTGGCCTGGAGGA
CTTGGCCTGGAGGAG
TTGGCCTGGAGGAGC
TGGCCTGGAGGAGCC
GGCCTGGAGGAGCCC
GCCTGGAGGAGCCCA
CCTGGAGGAGCCCAA
CTGGAGGAGCCCAAG
TGGAGGAGCCCAAGA
GGAGGAGCCCAAGAA
GAGGAGCCCAAGAAG
AGGAGCCCAAGAAGC
GGAGCCCAAGAAGCT
GAGCCCAAGAAGCTG
AGCCCAAGAAGCTGC
GCCCAAGAAGCTGCG
CCCAAGAAGCTGCGA
CCAAGAAGCTGCGAC
CAAGAAGCTGCGACC
AAGAAGCTGCGACCA
AGAAGCTGCGACCAC
GAAGCTGCGACCACC
AAGCTGCGACCACCC
AGCTGCGACCACCCC
GCTGCGACCACCCCC
CTGCGACCACCCCCT
TGCGACCACCCCCTG
GCGACCACCCCCTGC
CGACCACCCCCTGCC
GACCACCCCCTGCCA
ACCACCCCCTGCCAG
CCACCCCCTGCCAGG
CACCCCCTGCCAGGA
ACCCCCTGCCAGGAC
CCCCCTGCCAGGACT
CCCCTGCCAGGACTC
CCCTGCCAGGACTCC
CCTGCCAGGACTCCC
CTGCCAGGACTCCCT
TGCCAGGACTCCCTG
GCCAGGACTCCCTGC
CCAGGACTCCCTGCC
CAGGACTCCCTGCCA
AGGACTCCCTGCCAA
GGACTCCCTGCCAAC
GACTCCCTGCCAACA
ACTCCCTGCCAACAG
CTCCCTGCCAACAGG
TCCCTGCCAACAGGA
CCCTGCCAACAGGAA
CCTGCCAACAGGAAC
CTGCCAACAGGAACT
TGCCAACAGGAACTG
GCCAACAGGAACTGG
CCAACAGGAACTGGA
CAACAGGAACTGGAC
AACAGGAACTGGACC
ACAGGAACTGGACCA
CAGGAACTGGACCAG
AGGAACTGGACCAGG
GGAACTGGACCAGGT
GAACTGGACCAGGTC
AACTGGACCAGGTCC
ACTGGACCAGGTCCT
CTGGACCAGGTCCTG
TGGACCAGGTCCTGG
GGACCAGGTCCTGGA
GACCAGGTCCTGGAG
ACCAGGTCCTGGAGC
CCAGGTCCTGGAGCG
CAGGTCCTGGAGCGG
AGGTCCTGGAGCGGA
GGTCCTGGAGCGGAT
GTCCTGGAGCGGATC
TCCTGGAGCGGATCT
CCTGGAGCGGATCTC
CTGGAGCGGATCTCC
TGGAGCGGATCTCCA
GGAGCGGATCTCCAC
GAGCGGATCTCCACC
AGCGGATCTCCACCA
GCGGATCTCCACCAT
CGGATCTCCACCATG
GGATCTCCACCATGC
GATCTCCACCATGCG
ATCTCCACCATGCGC
TCTCCACCATGCGCC
CTCCACCATGCGCCT
TCCACCATGCGCCTT
CCACCATGCGCCTTC
CACCATGCGCCTTCC
ACCATGCGCCTTCCG
CCATGCGCCTTCCGG
CATGCGCCTTCCGGA
ATGCGCCTTCCGGAT
TGCGCCTTCCGGATG
GCGCCTTCCGGATGA
CGCCTTCCGGATGAG
GCCTTCCGGATGAGC
CCTTCCGGATGAGCG
CTTCCGGATGAGCGG
TTCCGGATGAGCGGG
TCCGGATGAGCGGGG
CCGGATGAGCGGGGC
CGGATGAGCGGGGCC
GGATGAGCGGGGCCC
GATGAGCGGGGCCCT
ATGAGCGGGGCCCTC
TGAGCGGGGCCCTCT
GAGCGGGGCCCTCTG
AGCGGGGCCCTCTGG
GCGGGGCCCTCTGGA
CGGGGCCCTCTGGAG
GGGGCCCTCTGGAGC
GGGCCCTCTGGAGCA
GGCCCTCTGGAGCAC
GCCCTCTGGAGCACC
CCCTCTGGAGCACCT
CCTCTGGAGCACCTC
CTCTGGAGCACCTCT
TCTGGAGCACCTCTA
CTGGAGCACCTCTAC
TGGAGCACCTCTACT
GGAGCACCTCTACTC
GAGCACCTCTACTCC
AGCACCTCTACTCCC
GCACCTCTACTCCCT
CACCTCTACTCCCTG
ACCTCTACTCCCTGC
CCTCTACTCCCTGCA
CTCTACTCCCTGCAC
TCTACTCCCTGCACA
CTACTCCCTGCACAT
TACTCCCTGCACATC
ACTCCCTGCACATCC
CTCCCTGCACATCCC
TCCCTGCACATCCCC
CCCTGCACATCCCCA
CCTGCACATCCCCAA
CTGCACATCCCCAAC
TGCACATCCCCAACT
GCACATCCCCAACTG
CACATCCCCAACTGT
ACATCCCCAACTGTG
CATCCCCAACTGTGA
ATCCCCAACTGTGAC
TCCCCAACTGTGACA
CCCCAACTGTGACAA
CCCAACTGTGACAAG
CCAACTGTGACAAGC
CAACTGTGACAAGCA
WO 00/78341 WO 0078341PCT/AUOO/00693 40
AACTGTGACAAGCAT
ACTGTGACAAGCATG
CTGTGACAAGCATGG
TGTGACAAGCATGGC
GTGACAAGCATGGCC
TGACAAGCATGGCCT
GACAAGCATGGCCTG
ACAAGCATGGCCTGT
CAAGCATGGCCTGTA
AAGCATGGCCTGTAC
AGCATGGCCTGTACA
GCATGGCCTGTACAA
CATGGCCTGTACAAC
ATGGCCTGTACAACC
TGGCCTGTACAACCT
GGCCTGTACAACCTC
GCCTGTACAACCTCA
CCTGTACAACCTCAA
CTGTACAACCTCAAA
TGTACAACCTCAAAC
GTACAACCTCAAACA
TACAACCTCAAACAG
ACAACCTCAAACAGT
CAACCTCAAACAGTG
AACCTCAAAC-AGTGC
ACCTCAAACAGTGCA
CCTCAAACAGTGCAA
CTCAAACAGTGCAAG
TCAAACAGTGCAAGA
CAAACAGTGCAAGAT
AAACAGTGCAAGATG
AACAGTGCAACATGT
ACAGTGCAAGATGTC
CAGTGCAAGATGTCT
AGTGCAAGATGTCTC
GTGCAAGATGTCTCT
TGCAAGATGTCTCTG
GCAAGATGTCTCTGA
CAAGATGTCTCTGAA
AAGATGTCTCTGAAC
AGATGTCTCTGAACG
GATGTCTCTGAACGG
ATGTCTCTGAACGGG
TGTCTCTGAACGGGC
GTCTCTGAACGGGCA
TCTCTGAACGGGCAG
CTCTGAACGGGCAGC
TCTGAACGGGCAGCG
CTGAACGGGCAGCGT
TGAACGGGCAGCGTG
GAACGGGCAGCGTGG
AACGGGCAGCGTGGG
ACGGGCAGCGTGGGG
CGGGCAGCGTGGGGA
GGGCAGCGTGGGGAG
GGCAGCGTGGGGAGT
GCAGCGTGGGGAGTG
CAGCGTGGGGAGTGC
AGCGTGGGGAGTGCT
GCGTGGGGAGTGCTG
CGTGGGGAGTGCTGG
GTGGGGAGTGCTGGT
TGGGGAGTGCTGGTG
GGGGAGTGCTGGTGT
GGGAGTGCTGGTGTG
GGAGTGCTGGTGTGT
GAGTGCTGGTGTGTG
AGTGCTGGTGTGTGA
GTGCTGGTGTGTGAA
TGCTGGTGTGTGAAC
GCTGGTGTGTGAACC
CTGGTGTGTGAACCC
TGGTGTGTGAACCCC
GGTGTGTGAACCCCA
GTGTGTGAACCCCAA
TGTGTGAACCCCAAC
GTGTGAACCCCAACA
TGTGAACCCCAACAC
GTGAACCCCAACACC
TGAACCCCAACACCG
GAACCCCAACACCGG
AACCCCAACACCGGG
ACCCCAACACCGGGA
CCCCAACACCGGGAA
CCCAACACCGGGAAG
CCAACACCGGGAAGC
CAACACCGGGAAGCT
AACACCGGGAAGCTG
ACACCGGGAAGCTGA
CACCGGGAAGCTGAT
ACCGGGAAGCTGATC
CCGGGAAGCTGATCC
CGGGAAGCTGATCCA
GGGAAGCTGATCCAG
GGAAGCTGATCCAGG
GAAGCTGATCCAGGG
AAGCTGATCCAGGGA
AGCTGATCCAGGGAG
GCTGATCCAGGGAGC
CTGATCCAGGGAGCC
TGATCCAGGGAGCCC
GATCCAGGGAGCCCC
ATCCAGGGAGCCCCC
TCCAGGGAGCCCCCA
CCAGGGAGCCCCCAC
CAGGGAGCCCCCACC
AGGGAGCCCCCACCA
GGGAGCCCCCACCAT
GGAGCCCCCACCATC
GAGCCCCCACCATCC
AGCCCCCACCATCCG
GCCCCCACCATCCGG
CCCCCACCATCCGGG
CCCCACCATCCGGGG
CCCACCATCCGGGGG
CCACCATCCGGGGGG
CACCATCCGGGGGGA
ACCATCCGGGGGGAC
CCATCCGGGGGGACC
CATCCGGGGGGACCC
ATCCGGGGGGACCCC
TCCGGGGGGACCCCG
CCGGGGGGACCCCGA
CGGGGGGACCCCGAG
GGGGGGACCCCGAGT
GGGGGACCCCGAGTG
GGGGACCCCGAGTGT
GGGACCCCGAGTGTC
GGACCCCGAGTGTCA
GACCCCGAGTGTCAT
ACCCCGAGTGTCATC
CCCCGAGTGTCATCT
CCCGAGTGTCATCTC
CCGAGTGTCATCTCT
CGAGTGTCATCTCTT
GAGTGTCATCTCTTC
AGTGTCATCTCTTCT
GTGTCATCTCTTCTA
TGTCATCTCTTCTAC
GTCATCTCTTCTACA
TCATCTCTTCTACAA
CATCTCTTCTACAAT
ATCTCTTCTACAATG
TCTCTTCTACAATGA
CTCTTCTACAATGAG
TCTTCTACAATGAGC
CTTCTACAATGAGCA
TTCTACAATGAGCAG
TCTACAATGAGCAGC
CTACAATGAGCAGCA
TACAATGAGCAGCAG
ACAATGAGCAGCAGG
CAATGAGCAGCAGGA
WO 00/78341 WO 00/834 1PCT/AUOO/00693 41-
AATGAGCAGCAGGAG
ATGAGCAGCAGGAGG
TGAGCAGCAGGAGGC
GAGCAGCAGGAGGCT
AGCAGCAGGAGGCTT
GCAGCAGGAGGCTTG
CAGCAGGAGGCTTGC
AGCAGGAGGCTTGCG
GCAGGAGGCTTGCGG
CAGGAGGCTTGCGGG
AGGAGGCTTGCGGGG
GGAGGCTTGCGGGGT
GAGGCTTGCGGGGTG
AGGCTTGCGGGGTGC
GGCTTGCGGGGTGCA
GCTTGCGGGGTGCAC
CTTGCGGGGTGCACA
TTGCGGGGTGCACAC
TGCGGGGTGCACACC
GCGGGGTGCACACCC
CGGGGTGCACACCCA
GGGGTGCACACCCAG
GGGTGCACACCCAGC
GGTGCACACCCAGCG
GTGCACACCCAGCGG
TGCACACCCAGCGGA
GCACACCCAGCGGAT
CACACCCAGCGGATG
ACACCCAGCGGATGC
CACCCAGCGGATGCA
ACCCAGCGGATGCAG
CCCAGCGGATGCAGT
CCAGCGGATGCAGTA
CAGCGGATGCAGTAG
AGCGGATGCAGTAGA
GCGGATGCAGTAGAC
CGGATGCAGTAGACC
GGATGCAGTAGACCG
GATGCAGTAGACCGC
ATGCAGTAGACCGCA
TGCAGTAGACCGCAG
GCAGTAGACCGCAGC
CAGTAGACCGCAGCC
AGTAGACCGCAGCCA
GTAGACCGCAGCCAG
TAGACCGCAGCCAGC
AGACCGCAGCCAGCC
GACCGCAGCCAGCCG
ACCGCAGCCAGCCGG
CCGCAGCCAGCCGGT
CGCAGCCAGCCGGTG
GCAGCCAGCCGGTGC
CAGCCAGCCGGTGCC
AGCCAGCCGGTGCCT
GCCAGCCGGTGCCTG
CCAGCCGGTGCCTGG
CAGCCGGTGCCTGGC
AGCCGGTGCCTGGCG
GCCGGTGCCTGGCGC
CCGGTGCCTGGCGCC
CGGTGCCTGGCGCCC
GGTGCCTGGCGCCCC
GTGCCTGGCGCCCCT
TGCCTGGCGCCCCTG
GCCTGGCGCCCCTGC
CCTGGCGCCCCTGCC
CTGGCGCCCCTGCCC
TGGCGCCCCTGCCCC
GGCGCCCCTGCCCCC
GCGCCCCTGCCCCCC
CGCCCCTGCCCCCCG
GCCCCTGCCCCCCGC
CCCCTGCCCCCCGCC
CCCTGCCCCCCGCCC
CCTGCCCCCCGCCCC
CTGCCCCCCGCCCCT
TGCCCCCCGCCCCTC
GCCCCCCGCCCCTCT
CCCCCCGCCCCTCTC
CCCCCGCCCCTCTCC
CCCCGCCCCTCTCCA
CCCGCCCCTCTCCAA
CCGCCCCTCTCCAAA
CGCCCCTCTCCAAAC
GCCCCTCTCCAAACA
CCCCTCTCCAAACAC
CCCTCTCCAAACACC
CCTCTCCAAACACCG
CTCTCCAAACACCGG
TCTCCAAACACCGGC
CTCCAAACACCGGCA
TCCAAACACCGGCAG
CCAAACACCGGCAGA
CAAACACCGGCAGAA
AAACACCGGCAGAAA
AACACCGGCAGAAAA
ACACCGGCAGAAAAC
CACCGGCAGAAAACG
ACCGGCAGAAAACCG
CCGGCAGAAAACGGA
CGGCAGAAAACGGAG
GGCAGAAAACGGAGA
GCAGAAAACGGAGAG
CAGAAAACGGAGAGT
AGAAAACGGAGAGTG
GAAAACGGAGAGTGC
AAAACGGAGAGTGCT
AAACGGAGAGTGCTT
AACGGAGAGTGCTTG
ACGGAGAGTGCTTGG
CGGAGAGTGCTTGGG
GGAGAGTGCTTGGGT
GAGAGTGCTTGGGTG
AGAGTGCTTGGGTGG
GAGTGCTTGGGTGGT
AGTGCTTGGGTGGTG
GTGCTTGGGTGGTGG
TGCTTGGGTGGTGGG
GCTTGGGTGGTGGGT
CTTGGGTGGTGGGTG
TTGGGTGGTGGGTGC
TGGGTGGTGGGTGCT
GGGTGGTGGGTGCTG
GGTGGTGGGTGCTGG
GTGGTGGGTGCTGGA
TGGTGGGTGCTGGAG
GGTGGGTGCTGGAGG
GTGGGTGCTGGAGGA
TGGGTGCTGGAGGAT
GGGTGCTGGAGGATT
GGTGCTGGAGGATTT
GTGCTGGAGGATTTT
TGCTGGAGGATTTTC
GCTGGAGGATTTTCC
CTGGAGGATTTTCCA
TGGAGGATTTTCCAG
GGAGGATTTTCCAGT
GAGGATTTTCCAGTT
AGGATTTTCCAGTTC
GGATTTTCCAGTTCT
GATTTTCCAGTTCTG
ATTTTCCAGTTCTGA
TTTTCCAGTTCTGAC
TTTCCAGTTCTGACA
TTCCAGTTCTGACAC
TCCAGTTCTGACACA
CCAGTTCTGACACAC
CAGTTCTGACACACG
AGTTCTGACACACGT
GTTCTGACACACGTA
TTCTGACACACGTAT
TCTGACACACGTATT
CTGACACACGTATTT
WO 00/78341 WO 0078341PCT/AUOO/00693 42
TGACACACGTATTTA
GACACACGTATTTAT
ACACACGTATTTATA
CACACGTATTTATAT
ACACGTATTTATATT
CACGTATTTATATTT
ACGTATTTATATTTG
CGTATTTATATTTGG
GTATTTATATTTGGA
TATTTATATTTGGAA
ATTTATATTTGGAAA
TTTATATTTGGAAAG
TTATATTTGGAAAGA
TATATTTGGAAAGAG
ATATTTGGAAAGAGA
TATTTGGAAAGAGAC
ATTTGGAAAGAGACC
TTTGGAAAGAGACCA
TTGGAAAGAGACCAG
TGGAAAGAGACCAGC
GGAAAGAGACCAGCA
GAAAGAGACCAGCAC
AAAGAGACCAGCACC
AAGAGACCAGCACCG
AGAGACCAGCACCGA
GAGACCAGCACCGAG
AGACCAGCACCGAGC
GACCAGCACCGAGCT
ACCAGCACCGAGCTC
CCAGCACCGAGCTCG
CAGCACCGAGCTCGG
AGCACCGAGCTCGGC
GCACCGAGCTCGGCA
CACCGAGCTCGGCAC
ACCGAGCTCGGCACC
CCGAGCTCGGCACCT
CGAGCTCGGCACCTC
GAGCTCGGCACCTCC
AGCTCGGCACCTCCC
GCTCGGCACCTCCCC
CTCGGCACCTCCCCG
TCGGCACCTCCCCGG
CGGCACCTCCCCGGC
GGCACCTCCCCGGCC
GCACCTCCCCGGCCT
CACCTCCCCGGCCTC
ACCTCCCCGGCCTCT
CCTCCCCGGCCTCTC
CTCCCCGGCCTCTCT
TCCCCGGCCTCTCTC
CCCCGGCCTCTCTCT
CCCGGCCTCTCTCTT
CCGGCCTCTCTCTTC
CGGCCTCTCTCTTCC
GGCCTCTCTCTTCCC
GCCTCTCTCTTCCCA
CCTCTCTCTTCCCAG
CTCTCTCTTCCCAGC
TCTCTCTTCCCAGCT
CTCTCTTCCCAGCTG
TCTCTTCCCAGCTGC
CTCTTCCCAGCTGCA
TCTTCCCAGCTGCAG
CTTCCCAGCTGCAGA
TTCCCAGCTGCAGAT
TCCCAGCTGCAGATG
CCCAGCTGCAGATGC
CCAGCTGCAGATGCC
CAGCTGCAGATGCCA
AGCTGCAGATGCCAC
GCTGCAGATGCCACA
CTGCAGATGCCACAC
TGCAGATGCCACACC
GCAGATGCCACACCT
CAGATGCCACACCTG
AGATGCCACACCTGC
GATGCCACACCTGCT
ATGCCACACCTGCTC
TGCCACACCTGCTCC
GCCACACCTGCTCCT
CCACACCTGCTCCTT
CACACCTGCTCCTTC
ACACCTGCTCCTTCT
CACCTGCTCCTTCTT
ACCTGCTCCTTCTTG
CCTGCTCCTTCTTGC
CTGCTCCTTCTTGCT
TGCTCCTTCTTGCTT
GCTCCTTCTTGCTTT
CTCCTTCTTGCTTTC
TCCTTCTTGCTTTCC
CCTTCTTGCTTTCCC
CTTCTTGCTTTCCCC
TTCTTGCTTTCCCCG
TCTTGCTTTCCCCGG
CTTGCTTTCCCCGGG
TTGCTTTCCCCGGGG
TGCTTTCCCCGGGGG
GCTTTCCCCGGGGGA
CTTTCCCCGGGGGAG
TTTCCCCGGGGGAGG
TTCCCCGGGGGAGGA
TCCCCGGGGGAGGAA
CCCCGGGGGAGGAAG
CCCGGGGGAGGAAGG
CCGGGGGAGGAAGGG
CGGGGGAGGAAGGGG
GGGGGAGGAAGGGGG
GGGGAGGAAGGGGGT
GGGAGGAAGGGGGTT
GGAGGAAGGGGGTTG
GAGGAAGGGGGTTGT
AGGAAGGGGGTTGTG
GGAAGGGGGTTGTGG
GAAGGGGGTTGTGGT
AAGGGGGTTGTGGTC
AGGGGGTTGTGGTCG
GGGGGTTGTGGTCGG
GGGGTTGTGGTCGGG
GGGTTGTGGTCGGGG
GGTTGTGGTCGGGGA
GTTGTGGTCGG.GGAG
TTGTGGTCGGGGAGC
TGTGGTCGGGGAGCT
GTGGTCGGGGAGCTG
TGGTCGGGGAGCTGG
GGTCGGGGAGCTGGG
GTCGGGGAGCTGGGG
TCGGGGAGCTGGGGT
CGGGGAGCTGGGGTA
GGGGAGCTGGGGTAC
GGGAGCTGGGGTACA
GGAGCTGGGGTACAG
GAGCTGGGGTACAGG
AGCTGGGGTACAGGT
GCTGGGGTACAGGTT
CTGGGGTACAGGTTT
TGGGGTACAGGTTTG
GGGGTACAGGTTTGG
GGGTACAGGTTTGGG
GGTACAGGTTTGGGG
GTACAGGTTTGGGGA
TACAGGTTTGGGGAG
ACAGGTTTGGGGAGG
CAGGTTTGGGGAGGG
AGGTTTGGGGAGGGG
GGTTTGGGGAGGGGG
GTTTGGGGAGGGGGA
TTTGGGGAGGGGGAA
TTGGGGAGGGGGAAG
TGGGGAGGGGGAAGA
GGGGAGGGGGAAGAG
GGGAGGGGGAAGAGA
WO 00/78341 WO 0078341PCT/AUOO/00693 43
GGAGGGGGAAGAGAA
GAGGGGGAAGAGAAA
AGGGGGAAGAGAAAT
GGGGGAAGAGAAATT
GGGGAAGAGAAATTT
GGGAAGAGAAATTTT
GGAAGAGAAATTTTT
GAAGAGAAATTTTTA
AAGAGAAATTTTTAT
AGAGAAATTTTTATT
GAGAAATTTTTATTT
AGAAATTTTTATTTT
GAAATTTTTATTTTT
AAATTTTTATTTTTG
AATTTTTATTTTTGA
ATTTTTATTTTTGAA
TTTTTATTTTTGAAC
TTTTATTTTTGAACC
TTTATTTTTGAACCC
TTATTTTTGAACCCC
TATTTTTGAACCCCT
ATTTTTGAACCCCTG
TTTTTGAACCCCTGT
TTTTGAACCCCTGTG
TTTGAACCCCTGTGT
TTGAACCCCTGTGTC
TGAACCCCTGTGTCC
GAACCCCTGTGTCCC
AACCCCTGTGTCCCT
ACCCCTGTGTCCCTT
CCCCTGTGTCCCTTT
CCCTGTGTCCCTTTT
CCTGTGTCCCTTTTG
CTGTGTCCCTTTTGC
TGTGTCCCTTTTGCA
GTGTCCCTTTTGCAT
TGTCCCTTTTGCATA
GTCCCTTTTGCATAA
TCCCTTTTGCATAAG
CCCTTTTGCATAAGA
CCTTTTGCATAAGAT
CTTTTGCATAAGATT
TTTTGCATAAGATTA
TTTGCATAAGATTAA
TTGCATAAGATTAAA
TGCATAAGATTAAAG
GCATAAGATTAAAGG
CATAAGATTAAAGGA
ATAAGATTAAAGGAA
TAAGATTAAAGGAAG
AAGATTAAAGGAAGG
AGATTAAAGGAAGGA
GATTAAAGGAAGGAA
ATTAAAGGAAGGAAA
TTAAAGGAAGGAAAA
TAAAGGAAGGAAAAG
AAAGGAAGGAAAAGT
WO 00/78341 WO 0078341PCT/AUOO/00693 44 EXAMPLE 7 Antisense oligonucleotides to IGFBP3 may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides:
CTCAGCGCCCAGCCG
TCAGCGCCCAGCCGC
CAGCGCCCAGCCGCT
AGCGCCCAGCCGCTT
GCGCCCAGCCGCTTC
CGCCCAGCCGCTTCC
GCCCAGCCGCTTCCT
CCCAGCCGCTTCCTG
CCAGCCGCTTCCTGC
CAGCCGCTTCCTGCC
AGCCGCTTCCTGCCT
GCCGCTTCCTGCCTG
CCGCTTCCTGCCTGG
CGCTTCCTGCCTGGA
GCTTCCTGCCTGGAT
CTTCCTGCCTGGATT
TTCCTGCCTGGATTC
TCCTGCCTGGATTCC
CCTGCCTGGATTCCA
CTGCCTGGATTCCAC
TGCCTGGATTCCACA
GCCTGGATTCCACAG
CCTGGATTCCACAGC
CTGGATTCCACAGCT
TGGATTCCACAGCTT
GGATTCCACAGCTTC
GATTCCACAGCTTCG
ATTCCACAGCTTCGC
TTCCACAGCTTCGCG
TCCACAGCTTCGCGC
C CACAGCTTCGCGC C
CACAGCTTCGCGCCG
ACAGCTTCGCGCCGT
CAGCTTCGCGCCGTG
AGCTTCGCGCCGTGT
GCTTCGCGCCGTGTA
CTTCGCGCCGTGTAC
TTCGCGCCGTGTACT
TCGCGCCGTGTACTG
CGCGCCGTGTACTGT
GCGCCGTGTACTGTC
CGCCGTGTACTGTCG
GCCGTGTACTGTCGC
CCGTGTACTGTCGCC
CGTGTACTGTCGCCC
GTGTACTGTCGCCCC
TGTACTGTCGCCCCA
GTACTGTCGCCCCAT
TACTGTCGCCCCATC
ACTGTCGCCCCATCC
CTGTCGCCCCATCCC
TGTCGCCCCATCCCT
GTCGCCCCATCCCTG
TCGCCCCATCCCTGC
CGCCCCATCCCTGCG
GCCCCATCCCTGCGC
CCCCATCCCTGCGCG
CCCATCCCTGCGCGC
CCATCCCTGCGCGCC
CATCCCTGCGCGCCC
ATCCCTGCCCGCCCA
TCCCTGCGCGCCCAG
CCCTGCGCGCCCAGC
CCTGCGCGCCCAGCC
CTGCGCGCCCAGCCT
TGCGCGCCCAGCCTG
GCGCGCCCAGCCTGC
CGCGCCCAGCCTGCC
GCGCCCAGCCTGCCA
CGCCCAGCCTGCCAA
GCCCAGCCTGCCAAG
CCCAGCCTGCCAAGC
CCAGCCTGCCAAGCA
CAGCCTGCCAAGCAG
AGCCTGCCAAGCAGC
GCCTGCCAAGCAGCG
CCTGCCAAGCAGCGT
CTGCCAAGCAGCGTG
TGCCAAGCAGCGTGC
GCCAAGCAGCGTGCC
CCAAGCAGCGTGCCC
CAAGCAGCGTGCCCC
AAGCAGCGTGCCCCG
AGCAGCGTGCCCCGG
GCAGCGTGCCCCGGT
CAGCGTGCCCCGGTT
AGCGTGCCCCGGTTG
GCGTGCCCCGGTTGC
CGTGCCCCGGTTGCA
GTGCCCCGGTTGCAG
TGCCCCGGTTGCAGG
GCCCCGGTTGCAGGC
CCCCGGTTGCAGGCG
CCCGGTTGCAGGCGT
CCGGTTGCAGGCGTC
CGGTTGCAGGCGTCA
GGTTGCAGGCGTCAT
GTTGCAGGCGTCATG
TTGCAGGCGTCATGC
TGCAGGCGTCATGCA
GCAGGCGTCATGCAG
CAGGCGTCATGCAGC
AGGCGTCATGCAGCG
GGCGTCATGCAGCGG
GCGTCATGCAGCGGG
CGTCATGCAGCGGGC
GTCATGCAGCGGGCG
TCATGCAGCGGGCGC
CATGCAGCGGGCGCG
ATGCAGCGGGCGCGA
TGCAGCGGGCGCGAC
GCAGCGGGCGCGACC
CAGCGGGCGCGACCC
AGCGGGCGCGACCCA
GCGGGCGCGACCCAC
CGGGCGCGACCCACG
GGGCGCGACCCACGC
GGCGCGACCCACGCT
GCGCGACCCACGCTC
CGCGACCCACGCTCT
GCGACCCACGCTCTG
CGACCCACGCTCTGG
GACCCACGCTCTGGG
ACCCACGCTCTGGGC
CCCACGCTCTGGGCC
CCACGCTCTGGGCCG
WO 00/78341 WO 0078341PCTIAUOO/00693 45
CACGCTCTGGGCCGC
ACGCTCTGGGCCGCT
CGCTCTGGGCCGCTG
GCTCTGGGCCGCTGC
CTCTGGGCCGCTGCG
TCTGGGCCGCTGCGC
CTGGGCCGCTGCGCT
TGGGCCGCTGCGCTG
GGGCCGCTGCGCTGA
GGCCGCTGCGCTGAC
GCCGCTGCGCTGACT
CCGCTGCGCTGACTC
CGCTGCGCTGACTCT
GCTGCGCTGACTCTG
CTGCGCTGACTCTGC
TGCGCTGACTCTGCT
GCGCTGACTCTGCTG
CGCTGACTCTGCTGG
GCTGACTCTGCTGGT
CTGACTCTGCTGGTG
TGACTCTGCTGGTGC
GACTCTGCTGGTGCT
ACTCTGCTGGTGCTG
CTCTGCTGGTGCTGC
TCTGCTGGTGCTGCT
CTGCTGGTGCTGCTC
TGCTGGTGCTGCTCC
GCTGGTGCTGCTCCG
CTGGTGCTGCTCCGC
TGGTGCTGCTCCGCG
GGTGCTGCTCCGCGG
GTGCTGCTCCGCGGG
TGCTGCTCCGCGGGC
GCTGCTCCGCGGGCC
CTGCTCCGCGGGCCG
TGCTCCGCGGGCCGC
GCTCCGCGGGCCGCC
CTCCGCGGGCCGCCG
TCCGCGGGCCGCCGG
CCGCGGGCCGCCGGT
CGCGGGCCGCCGGTG
GCGGGCCGCCGGTGG
CGGGCCGCCGGTGGC
GGGCCGCCGGTGGCG
GGCCGCCGGTGGCGC
GCCGCCGGTGGCGCG
CCGCCGGTGGCGCGG
CGCCGGTGGCGCGGG
GCCGGTGGCGCGGGC
CCGGTGGCGCGGGCT
CGGTGGCGCGGGCTG
GGTGGCGCGGGCTGG
GTGGCGCGGGCTGGC
TGGCGCGGGCTGGCG
GGCGCGGGCTGGCGC
GCGCGGGCTGGCGCG
CGCGGGCTGGCGCGA
GCGGGCTGGCGCGAG
CGGGCTGGCGCGAGC
GGGCTGGCGCGAGCT
GGCTGGCGCGAGCTC
GCTGGCGCGAGCTCG
CTGGCGCGAGCTCGG
TGGCGCGAGCTCGGG
GGCGCGAGCTCGGGG
GCGCGAGCTCGGGGG
CGCGAGCTCGGGGGG
GCGAGCTCGGGGGGC
CGAGCTCGGGGGGCT
GAGCTCGGGGGGCTT
AGCTCGGGGGGCTTG
GCTCGGGGGGCTTGG
CTCGGGGGGCTTGGG
TCGGGGGGCTTGGGT
CGGGGGGCTTGGGTC
GGGGGGCTTGGGTCC
GGGGGCTTGGGTCCC
GGGGCTTGGGTCCCG
GGGCTTGGGTCCCGT
GGCTTGGGTCCCGTG
GCTTGGGTCCCGTGG
CTTGGGTCCCGTGGT
TTGGGTCCCGTGGTG
TGGGTCCCGTGGTGC
GGGTCCCGTGGTGCG
GGTCCCGTGGTGCGC
GTCCCGTGGTGCGCT
TCCCGTGGTGCGCTG
CCCGTGGTGCGCTGC
CCGTGGTGCGCTGCG
CGTGGTGCGCTGCGA
GTGGTGCGCTGCGAG
TGGTGCGCTGCGAGC
GGTGCGCTGCGAGCC
GTGCGCTGCGAGCCG
TGCGCTGCGAGCCGT
GCGCTGCGAGCCGTG
CGCTGCGAGCCGTGC
GCTGCGAGCCGTGCG
CTGCGAGCCGTGCGA
TGCGAGCCGTGCGAC
GCGAGCCGTGCGACG
CGAGCCGTGCGACGC
GAGCCGTGCGACGCG
AGCCGTGCGACGCGC
GCCGTGCGACGCGCG
CCGTGCGACGCGCGT
CGTGCGACGCGCGTG
GTGCGACGCGCGTGC
TGCGACGCGCGTGCA
GCGACGCGCGTGCAC
CGACGCGCGTGCACT
GACGCGCGTGCACTG
ACGCGCGTGCACTGG
CGCGCGTGCACTGGC
GCGCGTGCACTGGCC
CGCGTGCACTGGCCC
GCGTGCACTGGCCCA
CGTGCACTGGCCCAG
GTGCACTGGCCCAGT
TGCACTGGCCCAGTG
GCACTGGCCCAGTGC
CACTGGCCCAGTGCG
ACTGGCCCAGTGCGC
CTGGCCCAGTGCGCG
TGGCCCAGTGCGCGC
GGCCCAGTGCGCGCC
GCCCAGTGCGCGCCT
CCCAGTGCGCGCCTC
CCAGTGCGCGCCTCC
CAGTGCGCGCCTCCG
AGTGCGCGCCTCCGC
GTGCGCGCCTCCGCC
TGCGCGCCTCCGCCC
GCGCGCCTCCGCCCG
CGCGCCTCCGCCCGC
GCGCCTCCGCCCGCCC
CGCCTCCGCCCGCCG
GCCTCCGCCCGCCGT
CCTCCGCCCGCCGTG
CTCCGCCCGCCGTGT
TCCGCCCGCCGTGTG
CCGCCCGCCGTGTGC
CGCCCGCCGTGTGCG
GCCCGCCGTGTGCGC
CCCGCCGTGTGCGCG
CCGCCGTGTGCGCGG
CGCCGTGTGCGCGGA
GCCGTGTGCGCGGAG
CCGTOTGCGCGGAGC
CGTGTGCGCGGAGCT
GTGTGCGCGGAGCTG
TGTGCGCGGAGCTGG
WO 00/78341 WO 0078341PCT/AUOO/00693 46
GTGCGCGGAGCTGGT
TGCGCGGAGCTGGTG
GCGCGGAGCTGGTGC
CGCGGAGCTGGTGCG
GCGGAGCTGGTGCGC
CGGAGCTGGTGCGCG
GGAGCTGGTGCGCGA
GAGCTGGTGCGCGAG
AGCTGGTGCGCGAGC
GCTGGTGCGCGAGCC
CTGGTGCGCGAGCCG
TGGTGCGCGAGCCGG
GGTGCGCGAGCCGGG
GTGCGCGAGCCGGGC
TGCGCGAGCCGGGCT
GCGCGAGCCGGGCTG
CGCGAGCCGGGCTGC
GCGAGCCGGGCTGCG
CGAGCCGGGCTGCGG
GAGCCGGCCTGCGGC
AGCCGGGCTGCGGCT
GCCGGGCTGCGGCTG
CCGGGCTGCGGCTGC
CGGGCTGCGGCTGCT
GGGCTGCGGCTGCTG
GGCTGCGGCTGCTGC
GCTGCGGCTGCTGCC
CTGCGGCTGCTGCCT
TGCGGCTGCTGCCTG
GCGGCTGCTGCCTGA
CGGCTGCTGCCTGAC
GGCTGCTGCCTGACG
GCTGCTGCCTGACGT
CTGCTGCCTGACGTG
TGCTGCCTGACGTGC
GCTGCCTGACGTGCG
CTGCCTGACGTGCGC
TGCCTGACGTGCGCA
GCCTGACGTGCGCAC
CCTGACGTGCGCACT
CTGACGTGCGCACTG
TGACGTGCGCACTGA
GACGTGCGCACTGAG
ACGTGCGCACTGAGC
CGTGCGCACTGAGCG
GTGCGCACTGAGCGA
TGCGCACTGAGCGAG
GCGCACTGAGCGAGG
CGCACTGAGCGAGGG
GCACTGAGCGAGGGC
CACTGAGCGAGGGCC
ACTGAGCGAGGG CCA
CTGAGCGAGGGCCAG
TGAGCGAGGGCCAGC
GAGCGAGGGCCAGCC
AGCGAGGGCCAGCCG
GCGAGGGCCAGCCGT
CGAGGGCCAGCCGTG
GAGGGCCAGCCGTGC
AGGGCCAGCCGTGCG
GGGCCAGCCGTGCGG
GGCCAGCCGTGCGGC
GCCAGCCGTGCGGCA
CCAGCCGTGCGGCAT
CAGCCGTGCGGCATC
AGCCGTGCGGCATCT
GCCGTGCGGCATCTA
CCGTGCGGCATCTAC
CGTGCGGCATCTACA
GTGCGGCATCTACAC.
TGCGGCATCTACACC
GCGGCATCTACACCG
CGGCATCTACACCGA
GGCATCTACACCGAG
GCATCTACACCGAGC
CATCTACACCGAGCG
ATCTACACCGAGCGC
TCTACACCGAGCGCT
CTACACCGAGCGCTG
TACACCGAGCGCTGT
ACACCGAGCGCTGTG
CACCGAGCGCTGTGG
ACCGAGCGCTGTGGC
CCGAGCGCTGTGGCT
CGAGCGCTGTGGCTC
GAGCGCTGTGGCTCC
AGCGCTGTGGCTCCG
GCGCTGTGGCTCCGG
CGCTGTGGCTCCGGC
GCTGTGGCTCCGGCC
CTGTGGCTCCGGCCT
TGTGGCTCCGGCCTT
GTGGCTCCGGCCTTC
TGGCTCCGGCCTTCG
GGCTCCGGCCTTCGC
GCTCCGGCCTTCGCT
CTCCGGCCTTCGCTG
TCCGGCCTTCGCTGC
CCGGCCTTCGCTGCC
CGGCCTTCGCTGCCA
GGCCTTCGCTGCCAG
GCCTTCGCTGCCAGC
CCTTCGCTGCCACCC
CTTCGCTGCCAGCCG
TTCGCTGCCAGCCGT
TCGCTGCCAGCCGTC
CGCTGCCAGCCGTCG
GCTGCCAGCCGTCGC
CTGCCAGCCGTCGCC
TGCCAGCCGTCGCCC
GCCAGCCGTCGCCCG
CCAGCCGTCGCCCGA
CAGCCGTCGCCCGAC
AGCCGTCGCCCGACG
GCCGTCGCCCGACGA
CCGTCGCCCGACGAG
CGTCGCCCGACGAGG
GTCGCCCGACGAGGC
TCGCCCGACGAGGCG
CGCCCGACGAGGCGC
GCCCGACGAGGCGCG
CCCGACGAGGCGCGA
CCGACGAGGCGCGAC
CGACGAGGCGCGACC
GACGAGGCGCGACCG
ACGAGGCGCGACCGC
CGAGGCGCGACCGCT
GAGGCGCGACCGCTG
AGGCGCGACCGCTGC
GGCGCGACCGCTGCA
GCGCGACCGCTGCAG
CGCGACCGCTGCAGG
GCGACCGCTGCAGGC
CGACCGCTGCAGGCG
GACCGCTGCAGGCGC
ACCGCTGCAGGCGCT
CCGCTGCAGGCGCTG
CGCTGCAGGCGCTGC
GCTGCAGGCGCTGCT
CTGCAGGCGCTGCTG
TGCAGGCGCTGCTGG
GCAGGCGCTGCTGGA
CAGGCGCTGCTGGAC
AGGCGCTGCTGGACG
GGCGCTGCTGGACGG
GCGCTGCTGGACGGC
CGCTGCTGGACGGCC
GCTGCTGGACGGCCG
CTGCTGGACGGCCGC
TGCTGGACGGCCGCG
GCTGGACGGCCGCGG
CTGGACGGCCGCGGG
TGGACGGCCGCGGGC
WO 00/78341 WO 00/834 1PCT/AUOO/00693 47
GGACGGCCGCGGGCT
GACGGCCGCGGGCTC
ACGGCCGCGGGCTCT
CGGCCGCGGGCTCTG
GGCCGCGGGCTCTGC
GCCGCGGGCTCTGCG
CCGCGGGCTCTGCGT
CGCGGGCTCTGCGTC
GCGGGCTCTGCGTCA
CGGGCTCTGCGTCAA
GGGCTCTGCGTCAAC
GGCTCTGCGTCAACG
GCTCTGCGTCAACGC
CTCTGCGTCAACGCT
TCTGCGTCAACGCTA
CTGCGTCAACGCTAG
TGCGTCAACGCTAGT
GCGTCAACGCTAGTG
CGTCAACGCTAGTGC
GTCAACGCTAGTGCC
TCAACGCTAGTGCCG
CAACGCTAGTGCCGT
AACGCTAGTGCCGTC
ACGCTAGTGCCGTCA
CGCTAGTGCCGTCAG
GCTAGTGCCGTCAGC
CTAGTGCCGTCAGCC
TAGTGCCGTCAGCCG
AGTGCCGTCAGCCGC
GTGCCGTCAGCCGCC
TGCCGTCAGCCGCCT
GCCGTCAGCCGCCTG
CCGTCAGCCGCCTGC
CGTCAGCCGCCTGCG
GTCAGCCGCCTGCGC
TCAGCCGCCTGCGCG
CAGCCGCCTGCGCGC
AGCCGCCTGCGCGCC
GCCGCCTGCGCGCCT
CCGCCTGCGCGCCTA
CGCCTGCGCGCCTAC
GCCTGCGCGCCTACC
CCTGCGCGCCTACCT
CTGCGCGCCTACCTG
TGCGCGCCTACCTGC
GCGCGCCTACCTGCT
CGCGCCTACCTGCTG
GCGCCTACCTGCTGC
CGCCTACCTGCTGCC
GCCTACCTGCTGCCA
CCTACCTGCTGCCAG
CTACCTGCTGCCAGC
TACCTGCTGCCAGCG
ACCTGCTGCCAGCGC
CCTGCTGCCAGCGCC
CTGCTGCCAGCGCCG
TGCTGCCAGCGCCGC
GCTGCCAGCGCCGCC
CTGCCAGCGCCGCCA
TGCCAGCGCCGCCAG
GCCAGCGCCGCCAGC
CCAGCGCCGCCAGCT
CAGCGCCGCCAGCTC
AGCGCCGCCAGCTCC
GCGCCGCCAGCTCCA
CGCCGCCAGCTCCAG
GCCGCCAGCTCCAGG
CCGCCAGCTCCAGGA
CGCCAGCTCCAGGAA
GCCAGCTCCAGGAAA
CCAGCTCCAGGAAAT
CAGCTCCAGGAAATG
AGCTCCAGGAAATGC
GCTCCAGGAAATGCT
CTCCAGGAAATGCTA
TCCAGGAAATGCTAG
CCAGGAAATGCTAGT
CAGGAAATGCTAGTG
AGGAAATGCTAGTGA
GGAAATGCTAGTGAG
GAAATGCTAGTGAGT
AAATGCTAGTGAGTC
AATGCTAGTGAGTCG
ATGCTAGTGAGTCGG
TGCTAGTGAGTCGGA
GCTAGTGAGTCGGAG
CTAGTGAGTCGGAGG
TAGTGAGTCGGAGGA
AGTGAGTCGGAGGAA
GTGAGTCGGAGGAAG
TGAGTCGGAGGAAGA
GAGTCGGAGGAAGAC
AGTCGGAGGAAGACC
GTCGGAGGAAGACCG
TCGGAGGAAGACCGC
CGGAGGAAGACCGCA
GGAGGAAGACCGCAG
GAGGAAGACCGCAGC
AGGAAGACCGCAGCG
GGAAGACCGCAGCGC
GAAGACCGCAGCGCC
AAGACCGCAGCGCCG
AGACCGCAGCGCCGG
GACCGCAGCGCCGGC
ACCGCAGCGCCGGCA
CCGCAGCGCCGGCAG
CGCAGCGCCGGCAGT
GCAGCGCCGGCAGTG
CAGCGCCGGCAGTGT
AGCGCCGGCAGTGTG
GCGCCGGCAGTGTGG
CGCCGGCAGTGTGGA
GCCGGCAGTGTGGAG
CCGGCAGTGTGGAGA
CGGCAGTGTGGAGAG
GGCAGTGTGGAGAGC
GCAGTGTGGAGAGCC
CAGTGTGGAGAGCCC
AGTGTGGAGAGCCCG
GTGTGGAGAGCCCGT
TGTGGAGAGCCCGTC
GTGGAGAGCCCGTCC
TGGAGAGCCCGTCCG
GGAGAGCCCGTCCGT
GAGAGCCCGTCCGTC
AGAGCCCGTCCGTCT
GAGCCCGTCCGTCTC
AGCCCGTCCGTCTCC
GCCCGTCCGTCTCCA
CCCGTCCGTCTCCAG
CCGTCCGTCTCCAGC
CGTCCGTCTCCAGCA
GTCCGTCTCCAGCAC
TCCGTCTCCAGCACG
CCGTCTCCAGCACGC
CGTCTCCAGCACGCA
GTCTCCAGCACGCAC
TCTCCAGCACGCACC
CTCCAGCACGCACCG
TCCAGCACGCACCGG
CCAGCACGCACCGGG
CAGCACGCACCGGGT
AGCACGCACCGGGTG
GCACGCACCGGGTGT
CACGCACCGGGTGTC
ACGCACCGGGTGTCT
CGCACCGGGTGTCTG
GCACCGGGTGTCTGA
CACCGGGTGTCTGAT
ACCGGGTGTCTGATC
CCGGGTGTCTGATCC
CGGGTGTCTGATCCC
GGGTGTCTGATCCCA
WO 00/78341 WO 0078341PCT/AUOO/00693 48
GGTGTCTGATCCCAA
GTGTCTGATCCCAAG
TGTCTGATCCCAAGT
GTCTGATCCCAAGTT
TCTGATCCCAAGTTC
CTGATCCCAAGTTCC
TGATCCCAAGTTCCA
GATCCCAAGTTCCAC
ATCCCAAGTTCCACC
TCCCAAGTTCCACCC
CCCAAGTTCCACCCC
CCAAGTTCCACCCCC
CAAGTTCCACCCCCT
AAGTTCCACCCCCTC
AGTTCCACCCCCTCC
GTTCCACCCCCTCCA
TTCCACCCCCTCCAT
TCCACCCCCTCCATT
CCACCCCCTCCATTC
CACCCCCTCCATTCA
ACCCCCTCCATTCAA
CCCCCTCCATTCAAA
CCCCTCCATTCAAAG
CCCTCCATTCAAAGA
CCTCCATTCAAAGAT
CTCCATTCAAAGATA
TCCATTCAAAGATAA
CCATTCAAAGATAAT
CATTCAAAGATAATC
ATTCAAAGATAATCA
TTCAAAGATAAT CAT
TCAAAGATAATCATC
CAAAGATAAT CAT CA AAAGATAATCAT CAT
AAGATAATCATCATC
AGATAATCATCATCA
GATAATCATCATCAA
ATAATCATCATCAAG
TAATCATCATCAAGA
AAT CAT CATCAACAA
ATCATCATCAAGAAA
TCATCATCAAGAAAG
CATCATCAAGAAAGG
ATCATCAAGAAAGGG
TCATCAAGAAAGGGC
CATCAAGAAAGGGCA
ATCAAGAAAGGGCAT
TCAAGAAAGGGCATG
CAAGAAAGGGCATGC
AAGAAAGGGCATGCT
AGAAAGGGCATGCTA
GAAAGGGCATGCTAA
AAAGGGCATGCTAAA
AAGGGCATGCTAAAG
AGGGCATGCTAAAGA
GGGCATGCTAAAGAC
GGCATGCTAAAGACA
GCATGCTAAAGACAG
CATGCTAAAGACAGC
ATGCTAAAGACAGCC
TGCTAAAGACAGCCA
GCTAAAGACAGCCAG
CTAAAGACAGCCAGC
TAAAGACAGCCAGCG
AAAGACAGCCAGCGC
AAGACAGCCAGCGCT
AGACAGCCAGCGCTA
GACAGCCAGCGCTAC
ACAGCCAGCGCTACA
CAGCCAGCGCTACAA
AGCCAGCGCTACAAA
GCCAGCGCTACAAAG
CCAGCGCTACAAAGT
CAGCGCTACAAAGTT
AGCGCTACAAAGTTG
GCGCTACAAAGTTGA
CGCTACAAAGTTGAC
GCTACAAAGTTGACT
CTACAAAGTTGACTA
TACAAAGTTGACTAC
ACAAAGTTGACTACG
CAAAGTTGACTACGA
AAAGTTGACTACGAG
AAGTTGACTACGAGT
AGTTGACTACGAGTC
GTTGACTACGAGTCT
TTGACTACGAGTCTC
TGACTACGAGTCTCA
GACTACGAGTCTCAG
ACTACGAGTCTCAGA
CTACGAGTCTCAGAG
TACGAGTCTCAGAGC
ACGAGTCTCAGAGCA
CGAGTCTCAGAGCAC
GAGTCTCAGAGCACA
AGTCTCAGAGCACAG
GTCTCAGAGCACAGA
TCTCAGAGCACAGAT
CTCAGAGCACAGATA
TCAGAGCACAGATAC
CAGAGCACAGATACC
AGAGCACAGATACCC
GAGCACAGATACCCA
AGCACAGATACCCAG
GCACAGATACCCAGA
CACAGATACCCAGAA
ACAGATACCCAGAAC
CAGATACCCAGAACT
AGATACCCAGAACTT
GATACCCAGAACTTC
ATACCCAGAACTTCT
TACCCAGAACTTCTC
ACCCAGAACTTCTCC
CCCAGAACTTCTCCT
CCAGAACTTCTCCTC
CAGAACTTCTCCTCC
AGAACTTCTCCTCCG
GAACTTCTCCTCCGA
AACTTCTCCTCCGAG
ACTTCTCCTCCGAGT
CTTCTCCTCCGAGTC
TTCTCCTCCGAGTCC
TCTCCTCCGAGTCCA
CTCCTCCGAGTCCAA
TCCTCCGAGTCCAAG
CCTCCGAGTCCAAGC
CTCCGAGTCCAAGCG
TCCGAGTCCAAGCGG
CCGAGTCCAAGCGGG
CGAGTCCAAGCGGGA
GAGTCCAAGCGGGAG
AGTCCAAGCGGGAGA
GTCCAAGCGGGAGAC
TCCAAGCGGGAGACA
CCAAGCGGGAGACAG
CAAGCGGGAGACAGA
AAGCGGGAGACAGAA
AGCGGGAGACAGAAT
GCGGGAGACAGAATA
CGGGAGACAGAATAT
GGGAGACAGAATATG
GGAGACAGAATATGG
GAGACAGAATATGGT
AGACAGAATATGGTC
GACAGAATATGGTCC
ACAGAATATGGTCCC
CAGAATATGGTCCCT
AGAATATGGTCCCTG
GAATATGGTCCCTGC
AATATGGTCCCTGCC
ATATGGTCCCTGCCG
TATGGTCCCTGCCGT
ATGGTCCCTGCCGTA
WO 00/78341 WO 0078341PCT/AUOO/00693 49
TGGTCCCTGCCGTAG
GGTCCCTGCCGTAGA
GTCCCTGCCGTAGAG
TCCCTGCCGTAGAGA
CCCTGCCGTAGAGAA
CCTGCCGTAGAGAAA
CTGCCGTAGAGAAAT
TGCCGTAGAGAAATG
GCCGTAGAGAAATGG
CCGTAGAGAAATGGA
CGTAGAGAAATGGAA
GTAGAGAAATGGAAG
TAGAGAAATGGAAGA
AGAGAAATGGAAGAC
GAGAAATGGAAGACA
AGAAATGGAAGACAC
GAAATGGAAGACACA
AAATGGAAGACACAC
AATGGAAGACACACT
ATGGAAGACACACTG
TGGAAGACACACTGA
GGAAGACACACTGAA
GAAGACACACTGAAT
AAGACACACTGAATC
AGACACACTGAATCA
GACACACTGAATCAC
ACACACTGAATCACC
CACACTGAATCACCT
ACACTGAATCACCTG
CACTGAATCACCTGA
ACTGAATCACCTGAA
CTGAATCACCTGAAG
TGAATCACCTGAAGT
GAATCACCTGAAGTT
AATCACCTGAAGTTC
ATCACCTGAAGTTCC
TCACCTGAAGTTCCT
CACCTGAAGTTCCTC
ACCTGAAGTTCCTCA
CCTGAAGTTCCTCAA
CTGAAGTTCCTCAAT
TGAAGTTCCTCAATG
GAAGTTCCTCAATGT
AAGTTCCTCAATGTG
AGTTCCTCAATGTGC
GTTCCTCAATGTGCT
TTCCTCAATGTGCTG
TCCTCAATGTGCTGA
CCTCAATGTGCTGAG
CTCAATGTGCTGAGT
TCAATGTGCTGAGTC
CAATGTGCTGAGTCC
AATGTGCTGAGTCCC
ATGTGCTGAGTCCCA
TGTGCTGAGTCCCAG
GTGCTGAGTCCCAGG
TGCTGAGTCCCAGGG
GCTGAGTCCCAGGGG
CTGAGTCCCAGGGGT
TGAGTCCCAGGGGTG
GAGTCCCAGGGGTGT
AGTCCCAGGGGTGTA
GTCCCAGGGGTGTAC
TCCCAGGGGTGTACA
CCCAGGGGTGTACAC
CCAGGGGTGTACACA
CAGGGGTGTACACAT
AGGGGTGTACACATT
GGGGTGTACACATTC
GGGTGTACACATTCC
GGTGTACACATTCCC
GTGTACACATTCCCA
TGTACACATTCCCAA
GTACACATTCCCAAC
TACACATTCCCAACT
ACACATTCCCAACTG
CACATTCCCAACTGT
ACATTCCCAACTGTG
CATTCCCAACTGTGA
ATTCCCAACTGTGAC
TTCCCAACTGTGACA
TCCCAACTGTGACAA
CCCAACTGTGACAAG
CCAACTGTGACAAGA
CAACTGTGACAAGAA
AACTGTGACAAGAZAG
ACTGTGACAAGAAGG
CTGTGACAAGAAGGG
TGTGACAAGAAGGGA
GTGACAAGAAGGGAT
TGACAAGAAGGGATT
GACAAGAAGGGATTT
ACAAGAAGGGATTTT
CAAGAAGGGATTTTA
AAGAAGGGATTTTAT
AGAAGGGATTTTATA
GAAGGGATTTTATAA
AAGGGATTTTATAAG
AGGGATTTTATAAGA
GGGATTTTATAAGAA
GGATTTTATAAGAAA
GATTTTATAAGAAAA
ATTTTATAAGAAAAA
TTTTATAAGAAAAAG
TTTATAAGAAAAAGC
TTATAAGAAAAAGCA
TATAAGAAAAAGCAG
ATAAGAAAAAGCAGT
TAAGAAAAAGCAGTG
AAGAAAAAGCAGTGT
AGAAAAAGCAGTGTC
GAAAAAGCAGTGTCG
AAAAAGCAGTGTCGC
AAAAGCAGTGTCGCC
AAAGCAGTGTCGCCC
AAGCAGTGTCGCCCT
AGCAGTGTCGCCCTT
GCAGTGTCGCCCTTC
CAGTGTCGCCCTTCC
AGTGTCGCCCTTCCA
GTGTCGCCCTTCCAA
TGTCGCCCTTCCAAA
GTCGCCCTTCCAAAG
TCGCCCTTCCAAAGG
CGCCCTTCCAAAGGC
GCCCTTCCAAAGGCA
CCCTTCCAAAGGCAG
CCTTCCAAALGGCAGG
CTTCCAAAGGCAGGA
TTCCAAAGGCAGGAA
TCCAAAGGCAGGAAG
CCAAAGGCAGGAAGC
CAAAGGCAGGAAGCG
AAAGGCAGGAAGCGG
AAGGCAGGAAGCGGG
AGGCAGGAAGCGGGG
GGCAGGAAGCGGGGC
GCAGGAAGCGGGGCT
CAGGAAGCGGGGCTT
AGGAAGCGGGGCTTC
GGAAGCGGGGCTTCT
GAAGCGGGGCTTCTG
AAGCGGGGCTTCTGC
AGCGGGGCTTCTGCT
GCGGGGCTTCTGCTG
CGGGGCTTCTGCTGG
GGGGCTTCTGCTGGT
GGGCTTCTGCTGGTG
GGCTTCTGCTGGTGT
GCTTCTGCTGGTGTG
CTTCTGCTGGTGTGT
TTCTGCTGGTGTGTG
TCTGCTGGTGTGTGG
WO 00/78341 WO 0078341PCT/AUOO/00693 50
CTGCTGGTGTGTGGA
TGCTGGTGTGTGGAT
GCTGGTGTGTGGATA
CTGGTGTGTGGATAA
TGGTGTGTGGATAAG
GGTGTGTGGATAAGT
GTGTGTGGATAAGTA
TGTGTGGATAAGTAT
GTGTGGATAAGTATG
TGTGGATAAGTATGG
GTGGATAAGTATGGG
TGGATAAGTATGGGC
GGATAAGTATGGGCA
GATAAGTATGGGCAG
ATAAGTATGGGCAGC
TAAGTATGGGCAGCC
AAGTATGGGCAGCCT
AGTATGGGCAGCCTC
GTATGGGCAGCCTCT
TATGGGCAGCCTCTC
ATGGGCAGCCTCTCC
TGGGCAGCCTCTCCC
GGGCAGCCTCTCCCA
GGCAGCCTCTCCCAG
GCAGCCTCTCCCAGG
CAGCCTCTCCCAGGC
AGCCTCTCCCAGGCT
GCCTCTCCCAGGCTA
CCTCTCCCAGGCTAC
CTCTCCCAGGCTACA
-TCTCCCAGGCTACAC
CTCCCAGGCTACACC
TCCCAGGCTACACCA
CCCAGGCTACACCAC
CCAGGCTACACCACC
CAGGCTACACCACCA
AGGCTACACCACCAA
GGCTACACCACCAAG
GCTACACCACCAAGG
CTACACCACCAAGGG
TACACCACCAAGGGG
ACACCACCAAGGGGA
CACCACCAAGGGGAA
ACCACCAAGGGGAAG
CCACCAAGGGGAAGG
CACCAAGGGGAAGGA
ACCAAGGGGAAGGAG
CCAAGGGGAAGGAGG
CAAGGGGAAGGAGGA
AAGGGGAAGGAGGAC
AGGGGAAGGAGGACG
GGGGAAGGAGGACGT
GGGAAGGAGGACGTG
GGAAGGAGGACGTGC
GAAGGAGGACGTGCA
AAGGAGGACGTGCAC
AGGAGGACGTGCACT
GGAGGACGTGCACTG
GAGGACGTGCACTGC
AGGACGTGCACTGCT
GGACGTGCACTGCTA
GACGTGCACTGCTAC
ACGTGCACTGCTACA
CGTGCACTGCTACAG
GTGCACTGCTACAGC
TGCACTGCTACAGCA
GCACTGCTACAGCAT
CACTGCTACAGCATG
ACTGCTACAGCATGC
CTGCTACAGCATGCA
TGCTACAGCATGCAG
GCTACAGCATGCAGA
CTACAGCATGCAGAG
TACAGCATGCACAGC
ACAGCATGCAGAGCA
CAGCATGCAGAGCAA
AGCATGCAGAGCAAG
GCATGCAGAGCAAGT
CATGCAGAGCAAGTA
ATGCAGAGCAAGTAG
TGCAGAGCAAGTAGA
GCAGAGCAAGTAGAC
CAGAGCAAGTAGACG
AGAGCAAGTAGACGC
GAGCAAGTAGACGCC
AGCAAGTAGACGCCT
GCAAGTAGACGCCTG
CAAGTAGACGCCTGC
AAGTAGACGCCTGCC
AGTAGACGCCTGCCG
GTAGACGCCTGCCGC
TAGACGCCTGCCGCA
AGACGCCTGCCGCAA
GACGCCTGCCGCAAG
ACGCCTGCCGCAAGT
CGCCTGCCGCAAGTT
GCCTGCCGCAAGTTA
CCTGCCGCAAGTTAA
CTGCCGCAAGTTAAT
TGCCGCAAGTTAATG
GCCGCAAGTTAATGT
CCGCAAGTTAATGTG
CGCAAGTTAATGTGG
GCAAGTTAATGTGGA
CAAG ETAATGTGGAG
AAGTTAATGTGGAGC
AGTTAATGTGGAGCT
GTTAATGTGGAGCTC
TTAATGTGGAGCTCA
TAATGTGGAGCTCAA
AATGTGGAGCTCAAA
ATGTGGAGCTCAAAT
TGTGGAGCTCAAATA
GTGGAGCTCAAATAT
TGGAGCTCAAATATG
GGAGCTCAAATATGC
GAGCTCAAATATGCC
AGCTCAAATATGCCT
GCTCAAATATGCCTT
CTCAAATATGCCTTA
TCAAATATGCCTTAT
CAAATATGCCTTATT
AAATATGCCTTATTT
AATATGCCTTATTTT
ATATGCCTTATTTTG
TATGCCTTATTTTGC
ATGCCTTATTTTGCA
TGCCTTATTTTGCAC
GCCTTATTTTGCACA
CCTTATTTTGCACAA
CTTATTTTGCACAAA
TTATTTTGCACAAAA
TATTTTGCACAAAAG
ATTTTGCACAAAAGA
TTTTGCACAAAAGAC
TTTGCACAAAAGACT
TTGCACAAAACACTG
TGCACAAAAGACTGC
GCACAAAAGACTGCC
CACAAAAGACTGCCA
ACAAAAGACTGCCAA
CAAAAGACTGCCAAG
AAAAGACTGCCAAGG
AAAGACTGCCAAGGA
AAGACTGCCAAGGAC
AGACTGCCAAGGACA
GACTGCCAAGGACAT
ACTGccAAGGACATG
CTGCCAAGGACATGA
TGCCAAGGACATGAC
GCCAAGGACATGACC
CCAAGGACATGACCA
CAAGGACATGACCAG
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AAGGACATGACCAGC
AGGACATGACCAGCA
GGACATGACCAGCAG
GACATGACCAGCAGC
ACATGACCAGCAGCT
CATGACCAGCAGCTG
ATGACCAGCAGCTCG
TGACCAGCAGCTGGC
GACCAGCAGCTGGCT
ACCAGCAGCTGGCTA
CCAGCAGCTGGCTAC
CAGCAGCTGGCTACA
AGCAGCTGGCTACAG
GCAGCTGGCTACAGC
CAGCTGGCTACAGCC
AGCTGGCTACAGCCT
GCTGGCTACAGCCTC
CTGGCTACAGCCTCG
TGGCTACAGCCTCGA
GGCTACAGCCTCGAT
GCTACAGCCTCGATT
CTACAGCCTCGATTT
TACAGCCTCGATTTA
ACAGCCTCGATTTAT
CAGCCTCGATTTATA
AGCCTCGATTTATAT
GCCTCGATTTATATT
CCTCGATTTATATTT
CTCGATTTATATTTC
TCGATTTATATTTCT
CGATTTATATTTCTG
GATTTATATTTCTGT
ATTTATATTTCTGTT
TTTATATTTCTGTTT
TTATATTTCTGTTTG
TATATTTCTGTTTGT
ATATTTCTGTTTGTG
TATTTCTGTTTGTGG
ATTTCTGTTTGTGGT
TTTCTGTTTGTGGTG
TTCTGTTTGTGGTGA
TCTGTTTGTGGTGAA
CTGTTTGTGGTGAAC
TGTTTGTGGTGAACT
GTTTGTGGTGAACTG
TTTGTGGTGAACTGA
TTGTGGTGAACTGAT
TGTGGTGAACTGATT
GTGGTGAACTGATTT
TGGTGAACTGATTTT
GGTGAACTGATTTTT
GTGAACTGATTTTTT
TGAACTGATTTTTTT
GAACTGATTTTTTTT
AACTGATTTTTTTTA
ACTGATTTTTTTTAA
CTGAT'rrTTTTTAAA
TGATTTTTTTTAAAC
GATTTTTTTTAAACC
ATTTTTTTTAAACCA
TTTTTTTTAAACCAA
TTTTTTTAAACCAAA
TTTTTTAAACCAAAG
TTTTTAAACCAAAGT
TTTTAAACCAAAGTT
TTTAAACCAAAGTTT
TTAAACCAAAGTTTA
TAAACCAAAGTTTAG
AAACCAAAGTTTAGA
AACCAAAGTTTAGAA
ACCAAAGTTTAGAAA
CCAAAGTTTAGAAAG
CAAAGTTTAGAAAGA
AAAGTTTAGAAAGAG
AAGTTTAGAAAGAGG
AGTTTAGAAAGAGGT
GTTTAGAAAGAGGTT
TTTAGAAAGAGGTTT
TTAGAAAGAGGTT'TT
TAGAAAGAGGTTTTT
AGAAAGAGGTTTTTG
GAAAGAGGTTTTTGA
AAAGAGGTTTTTGAA
AAGAGGTTTTTGAAA
AGAGGTTTTTGAAAT
GAGGTTTTTGAAATG
AGGTTTTTGAAATGC
GGTTTTTGAAATGCC
GTTTTTGAAATGCCT
TTTTTGAAATGCCTA
TTTTGAAATGCCTAT
TTTGAAATGCCTATG
TTGAAATGCCTATGG
TGAAATGCCTATGGT
GAAATGCCTATGGTT
AAATGCCTATGGTTT
AATGCCTATGGTTTC
ATGCCTATGGTTTCT
TGCCTATGGTTTCTT
GCCTATGGTTTCTTT
CCTATGGTTTCTTTG
CTATGGTTTCTTTGA
TATGGTTTCTTTGAA
ATGGTTTCTTTGAAT
TGGTTTCTTTGAATG
GGTTTCTTTGAATGG
GTTTCTTTGAATGGT
TTTCTTTGAATGGTA
TTCTTTGAATGGTAA
TCTTTGAATGGTAAA
CTTTGAATGGTAAAC
TTTGAATGGTAAACT
TTGAATGGTAAACTT
TGAATGGTAAACTTG
GAATGGTAAACTTGA
AATGGTAAACTTGAG
ATGGTAAACTTGAGC
TGGTAAACTTGAGCA
GGTAAACTTGAGCAT
GTAAACTTGAGCATC
TAAACTTGAGCATCT
AAACTTGAGCATCTT
AACTTGAGCATCTTT
ACTTGAGCATCTTTT
CTTGAGCATCTTTTC
TTGAGCATCTTTTCA
TGAGCATCTTTTCAC
GAGCATCTTTTCACT
AGCATCTTTTCACTT
GCATCTTTTCACTTT
CATCTTTTCACTTTC
ATCTTTTCACTTTCC
TCTTTTCACTTTCCA
CTTTTCACTTTCCAG
TTTTCACTTTCCAGT
TTTCACTTTCCAGTA
TTCACTTTCCAGTAG
TCACTTTCCAGTAGT
CACTTTCCAGTAGTC
ACTTTCCAGTAGTCA
CTTTCCAGTAGTCAG
TTTCCAGTAGTCAGC
TTCCAGTAGTCAGCA
TCCAGTAGTCAGCAA
CCAGTAGTCAGCAAA
CAGTAGTCAGCAAAG
AGTAGTCAGCAAAGA
GTAGTCAGCAAAGAG
TAGTCAGCAAAGAGC
AGTCAGCAAAGAGCA
GTCAGCAAAGAGCAG
TCAGCAAAGAGCAGT
CAGCAAAGAGCAGTT
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AGCAAAGAGCAGTTT
GCAAAGAGCAGTTTG
CAAAGAGCAGTTTGA
AAAGAGCAGTTTGAA
AAGAGCAGTTTGAAT
AGAGCAGTTTGAATT
GAGCAGTTTGAATTT
AGCAGTTTGAATTTT
GCAGTTTGAATTTTC
CAGTTTGAATTTTCT
AGTTTGAATTTTCTT
GTTTGAATTTTCTTG
TTTGAATTTTCTTGT
TTGAATTTTCTTGTC
TGAATTTTCTTGTCG
GAATTTTCTTGTCGC
AATTTTCTTGTCGCT
ATTTTCTTGTCGCTT
TTTTCTTGTCGCTTC
TTTCTTGTCGCTTCC
TTCTTGTCGCTTCCT
TCTTGTCGCTTCCTA
CTTGTCGCTTCCTAT
TTGTCGCTTCCTATC
TGTCGCTTCCTATCA
GTCGCTTCCTATCAA
TCGCTTCCTATCAAA
CGCTTCCTATCAAAA
GCTTCCTATCAAAAT
CTTCCTATCAAAATA
TTCCTATCAAAATAT
TCCTATCAAAATATT
CCTATCAAAAtATTC
CTATCAA.AATATTCA
TATCAAAATATTCAG
ATCAAAATATTCAGA
TCAAAATATTCAGAG
CAAAATATTCAGAGA
AAAATATTCAGAGAC
AAATATTCAGAGACT
AATATTCAGAGACTC
ATATTCAGAGACTCG
TATTCAGAGACTCGA
ATTCAGAGACTCGAG
TTCAGAGACTCGAGC
TCAGAGACTCGAGCA
CAGAGACTCGAGCAC
AGAGACTCGAGCACA
GAGACTCGAGCACAG
AGACTCGAGCACAGC
GACTCGAGCACAGCA
ACTCGAGCACAGCAC
CTCGAGCACAGCACC
TCGAGCACAGCACCC
CGAGCACAGCACCCA
GAGCACAGCACCCAG
AGCACAGCACCCAGA
GCACAGCACCCAGAC
CACAGCACCCAGACT
ACAGCACCCAGACTT
CAGCACCCAGACTTC
AGCACCCAGACTTCA
GCACCCAGACTTCAT
CACCCAGACTTCATC
ACCCAGACTTCATGC
CCCAGACTTCATGCG
CCAGACTTCATGCGC
CAGACTTCATGCGCC
AGACTTCATGCGCCC
GACTTCATGCGCCCG
ACTTCATGCGCCCGT
CTTCATGCGCCCGTG
TTCATGCGCCCGTGG
TCATGCGCCCGTGGA
CATGCGCCCGTGGAA
ATGCGCCCGTGGAAT
TGCGCCCGTGGAATG
GCGCCCGTGGAATGC
CGCCCGTGGAATGCT
GCCCGTGGAATGCTC
CCCGTGGAATGCTCA
CCGTGGAATGCTCAC
CGTGGAATGCTCACC
GTGGAATGCTCACCA
TGGAATGCTCACCAC
GGAATGCTCACCACA
GAATGCTCACCACAT
AATGCTCACCACATG
ATGCTCACCACATGT
TGCTCACCACATGTT
GCTCACCACATGTTG
CTCACCACATGTTGG
TCACCACATGTTGGT
CACCACATGTTGGTC
ACCACATGTTGGTCG
CCACATGTTGGTCGA
CACATGTTGGTCGAA
ACATGTTGGTCGAAG
CATGTTGGTCGAAGC
ATGTTGGTCGAAGCG
TGTTGGTCGAAGCGG
GTTGGTCGAAGCGGC
TTGGTCGAAGCGGCC
TGGTCGAAGCGGCCG
GGTCGAAGCGGCCGA
GTCGAAGCGGCCGAC
TCGAAGCGGCCGACC
CGAAGCGGCCGACCA
GAAGCGGCCGACCAC
AAGCGGCCGACCACT
AGCGGCCGACCACTG
GCGGCCGACCACTGA
CGGCCGACCACTGAC
GGCCGACCACTGACT
GCCGACCACTGACTT
CCGACCACTGACTTT
CGACCACTGACTTTG
GACCACTGACTTTGT
ACCACTGACTTTGTG
CCACTGACTTTGTGA
CACTGACTTTGTGAC
ACTGACTTTGTOACT
CTGACTTTGTGACTT
TGACTTTGTGACTTA
GACTTTGTGACTTAG
ACTTTGTGACTTAGG
CTTTGTGACTTAGGC
TTTGTGACTTAGGCG
TTGTGACTTAGGCGG
TGTGACTTAGGCGGC
GTGACTTAGGCGGCT
TGACTTAGGCGGCTG
GACTTAGGCGGCTGT
ACTTAGGCGGCTGTG
CTTAGGCGGCTGTGT
TTAGGCGGCTGTGTT
TAGGCGGCTGTGTTG
AGGCGGCTGTGTTGC
GGCGGCTGTGTTGCC
GCGGCTGTGTTGCCT
CGGCTGTGTTGCCTA
GGCTGTGTTGCCTAT
GCTGTGTTGCCTATG
CTGTGTTGCCTATGT
TGTGTTGCCTATGTA
GTGTTGCCTATGTAG
TGTTGCCTATGTAGA
GTTGCCTATGTAGAG
TTGCCTATGTAGAGA
TGCCTATGTAGAGAA
GCCTATGTAGAGAAC
CCTATGTAGAGAACA
CTATGTAGAGAACAC
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TATGTAGAGAACACG
ATGTAGAGAACACGC
TGTAGAGAACACGCT
GTAGAGAACACGCTT
TAGAGAACACGCTTC
AGAGAACACGCTTCA
GAGAACACGCTTCAC
AGAACACGCTTCACC
GAACACGCTTCACCC
AACACGCTTCACCCC
ACACGCTTCACCCCC
CACGCTTCACCCCCA
ACGCTTCACCCCCAC
CGCTTCACCCCCACT
GCTTCACCCCCACTC
CTTCACCCCCACTCC
TTCACCCCCACTCCC
TCACCCCCACTCCCC
CACCCCCACTCCCCG
ACCCCCACTCCCCGT
CCCCCACTCCCCGTA
CCCCACTCCCCGTAC
CCCACTCCCCGTACA
CCACTCCCCGTACAG
CACTCCCCGTACAGT
ACTCCCCGTACAGTG
CTCCCCGTACAGTGC
TCCCCGTACAGTGCG
CCCCGTACAGTGCGC
CCCGTACAGTGCGCA
CCGTACAGTGCGCAC
CGTACAGTGCGCACA
GTACAGTGCGCACAG
TACAGTGCGCACAGG
ACAGTGCGCACAGGC
CAGTGCGCACAGGCT
AGTGCGCACAGGCTT
GTGCGCACAGGCTTT
TGCGCACAGGCTTTA
GCGCACAGGCTTTAT
CGCACAGGCTTTATC
GCACAGGCTTTATCG
CACAGGCTTTATCGA
ACAGGCTTTATCGAG
CAGGCTTTATCGAGA
AGGCTTTATCGAGAA
GGCTTTATCGAGAAT
GCTTTATCGAGAATA
CTTTATCGAGAATAG
TTTATCGAGAATAGG
TTATCGAGAATAGGA
TAT CGAGAATAGGAA
ATCGAGAATAGGAAA
TCGAGAATAGGAAAA
CGAGAATAGGAAAAC
GAGAATAGGAAAACC
AGAATAGGAAAACCT
GAATAGGAAAACCTT
AATAGGAAAACCTTT
ATAGGAAAACCTTTA
TAGGAAAACCTTTAA
AGGAAAACCTTTAAA
GGAAAACCTTTAAAC
GAAAACCTTTAAACC
AAAACCTTTAAACCC
AAACCTTTAAACCCC
AACCTTTAAACCCCG
ACCTTTAAACCCCGG
CCTTTAAACCCCGGT
CTTTAAACCCCGGTC
TTTAAACCCCGGTCA
TTAAACCCCGGTCAT
TAA.ACCCCGGTCATC
AAACCCCGGTCATCC
AACCCCGGTCATCCG
ACCCCGGTCATCCGG
CCCCGGTCATCCGGA
CCCGGTCATCCGGAC
CCGGTCATCCGGACA
CGGTCATCCGGACAT
GGTCATCCGGACATC
GTCATCCGGACATCC
TCATCCGGACATCCC
CATCCGGACATCCCA
ATCCGGACATCCCAA
TCCGGACATCCCAAC
CCGGACATCCCAACG
CGGACATCCCAACGC
GGACATCCCAACGCA
GACATCCCAACGCAT
ACATCCCAACGCATG
CATCCCAACGCATGC
ATCCCAACGCATGCT
TCCCAACGCATGCTC
CCCAACGCATGCTCC
CCAACGCATGCTCCT
CAACGCATGCTCCTG
AACGCATGCTCCTGG
ACGCATGCTCCTGGA
CGCATGCTCCTGGAG
GCATGCTCCTGGAGC
CATGCTCCTGGAGCT
ATGCTCCTGGAGCTC
TGCTCCTGGAGCTCA
GCTCCTGGAGCTCAC
CTCCTGGAGCTCACA
TCCTGGAGCTCACAG
CCTGGAGCTCACAGC
CTGGAGCTCACAGCC
TGGAGCTCACAGCCT
GGAGCTCACAGCCTT
GAGCTCACAGCCTTC
AGCTCACAGCCTTCT
GCTCACAGCCTTCTG
CTCACAGCCTTCTGT
TCACAGCCTTCTGTG
CACAGCCTTCTGTGG
ACAGCCTTCTGTGGT
CAGCCTTCTGTGGTG
AGCCTTCTGTGGTGT
GCCTTCTGTGGTGTC
CCTTCTGTGGTGTCA
CTTCTGTGGTGTCAT
TTCTGTGGTGTCATT
TCTGTGGTGTCATTT
CTGTGGTGTCATTTC
TGTGGTGTCATTTCT
GTGGTGTCATTTCTG
TGGTGTCATTTCTGA
GGTGTCATTTCTGAA
GTGTCATTTCTGAAA
TGTCATTTCTGAAAC
GTCATTTCTGAAACA
TCATTTCTGAAACAA
CATTTCTGAAACAAG
ATTTCTGAAACAAGG
TTTCTGAAACAAGGG
TTCTGAAACAAGGGC
TCTGAAACAAGGGCG
CTGAAACAAGGGCGT
TGAAACAAGGGCGTG
GAAACAAGGGCGTGG
AAACAAGGGCGTGGA
AACAAGGGCGTGGAT
ACAAGGGCGTGGATC
CAAGGGCGTGGATCC
AAGGGCGTGGATCCC
AGGGCGTGGATCCCT
GGGCGTGGATCCCTC
GGCGTGGATCCCTCA
GCGTGGATCCCTCAA
CGTGGATCCCTCAAC
GTGGATCCCTCAACC
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TGGATCCCTCAACCA
GGATCCCTCAACCAA
GATCCCTCAACCAAG
ATCCCTCAACCAAGA
TCCCTCAACCAAGAA
CCCTCAACCAAGAAG
CCTCAACCAAGAAGA
CTCAACCAAGAAGAA
TCAACCAAGAAGAAT
CAACCAAGAAGAATG
AACCAAGAAGAATGT
ACCAAGAAGAATGTT
CCAAGAAGAATGTTT
CAAGAAGAATGTTTA
AAGAAGAATGTTTAT
AGAAGAATGTTTATG
GAAGAATGTTTATGT
AAGAATGTTTATGTC
AGAATGTTTATGTCT
GAATGTTTATGTCTT
AATGTTTATGTCTTC
ATGTTTATGTCTTCA
TGTTTATGTCTTCAA
GTTTATGTCTTCAAG
TTTATGTCTTCAAGT
TTATGTCTTCAAGTG
TATGTCTTCAAGTGA
ATGTCTTCAAGTGAC
TGTCTTCAAGTGACC
GTCTTCAAGTGACCT
TCTTCAAGTGACCTG
CTTCAAGTGACCTGT
TTCAAGTGACCTGTA
TCAAGTGACCTGTAC
CAAGTGACCTGTACT
AAGTGACCTGTACTG
AGTGACCTGTACTGC
GTGACCTGTACTGCT
TGACCTGTACTGCTT
GACCTGTACTGCTTG
ACCTGTACTGCTTGG
CCTGTACTGCTTGGG
CTGTACTGCTTGGGG
TGTACTGCTTGGGGA
GTACTGCTTGGGGAC
TACTGCTTGGGGACT
ACTGCTTGGGGACTA
CTGCTTGGGGACTAT
TGCTTGGGGACTATT
GCTTGGGGACTATTG
CTTGGGGACTATTGG
TTGGGGACTATTGGA
TGGGGACTATTGGAG
GGGGACTATTGGAGA
GGGACTATTGGAGAA
GGACTATTGGAGAAA
GACTATTGGAGAAAA
ACTATTGGAGAAAAT
CTATTGGAGAAAATA
TATTGGAGAAAATAA
ATTGGAGAAAATAAG
TTGGAGAAAATAAGG
TGGAGAAAATAAGGT
GGAGAAAATAAGGTG
GAGAAAATAAGGTGG
AGAAAATAAGGTGGA
GAAAATAAGGTGGAG
AAAATAAGGTGGAGT
AAATAAGGTGGAGTC
AATAAGGTGGAGTCC
ATAAGGTGGAGTCCT
TAAGGTGGAGTCCTA
AAGGTGGAGTCCTAC
AGGTGGAGTCCTACT
GGTGGAGTCCTACTT
GTGGAGTCCTACTTG
TGGAGTCCTACTTGT
GGAGTCCTACTTGTT
GAGTCCTACTTGTTT
AGTCCTACTTGTTTA
GTCCTACTTGTTTAA
TCCTACTTGTTTAAA
CCTACTTGTTTAAAA
CTACTTGTTTAAAAA
TACTTGTTTAAAAAA
ACTTGTTTAAAAAAT
CTTGTTTAAAAAATA
TTGTTTAAAAAATAT
TGTTTAAAAAATATG
GTTTAAAAAATATGT
TTTAAAAAATATGTA
TTAAAAAATATGTAT
TAAAAAATATGTATC
AAAAAATATGTATCT
AAAAATATGTATCTA
AAAATATGTATCTAA
AAATATGTATCTAAG
AATATGTATCTAAGA
ATATGTATCTAAGAA
TATGTATCTAAGAAT
ATGTATCTAAGAATG
TGTATCTAAGAATGT
GTATCTAAGAATGTT
TATCTAAGAATGTTC
ATCTAAGAATGTTCT
TCTAAGAATGTTCTA
CTAAGAATGTTtTAG
TAAGAATGTTCTAGG
AAGAATGTTCTAGGG
AGAATGTTCTAGGGC
GAATGTTCTAGGGCA
AATGTTCTAGGGCAC
ATGTTCTAGGGCACT
TGTTCTAGGGCACTC
GTTCTAGGGCACTCT
TTCTAGGGCACTCTG
TCTAGGGCACTCTGG
CTAGGGCACTCTGGG
TAGGGCACTCTGGGA
AGGGCACTCTGGGAA
GGGCACTCTGGGAAC
GGCACTCTGGGAACC
GCACTCTGGGAACCT
CACTCTGGGAACCTA
ACTCTGGGAACCTAT
CTCTGGGAACCTATA
TCTGGGAACCTATAA
CTGGGAACCTATAAA
TGGGAACCTATAAAG
GGGAACCTATAAAGG
GGAACCTATAAAGGC
GAACCTATAAAGGCA
AACCTATAAAGGCAG
ACCTATAAAGGCAGG
CCTATAAAGGCAGGT
CTATAAAGGCAGGTA
TATAAAGGCAGGTAT
ATAAAGGCAGGTATT
TAAAGGCAGGTATTT
AAAGGCAGGTATTTC
AAGGCAGGTATTTCG
AGGCAGGTATTTCGG
GGCAGGTATTTCGGG
GCAGGTATTTCGGGC
CAGGTATTTCGGGCC
AGGTATTTCGGGCCC
GGTATTTCGGGCCCT
GTATTTCGGGCCCTC
TATTTCGGGCCCTCC
ATTTCGGGCCCTCCT
TTTCGGGCCCTCCTC
TTCGGGCCCTCCTCT
TCGGGCCCTCCTCTT
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CGGGCCCTCCTCTTC
GGGCCCTCCTCTTCA
GGCCCTCCTCTTCAG
GCCCTCCTCTTCAGG
CCCTCCTCTTCAGGA
CCTCCTCTTCAGGAA
CTCCTCTTCAGGAAT
TCCTCTTCAGGAATC
CCTCTTCAGGAATCT
CTCTTCAGGAATCTT
TCTTCAGGAATCTTC
CTTCAGGAATCTTCC
TTCAGGAATCTTCCT
TCAGGAATCTTCCTG
CAGGAATCTTCCTGA
AGGAATCTTCCTGAA
GGAATCTTCCTGAAG
GAATCTTCCTGAAGA
AATCTTCCTGAAGAC
ATCTTCCTGAAGACA
TCTTCCTGAAGACAT
CTTCCTGAAGACATG
TTCCTGAAGACATGG
TCCTGAAGACATGGC
CCTGAAGACATGGCC
CTGAAGACATGGCCC
TGAAGACATGGCCCA
GAAGACATGGCCCAG
AAGACATGGCCCAGT
AGACATGGCCCAGTC
GACATGGCCCAGTCG
ACATGGCCCAGTCGA
CATGGCCCAGTCGAA
ATGGCCCAGTCGAAG
TGGCCCAGTCGAAGG
GGCCCAGTCGAAGGC
GCCCAGTCGAAGGCC
CCCAGTCGAAGGCCC
CCAGTCGAAGGCCCA
CAGTCGAAGGCCCAG
AGTCGAAGGCCCAGG
GTCGAAGGCCCAGGA
TCGAAGGCCCAGGAT
CGAAGGCCCAGGATG
GAAGGCCCAGGATGG
AAGGCCCAGGATGGC
AGGCCCAGGATGGCT
GGCCCAGGATGGCTT
GCCCAGGATGGCTTT
CCCAGGATGGCTTTT
CCAGGATGGCTTTTG
CAGGATGGCTTTTGC
AGGATGGCTTTTGCT
GGATGGCTTTTGCTG
GATGGCTTTTGCTGC
ATGGCTTTTGCTGCG
TGGCTTTTGCTGCGG
GGCTTTTGCTGCGGC
GCTTTTGCTGCGGCC
CTTTTGCTGCGGCCC
TTTTGCTGCGGCCCC
TTTGCTGCGGCCCCG
TTGCTGCGGCCCCGT
TGCTGCGGCCCCGTG
GCTGCGGCCCCGTGG
CTGCGGCCCCGTGGG
TGCGGCCCCGTGGGG
GCGGCCCCGTGGGGT
CGGCCCCGTGGGGTA
GGCCCCGTGGGGTAG
GCCCCGTGGGGTAGG
CCCCGTGGGGTAGGA
CCCGTGGGGTAGGAG
CCGTGGGGTAGGAGG
CGTGGGGTAGGAGGG
GTGGGGTAGGAGGGA
TGGGGTAGGAGGGAC
GGGGTAGGAGGGACA
GGGTAGGAGGGACAG
GGTAGGAGGGACAGA
GTAGGAGGGACAGAG
TAGGAGGGACAGAGA
AGGAGGGACAGAGAG
GGAGGGACAGAGAGA
GAGGGACAGAGAGAC
AGGGACAGAGAGACG
GGGACAGAGAGACGG
GGACAGAGAGACGGG
GACAGAGAGACGGGA
ACAGAGAGACGGGAG
CAGAGAGACGGGAGA
AGAGAGACGGGAGAG
GAGAGACGGGAGAGT
AGAGACGGGAGAGTC
GAGACGGGAGAGTCA
AGACGGGAGAGTCAG
GACGGGAGAGTCAGC
ACGGGAGAGTCAGCC
CGGGAGAGTCAGCCT
GGGAGAGTCAGCCTC
GGAGAGTCAGCCTCC
GAGAGTCAGCCTCCA
AGAGTCAGCCTCCAC
GAGTCAGCCTCCACA
AGTCAGCCTCCACAT
GTCAGCCTCCACATT
TCAGCCTCCACATTC
CAGCCTCCACATTCA
AGCCTCCACATTCAG
GCCTCCACATTCAGA
CCTCCACATTCAGAG
CTCCACATTCAGAGG
TCCACATTCAGAGGC
CCACATTCAGAGGCA
CACATTCAGAGGCAT
ACATTCAGAGGCATC
CATTCAGAGGCATCA
ATTCAGAGGCATC-AC
TTCAGAGGCATCACA
TCAGAGGCATCACAA
CAGAGGCATCACAAG
AGAGGCATCACAAGT
GAGGCATCACAAGTA
AGGCATCACAAGTAA
GGCATCACAAGTAAT
GCATCACAAGTAATG
CATCACAAGTAATGG
ATCACAAGTAATGGC
TCACAAGTAATGGCA
CACAAGTAATGGCAC
ACAAGTAATGGCACA
CAAGTAATGGCACAA
AAGTAATGGCACAAT
AGTAATGGCACAATT
GTAATGGCACAATTC
TAATGGCACAATTCT
AATGGCACAATTCTT
ATGGCACAATTCTTC
TGGCACAATTCTTCG
GGCACAATTCTTCGG
GCACAATTCTTCGGA
CACAATTCTTCGGAT
ACAATTCTTCGGATG
CAATTCTTCGGATGA
AATTCTTCGGATGAC
ATTCTTCGGATGACT
TTCTTCGGATGACTG
TCTTCGGATGACTGC
CTTCGGATGACTGCA
TTCGGATGACTGCAG
TCGGATGACTGCAGA
CGGATGACTGCAGAA
GGATGACTGCAGAAA
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GATGACTGCAGAAAA
ATGACTGCAGAAAAT
TGACTGCAGAAAATA
GACTGCAGAAAATAG
ACTGCAGAAAATAGT
CTGCAGAAAATAGTG
TGCAGAAAATAGTGT
GCAGAAAATAGTGTT
CAGAAAATAGTGTTT
AGAAAATAGTGTTTT
GAAAATAGTGTTTTG
AAAATAGTGTTTTGT
AAATAGTGTTTTGTA
AATAGTGTTTTGTAG
ATAGTGTTTTGTAGT
TAGTGTTTTGTAGTT
AGTGTTTTGTAGTTC
GTGTTTTGTAGTTCA
TGTTTTGTAGTTCAA
GTTTTGTAGTTCAAC
TTTTGTAGTTCAACA
TTTGTAGTTCAACAA
TTGTAGTTCAACAAC
TGTAGTTCAACAACT
GTAGTTCAACAACTC
TAGTTCAACAACTCA
AGTTCAACAACTCAA
GTTCAACAACTCAAG
TTCAACAACTCAAGA
TCAACAACTCAAGAC
CAACAACTCAAGACG
AACAACTCAAGACGA
ACAACTCAAGACGAA
CAACTCAAGACGAAG
AACTCAAGACGAAGC
ACTCAAGACGAAGCT
CTCAAGACGAAGCTT
TCAAGACGAAGCTTA
CAAGACGAAGCTTAT
AAGACGAAGCTTATT
AGACGAAGCTTATTT
GACGAAGCTTATTTC
ACGAAGCTTATTTCT
CGAAGCTTATTTCTG
GAAGCTTATTTCTGA
AAGCTTATTTCTGAG
AGCTTATTTCTGAGG
GCTTATTTCTGAGGA
CTTATTTCTGAGGAT
TTATTTCTGAGGATA
TATTTCTGAGGATAA
ATTTCTGAGGATAAG
TTTCTGAGGATAAGC
TTCTGAGGATAAGCT
TCTGAGGATAAGCTC
CTGAGGATAAGCTCT
TGAGGATAAGCTCTT
GAGGATAAGCTCTTT
AGGATAAGCTCTTTA
GGATAAGCTCTTTAA
GATAAGCTCTTTAAA
ATAAGCTCTTTAAAG
TAAGCTCTTTAAAGG
AAGCTCTTTAAAGGC
AGCTCTTTAAAGGCA
GCTCTTTAAAGGCAA
CTCTTTAAAGGCAAA
TCTTTAAAGGCAAAG
CTTTAAAGGCAAAGC
TTTAAAGGCAAAGCT
TTAAAGGCAAAGCTT
TAAAGGCAAAGCTTT
AAAGGCAAAGCTTTA
AAGGCAAAGCTTTAT
AGGCAAAGCTTTATT
GGCAAAGCTTTATTT
GCAAAGCTTTATTTT
CAAAGCTTTATTTTC
AAAGCTTTATTTTCA
AAGCTTTATTTTCAT
AGCTTTATTTTCATC
GCTTTATTTTCATCT
CTTTATTTTCATCTC
TTTATTTTCATCTCT
TTATTTTCATCTCTC
TATTTTCATCTCTCA
ATTTTCATCTCTCAT
TTTTCATCTCTCATC
TTTCATCTCTCATCT
TTCATCTCTCATCTT
TCATCTCTCATCTTT
CATCTCTCATCTTTT
ATCTCTCATCTTTTG
TCTCTCATCTTTTGT
CTCTCATCTTTTGTC
TCTCATCTTTTGTCC
CTCATCTTTTGTCCT
TCATCTTTTGTCCTC
CATCTTTTGTCCTCC
ATCTTTTGTCCTCCT
TCTTTTGTCCTCCTT
CTTTTGTCCTCCTTA
TTTTGTCCTCCTTAG
TTTGTCCTCCTTAGC
TTGTCCTCCTTAGCA
TGTCCTCCTTAGCAC
GTCCTCCTTAGCACA
TCCTCCTTAGCACAA
CCTCCTTAGCACAAT
CTCCTTAGCACAATG
TCCTTAGCACAATGT
CCTTAGCACAATGTA
CTTAGCACAATGTAA
TTAGCACAATGTAAA
TAGCACAATGTAAAA
AGCACAATGTAAAAA
GCACAATGTAAAAAA
CACAATGTAAAAAAG
ACAATGTAAAAAAGA
CAATGTAAAAAAGAA
AATGTAAAAAAGAAT
ATGTAAAAAAGAATA
TGTAAAAAAGAATAG
GTAAAAAAGAATAGT
TAAAAAAGAATAGTA
AAAAAAGAATAGTAA
AAAAAGAATAGTAAT
AAAAGAATAGTAATA
AAAGAATAGTAATAT
AAGAATAGTAATATC
AGAATAGTAATATCA
GAATAGTAATATCAG
AATAGTAATATCAGA
ATAGTAATATCAGAA
TAGTAATATCAGAAC
AGTAATATCAGAACA
GTAATATCAGAACAG
TAATATCAGAACAGG
AATATCAGAACAGGA
ATATCAGAACAGGAA
TATCAGAACAGGAAG
ATCAGAACAGGAAGG
TCAGAACAGGAAGGA
CAGAACAGGAAGGAG
AGAACAGGAAGGAGG
GAACAGGAAGGAGGA
AACAGGAAGGAGGAA
ACAGGAAGGAGGAAT
CAGGAAGGAGGAATG
AGGAAGGAGGAATGG
GGAAGGAGGAATGGC
GAAGGAGGAATGGCT
AAGGAGGAATGGCTT
WO 00/78341 WO 0078341PCT/AUOO/00693 -57-
AGGAGGAATGGCTTG
GGAGGAATGGCTTGC
GAGGAATGGCTTGCT
AGGAATGGCTTGCTG
GGAATGGCTTGCTGG
GAATGGCTTGCTGGG
AATGGCTTGCTGGGG
ATGGCTTGCTGGGGA
TGGCTTGCTGGGGAG
GGCTTGCTGGGGAGC
GCTTGCTGGGGAGCC
CTTGCTGGGGAGCCC
TTGCTGGGGAGCCCA
TGCTGGGGAGCCCAT
GCTGGGGAGCCCATC
CTGGGGAGCCCATCC
TGGGGAGCCCATCCA
GGGGAGCCCATCCAG
GGGAGCCCATCCAGG
GGAGCCCATCCAGGA
GAGCCCATCCAGGAC
AGCCCATCCAGGACA
GCCCATCCAGGACAC
CCCATCCAGGACACT
CCATCCAGGACACTG
CATCCAGGACACTGG
ATCCAGGACACTGGG
TCCAGGACACTGGGA
CCAGGACACTGGGAG
CAGGACACTGGGAGC
AGGACACTGGGAGCA
GGACACTGGGAGCAC
GACACTGGGAGCACA
ACACTGGGAGCACAT
CACTGGGAGCACATA
ACTGGGAGCACATAG
CTGGGAGCACATAGA
TGGGAGCACATAGAG
GGGAGCACATAGAGA
GGAGCACATAGAGAT
GAGCACATAGAGATT
AGCACATAGAGATTC
GCACATAGAGATTCA
CACATAGAGATTCAC
ACATAGAGATTCACC
CATAGAGATTCACCC
ATAGAGATTCACCCA
TAGAGATTCACCCAT
AGAGATTCACCCATG
GAGATTCACCCATGT
AGATTCACCCATGTT
GATTCACCCATGTTT
ATTCACCCATGTTTG
TTCACCCATGTTTGT
TCACCCATGTTTGTT
CACCCATGTTTGTTG
ACCCATGTTTGTTGA
CCCATGTTTGTTGAA
CCATGTTTGTTGAAC
CATGTTTGTTGAACT
ATGTTTGTTGAACTT
TGTTTGTTGAACTTA
GTTTGTTGAACTTAG
TTTGTTGAACTTAGA
TTGTTGAACTTAGAG
TGTTGAACTTAGAGT
GTTGAACTTAGAGTC
TTGAACTTAGAGTCA
TGAACTTAGAGTCAT
GAACTTAGAGTCATT
AACTTAGAGTCATTC
ACTTAGAGTCATTCT
CTTAGAGTCATTCTC
TTAGAGTCATTCTCA
TAGAGTCATTCTCAT
AGAGTCATTCTCATG
GAGTCATTCTCATGC
AGTCATTCTCATGCT
GTCATTCTCATGCTT
TCATTCTCATGCTTT
CATTCTCATGCTTTT
ATTCTCATGCTTTTC
TTCTCATGCTTTTCT
TCTCATGCTTTTCTT
CTCATGCTTTTCTTT
TCATGCTTTTCTTTA
CATGCTTTTCTTTAT
ATGCTTTTCTTTATA
TGCTTTTCTTTATAA
GCTTTTCTTTATAAT
CTTTTCTTTATAATT
TTTTCTTTATAATTC
TTTCTTTATAATTCA
TTCTTTATAATTCAC
TCTTTATAATTCACA
CTTTATAATTCACAC
TTTATAATTCACACA
TTATAATTCACACAT
TATAATTCACACATA
ATAATTCACACATAT
TAATTCACACATATA
AATTCACACATATAT
ATTCACACATATATG
TTCACACATATATGC
TCACACATATATGCA
CACACATATATGCAG
ACACATATATGCAGA
CACATATATGCAGAG
ACATATATGCAGAGA
CATATATGCAGAGAA
ATATATGCAGAGAAG
TATATGCAGAGAAGA
ATATGCAGAGAAGAT
TATGCAGAGAAGATA
ATGCAGAGAAGATAT
TGCAGAGAAGATATG
GCAGAGAAGATATGT
CAGAGAAGATATGTT
AGAGAAGATATGTTC
GAGAAGATATGTTCT
AGAAGATATGTTCTT
GAAGATATGTTCTTG
AAGATATGTTCTTGT
AGATATGTTCTTGTT
GATATGTTCTTGTTA
ATATGTTCTTGTTAA
TATGTTCTTGTTAAC
ATGTTCTTGTTAACA
TGTTCTTGTTAACAT
GTTCTTGTTAACATT
TTCTTGTTAACATTG
TCTTGTTAACATTGT
CTTGTTAACATTGTA
TTGTTAACATTGTAT
TGTTAACATTGTATA
GTTAACATTGTATAC
TTAACATTGTATACA
TAACATTGTATACAA
AACATTGTATACAAC
ACATTGTATACAACA
CATTGTATACAACAT
ATTGTATACAACATA
TTGTATACAACATAG
TGTATACAACATAGC
GTATACAACATAGCC
TATACAACATAGCCC
ATACAACATAGCCCC
TACAACATAGCCCCA
ACAACATAGCCCCAA
CAACATAGCCCCAAA
AACATAGCCCCAAAT
ACATAGCCCCAAATA
CATAGCCCCAAATAT
WO 00/78341 WO 0/7341PCT/AULOO/00693 58-
ATAGCCCCAAATATA
TAGCCCCAAATATAG
AGCCCCAAATATAGT
GCCCCAAATATAGTA
CCCCAAATATAGTAA
CCCAAATATAGTAAG
CCAAATATAGTAAGA
CAAATATAGTAAGAT
AAATATAGTAAGATC
AATATAGTAAGATCT
ATATAGTAAGATCTA
TATAGTAAGATCTAT
ATAGTAAGATCTATA
TAGTAAGATCTATAC
AGTAAGATCTATACT
GTAAGATCTATACTA
TAAGATCTATACTAG
AAGATCTATACTAGA
AGATCTATACTAGAT
GATCTATACTAGATA
ATCTATACTAGATAA
TCTATACTAGATAAT
CTATACTAGATAATC
TATACTAGATAATCC
ATACTAGATAATCCT
TACTAGATAATCCTA
ACTAGATAATCCTAG
CTAGATAATCCTAGA
TAGATAATCCTAGAT
AGATAATCCTAGATG
GATAATCCTAGATGA
ATAATCCTAGATGAA
TAATCCTAGATGAAA
AATCCTAGATGAAAT
ATCCTAGATGAAATG
TCCTAGATGAAATGT
CCTAGATGAAATGTT
CTAGATGAAATGTTA
TAGATGAAATGTTAG
AGATGAAATGTTAGA
GATGA1AATGTTAGAG
ATGAAATGTTAGAGA
TGAAATGTTAGAGAT
GAAATGTTAGAGATG
AAATGTTAGAGATGC
AATGTTAGAGATGCT
ATGTTAGAGATGCTA
TGTTAGAGATGCTAT
GTTAGAGATGCTATA
TTAGAGATGCTATAT
TAGAGATGCTATATG
AGAGATGCTATATGA
GAGATGCTATATGAT
AGATGCTATATGATA
GATGCTATATGATAC
ATGCTATATGATACA
TGCTATATGATACAA
GCTATATGATACAAC
CTATATGATACAACT
TATATGATACAACTG
ATATGATACAACTGT
TATGATACAACTGTG
ATGATACAACTGTGG
TGATACAACTGTGGC
GATACAACTGTGGCC
ATACAACTGTGGCCA
TACAACTGTGGC CAT
ACAACTGTGGCCATG
CAACTGTGGCCATGA
AACTGTGGCCATGAC
ACTGTGGCCATGACT
CTGTGGCCATGACTG
TGTGGCCATGACTGA
GTGGCCATGACTGAG
TGGCCATGACTGAGG
GGCCATGACTGAGGA
GCCATGACTGAGGAA
CCATGACTGAGGAAA
CATGACTGAGGAAAG
ATGACTGAGGAAAGG
TGACTGAGGAAAGGA
GACTGAGGAAAGGAG
ACTGAGGAAAGGAGC
CTGAGGAAAGGAGCT
TGAGGAAAGGAGCTC
GAGGAAAGGAGCTCA
AGGAAAGGAGCTCAC
GGAAAGGAGCTCACG
GAAAGGAGCTCACGC
AAAGGAGCTCACGCC
AAGGAGCTCACGCCC
AGGAGCTCACGCCCA
GGAGCTCACGCCCAG
GAGCTCACGCCCAGA
AGCTCACGCCCAGAG
GCTCACGCCCAGAGA
CTCACGCCCAGAGAC
TCACGCCCAGAGACT
CACGCCCAGAGACTG
ACGCCCAGAGACTGG
CGCCCAGAGACTGGG
GCCCAGAGACTGGGC
CCCAGAGACTGGGCT
CCAGAGACTGGGCTG
CAGAGACTGGGCTGC
AGAGACTGGGCTGCT
GAGACTGGGCTGCTC
AGACTGGGCTGCTCT
GACTGGGCTGCTCTC
ACTGGGCTGCTCTCC
CTGGGCTGCTCTCCC
TGGGCTGCTCTCCCG
GGGCTGCTCTCCCGG
GGCTGCTCTCCCGGA
GCTGCTCTCCCGGAG
CTGCTCTCCCGGAGG
TGCTCTCCCGGAGGC
GCTCTCCCGGAGGCC
CTCTCCCGGAGGCCA
TCTCCCGGAGGCCAA
CTCCCGGAGGCCAAA
TCCCGGAGGCCAAAC
CCCGGAGGCCAAACC
CCGGAGGCCAAACCC
CGGAGGCCAAACCCA
GGAGGCCAAACCCAA
GAGGCCAAACCCAAG
AGGCCAAACCCAAGA
GGCCAAACCCAAGAA
GCCAAACCCAAGAAG
CCAAACCCAAGAAGG
CAAACCCAAGAAGGT
AAACCCAAGAAGGTC
AACCCAAGAAGGTCT
ACCCAAGAAGGTCTG
CCCAAGAAGGTCTGG
CCAAGAAGGTCTGGC
CAAGAAGGTCTGGCA
AAGAAGGTCTGGCAA
AGAAGGTCTGGCAAA
GAAGGTCTGGCAAAG
AAGGTCTGGCAAAGT
AGGTCTGGCAAAGTC
GGTCTGGCAAAGTCA
GTCTGGCAAAGTCAG
TCTGGCAAAGTCAGG
CTGGCAAAGTCAGGC
TGGCAAAGTCAGGCT
GGCAAAGTCAGGCTC
GCAAAGTCAGGCTCA
CAAAGTCAGGCTCAG
AAAGTCAGGCTCAGG
AAGTCAGGCTCAGGG
WO 00/78341 WO 0078341PCT/AUOO/00693 59
AGTCAGGCTCAGGGA
GTCAGGCTCAGGGAG
TCAGGCTCAGGGAGA
CAGGCTCAGGGAGAC
AGGCTCAGGGAGACT
GGCTCAGGGAGACTC
GCTCAGGGAGACTCT
CTCAGGGAGACTCTG
TCAGGGAGACTCTGC
CAGGGAGACTCTGCC
AGGGAGACTCTGCCC
GGGAGACTCTGCCCT
GGAGACTCTGCCCTG
GAGACTCTGCCCTGC
AGACTCTGCCCTGCT
GACTCTGCCCTGCTG
ACTCTGCCCTGCTGC
CTCTGCCCTGCTGCA
TCTGCCCTGCTGCAG
CTGCCCTGCTGCAGA
TGCCCTGCTGCAGAC
GCCCTGCTGCAGACC
CCCTGCTGCAGACCT
CCTGCTGCAGACCTC
CTGCTGCAGACCTCG
TGCTGCAGACCTCGG
GCTGCAGACCTCGGT
CTGCAGACCTCGGTG
TGCAGACCTCGGTGT
GCAGACCTCGGTGTG
CAGACCTCGGTGTGG
AGACCTCGGTGTGGA
GACCTCGGTGTGGAC
ACCTCGGTGTGGACA
CCTCGGTGTGGACAC
CTCGGTGTGGACACA
TCGGTGTGGACACAC
CGGTGTGGACACACG
GGTGTGGACACACGC
GTGTGGACACACGCT
TGTGGACACACGCTG
GTGGACACACGCTGC
TGGACACACGCTGCA
GGACACACGCTGCAT
GACACACGCTGCATA
ACACACGCTGCATAG
CACACGCTGCATAGA
ACACGCTGCATAGAG
CACGCTGCATAGAGC
ACGCTGCATAGAGCT
CGCTGCATAGAGCTC
GCTGCATAGAGCTCT
CTGCATAGAGCTCTC
TGCATAGAGCTCTCC
GCATAGAGCTCTCCT
CATAGAGCTCTCCTT
ATAGAGCTCTCCTTG
TAGAGCTCTCCTTGA
AGAGCTCTCCTTGAA
GAGCTCTCCTTGAAA
AGCTCTCCTTGAAAA
GCTCTCCTTGAAAAC
CTCTCCTTGAAAACA
TCTCCTTGAAAACAG
CTCCTTGAAAACAGA
TCCTTGAAAACAGAG
CCTTGAAAACAGAGG
CTTGAAAACAGAGGG
TTGAAAACAGAGGGG
TGAAAACAGAGGGGT
GAAAACAGAGGGGTC
AAAACAGAGGGGTCT
AAACAGAGGGGTCTC
AACAGAGGGGTCTCA
ACAGAGGGGTCTCAA
CAGAGGGGTCTCAAG
AGAGGGGTCTCAAGA
GAGGGGTCTCAAGAC
AGGGGTCTCAAGACA
GGGGTCTCAAGACAT
GGGTCTCAAGACATT
GGTCTCAAGACATTC
GTCTCAAGACATTCT
TCTCAAGACATTCTG
CTCAAGACATTCTGC
TCAAGACATTCTGCC
CAAGACATTCTGCCT
AAGACATTCTGCCTA
AGACATTCTGCCTAC
GACATTCTGCCTACC
ACATTCTGCCTACCT
CATTCTGCCTACCTA
ATTCTGCCTACCTAT
TTCTGCCTACCTATT
TCTGCCTACCTATTA
CTGCCTACCTATTAG
TGCCTACCTATTAGC
GCCTACCTATTAGCT
CCTACCTATTAGCTT
CTACCTATTAGCTTT
TACCTATTAGCTTTT
ACCTATTAGCTTTTC
CCTATTAGCTTTTCT
CTATTAGCTTTTCTT
TATTAGCTTTTCTTT
ATTAGCTTTTCTTTA
TTAGCTTTTCTTTAT
TAGCTTTTCTTTATT
AGCTTTCTTTATTT
GCTTTTCTTTATTTT
CTTTTCTTTATTTTT
TTTTCTTTATTTTTT
TTTCTTTATTTTTTT
TTCTTTATTTTTTTA
TCTTTATTTTTTTAA
CTTTATTTTTTTAAC
TTTATTTTTTTAACT
TTATTTTTTTAACTT
TATTTTTTTAACTTT
ATTTTTTTAACTTTT
TTTTTTTAACTTTTT
TTTTTTAACTTTTTG
TTTTTAACTTTTTGG
TTTTAACTTTTTGGG
TTTAACTTTTTGGGG
TTAACTTTTTGGGGG
TAACTTTTTGGGGGG
AACTTTTTGGGGGGA
ACTTTTTGGGGGGAA
CTTTTTGGGGGGAAA
TTTTTGGGGGGAAAA
TTTTGGGGGGAAAAG
TTTGGGGGGAAAAGT
TTGGGGGGAAAAGTA
TGGGGGGAAAAGTAT
GGGGGGAAAAGTATT
GGGGGAAAAGTATTT
GGGGAAAAGTATTTT
GGGAAAAGTATTTTT
GGAAAAGTATTTTTG
GAAAAGTATTTTTGA
AAAAGTATTTTTGAG
AAAGTATTTTTGAGA
AAGTATTTTTGAGAA
AGTATTTTTGAGAAG
GTATTTTTGAGAAGT
TATTTTTGAGAAGTT
ATTTTTGAGAAGTTT
TTTTTGAGAAGTTTG
TTTTGAGAAGTTTGT
TTTGAGAAGTTTGTC
TTGAGAAGTTTGTCT
TGAGAAGTTTGTCTT
WO 00/78341 WO 0078341PCT/AUOO/00693 60
GAGAAGTTTGTCTTG
AGAAGTTTGTCTTGC
GAAGTTTGTCTTGCA
AAGTTTGTCTTGCAA
AGTTTGTCTTGCAAT
GTTTGTCTTGCAATG
TTTGTCTTGCAATGT
TTGTCTTGCAATGTA
TGTCTTGCAATGTAT
GTCTTGCAATGTATT
TCTTGCAATGTATTT
CTTGCAATGTATTTA
TTGCAATGTATTTAT
TGCAATGTATTTATA
GCAATGTATTTATAA
CAATGTATTTATAAA
AATGTATTTATAAAT
ATGTATTTATAAATA
TGTATTTATAAATAG
GTATTTATAAATAGT
TATTTATAAATAGTA
ATTTATAAATAGTAA
TTTATAAATAGTAAA
TTATAAATAGTAAAT
TATAAATAGTAAATA
ATAAATAGTAAATAA
TAAATAGTAAATAAA
AAATAGTAAATAAAG
AATAGTAAATAAAGT
ATAGTAAATAAAGTT
TAGTAAATAAAGTTT
AGTAAATAAAGTTTT
GTAAATAAAGTTTTT
TAAATAAAGTTTTTA
AAATAAAGTTTTTAC
AATAAAGTTTTTACC
ATAA.AGTTTTTACCA
TAAAGTTTTTACCAT
AAAGTTTTTACCATT
EXAMPLE 8 Antisense oligonucleoticles to IGF-I may be selected fromn molecules capable of interacting with one or more of the following sense oligonucleotides: TTTTTTTTTTTTTTG TTTTTTTTTTTGAGA TTTTTTTTGAGAAAG TTTTTTTTTTTTTGA TTTTTTTTTTGAGAA TTTTTTTCAGAAAGG TTTTTTTTTTTTGAG TTTTTTTTTGAGAAA TTTTTTGAGAAAGGG WO 00/78341 WO 0078341PCT/AUOO/00693 -61-
TTTTTGAGAAAGGGA
TTTTGAGAAAGGGAA
TTTGAGAAAGGGAAT
TTGAGAAAGGGAATT
TGAGAAAGGGAATTT
GAGAAAGGGAATTTC
AGAAAGGGAATTTCA
GAAAGGGAATTTCAT
AAAG(GGAATTTCATC
AAGGGAATTTCATCC
AGGGAATTTCATCCC
GGGAATTTCATCCCA
GGAATTTCATCCCAA
GAATTTCATCCCAAA
AATTTCATCCCAAAT
ATTTCATCCCAAATA
TTTCATCCCAAATAA
TTCATCCCAAATAAA
TCATCCCAAATAAAA
CATCCCAAATAAAAG
ATCCCAAATAAAAGG
TCCCAAATAAAAGGA
CCCAAATAAAAGGAA
CCAAATAAAAGGAAT
CAAATAAAAGGAATG
AAATAAAAGGAATGA
AATAAAAGGAATGAA
ATAAAAGGAATGAAG
TAAAAGGAATGAAGT
AAAAGGAATGAAGTC
AAAGGAATGAAGTCT
AAGGAATGAAGTCTG
AGGAATGAAGTCTGG
GGAATGAAGTCTGGC
GAATGAAGTCTGGCT
AATGAAGTCTGGCTC
ATGAAGTCTGGCTCC
TGAAGTCTGGCTCCG
GAAGTCTGGCTCCGG
AAGTCTGGCTCCGGA
AGTCTGGCTCCGGAG
GTCTGGCTCCGGAGG
TCTGGCTCCGGAGGA
CTGGCTCCGGAGGAG
TGGCTCCGGAGGAGG
GGCTCCGGAGGAGGG
GCTCCGGAGGAGGGT
CTCCGGAGGAGGGTC
TCCGGAGGAGGGTCC
CCGGAGGAGGGTCCC
CGGAGGAGGGTCCCC
GGAGGAGGGTCCCCG
GAGGAGGGTCCCCGA
AGGAGGGTCCCCGAC
GGAGGGTCCCCGACC
GAGGGTCCCCGACCT
AGGGTCCCCGACCTC
GGGTCCCCGACCTCG
GGTCCCCGACCTCGC
GTCCCCGACCTCGCT
TCCCCGACCTCGCTG
CCCCGACCTCGCTGT
CCCGACCTCGCTGTG
CCGACCTCGCTGTGG
CGACCTCGCTGTGGG
GACCTCGCTGTGGGG
ACCTCGCTGTGGGGG
CCTCGCTGTGGGGGC
CTCGCTGTGGGGGCT
TCGCTGTGGGGGCTC
CGCTGTGGGGGCTCC
GCTGTGGGGGCTCCT
CTGTGGGGGCTCCTG
TGTGGGGGCTCCTGT
GTGGGGGCTCCTGTT
TGGGGGCTCCTGTTT
GGGGGCTCCTGTTTC
GGGGCTCCTGTTTCT
GGGCTCCTGTTTCTC
GGCTCCTGTTTCTCT
GCTCCTGTTTCTCTC
CTCCTGTTTCTCTCC
TCCTGTTTCTCTCCG
CCTGTTTCTCTCCGC
CTGTTTCTCTCCGCC
TGTTTCTCTCCGCCG
GTTTCTCTCCGCCGC
TTTCTCTCCGCCGCG
TTCTCTCCGCCGCGC
TCTCTCCGCCGCGCT
CTCTCCGCCGCGCTC
TCTCCGCCGCGCTCT
CTCCGCCGCGCTCTC
TCCGCCGCGCTCTCG
CCGCCGCGCTCTCGC
CGCCGCGCTCTCGCT
GCCGCGCTCTCGCTC
CCGCGCTCTCGCTCT
CGCGCTCTCGCTCTG
GCGCTCTCGCTCTGG
CGCTCTCGCTCTGGC
GCTCTCGCTCTGGCC
CTCTCGCTCTGGCCG
TCTCGCTCTGGCCGA
CTCGCTCTGGCCGAC
TCGCTCTGGCCGACG
CGCTCTGGCCGACGA
GCTCTGGCCGACGAG
CTCTGGCCGACGAGT
TCTGGCCGACGAGTG
CTGGCCGACGAGTGG
TGGCCGACGAGTGGA
GGCCGACGAGTGGAG
GCCGACGAGTGGAGA
CCGACGAGTGGAGAA
CGACGAGTGGAGAAA
GACGAGTGGAGAAAT
ACGAGTGGAGAAATC
CGAGTGGAGAAATCT
GAGTGGAGAAATCTG
AGTGGAGAAATCTGC
GTGGAGAAATCTGCG
TGGAGAAATCTGCGG
GGAGAAATCTGCGGG
GAGAAATCTGCGGGC
AGAAATCTGCGGGCC
GAAATCTGCGGGCCA
AAATCTGCGGGCCAG
AATCTGCGGGCCAGG
ATCTGCGGGCCAGGC
TCTGCGGGCCAGGCA
CTGCGGGCCAGGCAT
TGCGGGCCAGGCATC
GCGGGCCAGGCATCG
CGGGCCAGGCATCGA
GGGCCAGGCATCGAC
GGCCAGGCATCGACA
GCCAGGCATCGACAT
CCAGGCATCGACATC
CAGGCATCGACATCC
AGGCATCGACATCCG
GGCATCGACATCCGC
GCATCGACATCCGCA
CATCGACATCCGCAA
ATCGACATCCGCAAC
TCGACATCCGCAACG
CGACATCCGCAACGA
GACATCCGCAACGAC
ACATCCGCAACGACT
CATCCGCAACGACTA
ATCCGCAACGACTAT
TCCGCAACGACTATC
CCGCAACGACTATCA
WO 00/78341 WO 0078341PCT/AUOO/00693 -62
CGCAACGACTATCAG
GCAACGACTATCAGC
CAACGACTATCAGCA
AACGACTATCAGCAG
ACGACTATCAGCAGC
CGACTATCAGCAGCT
GACTATCAGCAGCTG
ACTATCAGCAGCTGA
CTATCAGCAGCTGAA
TATCAGCAGCTGAAG
ATCAGCAGCTGAAGC
TCAGCAGCTGAAGCG
CAGCAGCTGAAGCGC
AGCAGCTGAAGCGCC
GCAGCTGAAGCGCCT
CAGCTGAAGCGCCTG
AGCTGAAGCGCCTGG
GCTGAAGCGCCTGGA
CTGAAGCGCCTGGAG
TGAAGCGCCTGGAGA
GAAGCGCCTGGAGAA
AAGCGCCTGGAGAAC
AGCGCCTGGAGAACT
GCGCCTGGAGAACTG
CGCCTGGAGAACTGC
GCCTGGAGAACTGCA
CCTGGAGAACTGCAC
CTGGAGAACTGCACG
TGGAGAACTGCACGG
GGAGAACTGCACGGT
GAGAACTGCACGGTG
AGAACTGCACGGTGA
GAACTGCACGGTGAT
AACTGCACGGTGATC
ACTGCACGGTGATCG
CTGCACGGTGATCGA
TGCACGGTGATCGAG
GCACGGTGATCGAGG
CACGGTGATCGAGGG
ACGGTGATCGAGGGC
CGGTGATCGAGGGCT
GGTGATCGAGGGCTA
GTGATCGAGGGCTAC
TGATCGAGGGCTACC
GATCGAGGGCTACCT
ATCGAGGGCTACCTC
TCGAGGGCTACCTCC
CGAGGGCTACCTCCA
GAGGGCTACCTCCAC
AGGGCTACCTCCACA
GGGCTACCTCCACAT
GGCTACCTCCACATC
GCTACCTCCACATCC
CTACCTCCACATCCT
TACCTCCACATCCTG
ACCTCCACATCCTGC
CCTCCACATCCTGCT
CTCCACATCCTGCTC
TCCACATCCTGCTCA
CCACATCCTGCTCAT
CACATCCTGCTCATC
ACATCCTGCTCATCT
CATCCTGCTCATCTC
ATCCTGCTCATCTCC
TCCTGCTCATCTCCA
CCTGCTCATCTCCAA
CTGCTCATCTCCAAG
TGCTCATCTCCAAGG
GCTCATCTCCAAGGC
CTCATCTCCAAGGCC
TCATCTCCAAGGCCG
CATCTCCAAGGCCGA
ATCTCCAAGGCCGAG
TCTCCAAGGCCGAGG
CTCCAAGGCCGAGGA
TCCAAGGCCGAGGAC
CCAAGGCCGAGGACT
CAAGGCCGAGGACTA
AAGGCCGAGGACTAC
AGGCCGAGGACTACC
GGCCGAGGACTACCG
GCCGAGGACTACCGC
CCGAGGACTACCGCA
CGAGGACTACCGCAG
GAGGACTACCGCAGC
AGGACTACCGCAGCT
GGACTACCGCAGCTA
GACTACCGCAGCTAC
ACTACCGCAGCTACC
CTACCGCAGCTACCG
TACCGCAGCTACCGC
ACCGCAGCTACCGC'r
CCGCAGCTACCGCTT
CGCAGCTACCGCTTC
GCAGCTACCGCTTCC
CAGCTACCGCTTCCC
AGCTACCGCTTCCCC
GCTACCGCTTCCCCA
CTACCGCTTCCCCAA
TACCGCTTCCCCAAG
ACCGCTTCCCCAAGC
CCGCTTCCCCAAGCT
CGCTTCCCCAAGCTC
GCTTCCCCAAGCTCA
CTTCCCCAAGCTCAC
TTCCCCAAGCTCACG
TCCCCAAGCTCACGG
CCCCAAGCTCACGGT
CCCAAGCTCACGGTC
CCAAGCTCACGGTCA
CAAGCTCACGGTCAT
AAGCTCACGGTCATT
AGCTCACGGTCATTA
GCTCACGGTCATTAC
CTCACGGTCATTACC
TCACGGTCATTACCG
CACGGTCATTACCGA
ACGGTCATTACCGAG
CGGTCATTACCGAGT
GGTCATTACCGAGTA
GTCATTACCGAGTAC
TCATTACCGAGTACT
CATTACCGAGTACTT
ATTACCGAGTACTTG
TTACCGAGTACTTGC
TACCGAGTACTTGCT
ACCGAGTACTTGCTG
CCGAGTACTTGCTGC
CGAGTACTTGCTGCT
GAGTACTTGCTGCTG
AGTACTTGCTGCTGT
GTACTTGCTGCTGTT
TACTTGCTGCTGTTC
ACTTGCTGCTGTTCC
CTTGCTGCTGTTCCG
TTGCTGCTGTTCCGA
TGCTGCTGTTCCGAG
GCTGCTGTTCCGAGT
CTGCTGTTCCGAGTG
TGCTGTTCCGAGTGG
GCTGTTCCGAGTGGC
CTGTTCCGAGTGGCT
TGTTCCGAGTGGCTG
GTTCCGAGTGGCTGG
TTCCGAGTGGCTGGC
TCCGAGTGGCTGGCC
CCGAGTGGCTGGCCT
CGAGTGGCTGGCCTC
GAGTGGCTGGCCTCG
AGTGGCTGGCCTCGA
GTGGCTGGCCTCGAG
TGGCTGGCCTCGAGA
GGCTGGCCTCGAGAG
WO 00/78341 WO 0078341PCT/AUOO/00693 63
GCTGGCCTCGAGAGC
CTGGCCTCGAGAGCC
TGGCCTCGAGAGCCT
GGCCTCGAGAGC CT C
GCCTCGAGAGCCTCG
CCTCGAGAGCCTCGG
CTCGAGAGCCTCGGA
TCGAGAGCCTCGGAG
CGAGAGCCTCGGAGA
GAGAGCCTCGGAGAC
AGAGCCTCGGAGACC
GAGCCTCGGAGACCT
AGCCTCGGAGACCTC
GCCTCGGAGACCTCT
CCTCGGAGACCTCTT
CTCGGAGACCTCTTC
TCGGAGACCTCTTCC
CGGAGACCTCTTCCC
GGAGACCTCTTCCCC
GAGACCTCTTCCCCA
AGACCTCTTCCCCAA
GACCTCTTCCCCAAC
ACCTCTTCCCCAACC
CCTCTTCCCCAACCT
CTCTTCCCCAACCTC
TCTTCCCCAACCTCA
CTTCCCCAACCTCAC
TTCCCCAACCTCACG
TCCCCAACCTCACGG
CCCCAACCTCACGGT
CCCAACCTCACGGTC
CCAACCTCACGGTCA
CAACCTCACGGTCAT
AACCTCACGGTCATC
ACCTCACGGTCATCC
CCTCACGGTCATCCG
CTCACGGTCATCCGC
TCACGGTCATCCGCG
CACGGTCATCCGCGG
ACGGTCATCCGCGGC
CGGTCATCCGCGGCT
GGTCATCCGCGGCTG
GTCATCCGCGGCTGG
TCATCCGCGGCTGGA
CATCCGCGGCTGGAA
ATCCGCGGCTGGAAA
TCCGCGGCTGGAAAC
CCGCGGCTGGAAACT
CGCGGCTGGAAACTC
GCGGCTGGAAACTCT
CGGCTGGAAACTCTT
GGCTGGAAACTCTTC
GCTGGAAACTCTTCT
CTGGAAACTCTTCTA
TGGAAACTCTTCTAC
GGAAACTCTTCTACA
GAAACTCTTCTACAA
AAACTCTTCTACAAC
AACTCTTCTACAACT
ACTCTTCTACAACTA
CTCTTCTACAACTAC
TCTTCTACAACTACG
CTTCTACAACTACGC
TTCTACAACTACGCC
TCTACAACTACGCCC
CTACAACTACGCCCT
TACAACTACGCCCTG
ACAACTACGCCCTGG
CAACTACGCCCTGGT
AACTACGCCCTGGTC
ACTACGCCCTGGTCA
CTACGCCCTGGTCAT
TACGCCCTGGTCATC
ACGCCCTGGTCATCT
CGCCCTGGTCATCTT
GCCCTGGTCATCTTC
CCCTGGTCATCTTCG
CCTGGTCATCTTCGA
CTGGTCATCTTCGAG
TGGTCATCTTCGAGA
GGTCATCTTCGAGAT
GTCATCTTCGAGATG
TCATCTTCGAGATGA
CATCTTCGAGATGAC
ATCTTCGAGATGACC
TCTTCGAGATGACCA
CTTCGAGATGACCAA
TTCGAGATGACCAAT
TCGAGATGACCAATC
CGAGATGACCAATCT
GAGATGACCAATCTC
AGATGACCAATCTCA
GATGACCAATCTCAA
ATGACCAATCTCAAG
TGACCAATCTCAAGG
GACCAATCTCAAGGA
ACCAATCTCAAGGAT
CCAATCTCAAGGATA
CAATCTCAAGGATAT
AATCTCAAGGATATT
ATCTCAAGGATATTG
TCTCAAGGATATTGG
CTCAAGGATATTGGG
TCAAGGATATTGGGC
CAAGGATATTGGGCT
AAGGATATTGGGCTT
AGGATATTGGGCTTT
GGATATTGGGCTTTA
GATATTGGGCTTTAC
ATATTGGGCTTTACA
TATTGGGCTTTACAA
ATTGGGCTTTACAAC
TTGGGCTTTACAACC
TGGGCTTTACAACCT
GGGCTTTACAACCTG
GGCTTTACAACCTGA
GCTTTACAACCTGAG
CTTTACAACCTGAGG
TTTACAACCTGAGGA
TTACAACCTGAGGAA
TACAACCTGAGGAAC
ACAACCTGAGGAACA
CAACCTGAGGAACAT
AACCTGAGGAACATT
ACCTGAGGAACATTA
CCTGAGGAACATTAC
CTGAGGAACATTACT
TGAGGAACATTACTC
GAGGAACATTACTCG
AGGAACATTACTCGG
GGAACATTACTCGGG
GAACATTACTCGGGG
AACATTACTCGGGGG
ACATTACTCGGGGGG
CATTACTCGGGGGGC
ATTACTCGGGGGGCC
TTACTCGGGGGGCCA
TACTCGGGGGGCCAT
ACTCGGGGGGCCATC
CTCGGGGGGCCATCA
TCGGGGGGCCATCAG
CGGGGGGCCATCAGG
GGGGGGCCATCAGGA
GGGGGCCATCAGGAT
GGGGCCATCAGGATT
GGGCCATCAGGATTG
GGCCATCAGGATTGA
GCCATCAGGATTGAG
CCATCAGGATTGAGA
CATCAGGATTGAGAA
ATCAGGATTGAGAAA
TcAGGATTGAGAAAA
CAGGATTGAGAAAAA
WO 00/78341 WO 0078341PCT/AUOO/00693 -64-
AGGATTGAGAAAAAT
GGATTGAGAAAAATG
GATTGAGAAAAATGC
ATTGAGAAAAATGCT
TTGAGAAAAATGCTG
TGAGAAAAATGCTGA
GAGAAAAATGCTGAC
AGAAAAATGCTGACC
GAAAAATGCTGACCT
AAAAATGCTGACCTC
AAAATGCTGACCTCT
AAATGCTGACCTCTG
AATGCTGACCTCTGT
ATGCTGACCTCTGTT
TGCTGACCTCTGTTA
GCTGACCTCTGTTAC
CTGACCTCTGTTACC
TGACCTCTGTTACCT
CACCTCTGTTACCTC
ACCTCTGTTACCTCT
CCTCTGTTACCTCTC
CTCTGTTACCTCTCC
TCTGTTACCTCTCCA
CTGTTACCTCTCCAC
TGTTACCTCTCCACT
GTTACCTCTCCACTG
TTACCTCTCCACTGT
TACCTCTCCACTGTG
ACCTCTCCACTGTGG
CCTCTCCACTGTGGA
CTCTCCACTGTGGAC
TCTCCACTGTGGACT
CTCCACTGTGGACTG
TCCACTGTGGACTGG
CCACTGTGGACTGGT
CACTGTGGACTGGTC
ACTGTGGACTGGTCC
CTGTGGACTGGTCCC
TGTGGACTGGTCCCT
GTGGACTGGTCCCTG
TGGACTGGTCCCTGA
GGACTGGTCCCTGAT
GACTGGTCCCTGATC
ACTGGTCCCTGATCC
CTGGTCCCTGATCCT
TGGTCCCTGATCCTG
GGTCCCTGATCCTGG
GTCCCTGATCCTGGA
TCCCTGATCCTGGAT
CCCTGATCCTGGATG
CCTGATCCTGGATGC
CTGATCCTGGATGCG
TGATCCTGGATGCGG
GATCCTGGATGCGGT
ATCCTGGATGCGGTG
TCCTGGATGCGGTGT
CCTGGATGCGGTGTC
CTGGATGCGGTGTCC
TGGATGCGGTGTCCA
GGATGCGGTGTCCAA
GATGCGGTGTCCAAT
ATGCGGTGTCCAATA
TGCGGTGTCCAATAA
GCGGTGTCCAATAAC
CGGTGTCCAATAACT
GGTGTCCAATAACTA
GTGTCCAATAACTAC
TGTCCAATAACTACA
GTCCAATAACTACAT
TCCAATAACTACATT
CCAATAACTACATTG
CAATAACTACATTGT
AATAACTACATTGTG
ATAACTACATTGTGG
TAACTACATTGTGGG
AACTACATTGTGGGG
ACTACATTGTGGGGA
CTACATTGTGGGGAA
TACATTGTGGGGAAT
ACATTGTGGGGAATA
CATTGTGGGGAATAA
ATTGTGGGGAATAAG
TTGTGGGGAATAAGC
TGTGGGGAATAAGCC
GTGGGGAATAAGCCC
TGGGGAATAAGCCCC
GGGGAATAAGCCCCC
GGGAATAAGCCCCCA
GGAATAAGCCCCCAA
GAATAAGCCCCCAAA
AATAAGCCCCCAAAG
ATAAGCCCCCAAAGG
TAAGCCCCCAAAGGA
AAGCCCCCAAAGGAA
AGCCCCCAAAGGAAT
GCCCCCAAAGGAATG
CCCCCAAAGGAATGT
CCCCAAAGGAATGTG
CCCAAAGGAATGTGG
CCAAAGGAATGTGGG
CAAAGGAATGTGGGG
AAAGGAATGTGGGGA
AAGGAATGTGGGGAC
AGGAATGTGGGGACC
GGAATGTGGGGACCT
GAATGTGGGGACCTG
AATGTGGGGACCTGT
ATGTGGGGACCTGTG
TGTGGGGACCTGTGT
GTGGGGACCTGTGTC
TGGGGACCTGTGTCC
GGGGACCTGTGTCCA
GGGACCTGTGTCCAG
GGACCTGTGTCCAGG
GACCTGTGTCCAGGG
ACCTGTGTCCAGGGA
CCTGTGTCCAGGGAC
CTGTGTCCAGGGACC
TGTGTCCAGGGACCA
GTGTCCAGGGACCAT
TGTCCAGGGACCATG
GTCCAGGGACCATGG
TCCAGGGACCATGGA
CCAGGGACCATGGAG
CAGGGACCATGGAGG
AGGGACCATGGAGGA
GGGACCATGGAGGAG
GGACCATGGAGGAGA
GACCATGGAGGAGAA
ACCATGGAGGAGAAG
CCATGGAGGAGAAGC
CATGGAGGAGAAGCC
ATGGAGGAGAAGCCG
TGGAGGAGAAGCCGA
GGAGGAGAAGCCGAT
GAGGAGAAGCCGATG
AGGAGAAGCCGATGT
GGAGAAGCCGATGTG
GAGAAGCCGATGTGT
AGAAGCCGATGTGTG
GAAGCCGATGTGTGA
AAGCCGATGTGTGAG
AGCCGATGTGTGAGA
GCCGATGTGTGAGAA
CCGATGTGTGAGAAG
CGATGTGTGAGAAGA
GATGTGTGAGAAGAC
ATGTGTGAGAAGACC
TGTGTGAGAAGACCA
GTGTGAGAAGACCAC
TGTGAGAAGACCACC
GTGAGAAGACCACCA
TGAGAAGACCACCAT
WO 00/78341 WO 0078341PCT/AUOO/00693 65
GAGAAGACCACCATC
AGAAGACCACCATCA
GAAGACCACCATCAA
AAGACCACCATCAAC
AGACCACCATCAACA
GACCACCATCAACAA
ACCACCATCAACAAT
CCACCATCAACAATG
CACCATCAACAATGA
ACCATCAACAATGAG
CCATCAACAATGAGT
CATCAACAATGAGTA
ATCAACAATGAGTAC
TCAACAATGAGTACA
CAACAATGAGTACAA
AACAATGAGTACAAC
ACAATGAGTACAACT
CAATGAGTACAACTA
AATGAGTACAACTAC
ATGAGTACAACTACC
TGAGTACAACTACCG
GAGTACAACTACCGC
AGTACAACTACCGCT
GTACAACTACCGCTG
TACAACTACCGCTGC
ACAACTACCGCTGCT
CAACTACCGCTGCTG
AACTACCGCTGCTGG
ACTACCGCTGCTGGA
CTACCGCTGCTGGAC
TACCGCTGCTGGACC
ACCGCTGCTGGACCA
CCGCTGCTGGACCAC
CGCTGCTGGACCACA
GCTGCTGGACCACAA
CTGCTGGACCACAAA
TGCTGGACCACAAAC
GCTGGACCACAAACC
CTGGACCACAAACCG
TGGACCACAAACCGC
GGACCACAAACCGCT
GACCACAAACCGCTG
ACCACAAACCGCTGC
CCACAAACCGCTGCC
CACAAACCGCTGCCA
ACAAACCGCTGCCAG
CAAACCGCTGCCAGA
AAACCGCTGCCAGAA
AACCGCTGCCAGAAA
ACCGCTGCCAGAAAA
CCGCTGCCAGAAAAT
CGCTGCCAGAAAATG
GCTGCCAGAAAATGT
CTGCCAGAAAATGTG
TGCCAGAAAATGTGC
GCCAGAAAATGTGCC
CCAGAAAATGTGCCC
CAGAAAATGTGCCCA
AGAAAATGTGCCCAA
GAAAATGTGCCCAAG
AAAATGTGCCCAAGC
AAATGTGCCCAAGCA
AATGTGCCCAAGCAC
ATGTGCCCAAGCACG
TGTGCCCAAGCACGT
GTGCCCAAGCACGTG
TGCCCAAGCACGTGT
GCCCAAGCACGTGTG
CCCAAGCACGTGTGG
CCAAGCACGTGTGGG
CAAGCACGTGTGGGA
AAGCACGTGTGGGAA
AGCACGTGTGGGAAG
GCACGTGTGGGAAGC
CACGTGTGGGAAGCG
ACGTGTGGGAAGCGG
CGTGTGGGAAGCGGG
GTGTGGGAAGCGGGC
TGTGGGAAGCGGGCG
GTGGGAAGCGGGCGT
TGGGAAGCGGGCGTG
GGGAAGCGGGCGTGC
GGAAGCGGGCGTGCA
GAAGCGGGCGTGCAC
AAGCGGGCGTGCACC
AGCGGGCGTGCACCG
GCGGGCGTGCACCGA
CGGGCGTGCACCGAG
GGGCGTGCACCGAGA
GGCGTGCACCGAGAA
GCGTGCACCGAGAAC
CGTGCACCGAGAACA
GTGCACCGAGAACAA
TGCACCGAGAACAAT
GCACCGAGAACAATG
CACCGAGAACAATGA
ACCGAGAACAATGAG
CCGAGAACAATGAGT
CGAGAACAATGAGTG
GAGAACAATGAGTGC
AGAACAATGAGTGCT
GAACAATGAGTGCTG
AACAATGAGTGCTGC
ACAATGAGTGCTGCC
CAATGAGTGCTGCCA
AATGAGTGCTGCCAC
ATGAGTGCTGCCACC
TGAGTGCTGCCACCC
GAGTGCTGCCACCCC
AGTGCTGCCACCCCG
GTGCTGCCACCCCGA
TGCTGCCACCCCGAG
GCTGCCACCCCGAGT
CTGCCACCCCGAGTG
TGCCACCCCGAGTGC
GCCACCCCGAGTGCC
CCACCCCGAGTGCCT
CACCCCGAGTGCCTG
ACCCCGAGTGCCTGG
CCCCGAGTGCCTGGG
CCCGAGTGCCTGGGC
CCGAGTGCCTGGGCA
CGAGTGCCTGGGCAG
GAGTGCCTGGGCAGC
AGTGCCTGGGCAGCT
GTGCCTGGGCAGCTG
TGCCTGGGCAGCTGC
GCCTGGGCAGCTGCA
CCTGGGCAGCTGCAG
CTGGGCAGCTGCAGC
TGGGCAGCTGCAGCG
GGGCAGCTGCAGCGC
GGCAGCTGCAGCGCG
GCAGCTGCAGCGCGC
CAGCTGCAGCGCGCC
AGCTGCAGCGCGCCT
GCTGCAGCGCGCCTG
CTGCAGCGCGCCTGA
TGCAGCGCGCCTGAC
GCAGCGCGCCTGACA
CAGCGCGCCTGACAA
AGCGCGCCTGACAAC
GCGCGCCTGACAACG
CGCGCCTGACAACGA
GCGCCTGACAACGAC
CGCCTGACAACGACA
GCCTGACAACGACAC
CCTGACAACGACACG
CTGACAACGACACGG
TGACAACGACACGGC
GACAACGACACGGCC
ACAACGACACGGCCT
CAACGACACGGCCTG
WO 00/78341 WO 00/834 1PCT/AUOO/00693 66
AACGACACGG~CCTGT
ACGACACGGCCTGTG
CGACACGGCCTGTGT
GACACGGCCTGTGTA
ACACGGCCTGTGTAG
CACGGCCTGTGTAGC
ACGGCCTGTGTAGCT
CGGCCTGTGTAGCTT
GGCCTGTGTAGCTTG
GCCTGTGTAGCTTGC
CCTGTGTAGCTTGCC
CTGTGTAGCTTGCCG
TGTGTAGCTTGCCGC
GTGTAGCTTGCCGCC
TGTAGCTTGCCGCCA
GTAGCTTGCCGCCAC
TAGCTTGCCGCCACT
AGCTTGCCGCCACTA
GCTTGCCGCCACTAC
CTTGCCGCCACTACT
TTGCCGCCACTACTA
TGCCGCCACTACTAC
GCCGCCACTACTACT
CCGCCACTACTACTA
CGCCACTACTACTAT
GCCACTACTACTATG
CCACTACTACTATGC
CACTACTACTATGCC
ACTACTACTATGCCG
CTACTACTATGCCGG
TACTACTATGCCGGT
ACTACTATGCCGGTG
CTACTATGCCGGTGT
TACTATGCCGGTGTC
ACTATGCCGGTGTCT
CTATGCCGGTGTCTG
TATGCCGGTGTCTGT
ATGCCGGTGTCTGTG
TGCCGGTGTCTGTGT
GCCGGTGTCTGTGTG
CCGGTGTCTGTGTGC
CGGTGTCTGTGTGCC
GGTGTCTGTGTGCCT
GTGTCTGTGTGCCTG
TGTCTGTGTGCCTGC
GTCTGTGTGCCTGCC
TCTGTGTGCCTGCCT
CTGTGTGCCTGCCTG
TGTGTGCCTGCCTGC
GTGTGCCTGCCTGCC
TGTGCCTGCCTGCCC
GTGCCTGCCTGCCCG
TGCCTGCCTGCCCGC
GCCTGCCTGCCCGCC
CCTGCCTGCCCGCCC
CTGCCTGCCCGCCCA
TGCCTGCCCGCCCAA
GCCTGCCCGCCCAAC
CCTGCCCGCCCAACA
CTGCCCGCCCAACAC
TGCCCGCCCAACACC
GCCCGCCCAACACCT
CCCGCCCAACACCTA
CCGCCCAACACCTAC
CGCCCAACACCTACA
GCCCAACACCTACAG
CCCAACACCTACAGG
CCAACACCTACAGGT
CAACACCTACAGGTT
AACACCTACAGGTTT
ACACCTACAGGTTTG
CACCTACAGGTTTGA
ACCTACAGGTTTGAG
CCTACAGGTTTGAGG
CTACAGGTTTGAGGG
TACAGGTTTGAGGGC
ACAGGTTTGAGGGCT
CAGGTTTGAGGGCTG
AGGTTTGAGGGCTGG
GGTTTGAGGGCTGGC
GTTTGAGGGCTGGCG
TTTGAGGGCTGGCGC
TTGAGGGCTGGCGCT
TGAGGGCTGGCGCTG
GAGGGCTGGCGCTGT
AGGGCTGGCGCTGTG
GGGCTGGCGCTGTGT
GGCTGGCGCTGTGTG
GCTGGCGCTGTGTGG
CTGGCGCTGTGTGGA
TGGCGCTGTGTGGAC
GGCGCTGTGTGGACC
GCGCTGTGTGGACCG
CGCTGTGTGGACCGT
GCTGTGTGGACCGTG
CTGTGTGGACCGTGA
TGTGTGGACCGTGAC
GTGTGGACCGTGACT
TGTGGACCGTGACTT
GTGGACCGTGACTTC
TGGACCGTGACTTCT
GGACCGTGACTTCTG
GACCGTGACTTCTGC
ACCGTGACTTCTGCG
CCGTGACTTCTGCGC
CGTGACTTCTGCGCC
GTGACTTCTGCGCCA
TGACTTCTGCGCCAA
GACTTCTGCGCCAAC
ACTTCTGCGCCA-ACA
CTTCTGCGCCAACAT
TTCTGCGCCAACATC
TCTGCGCCAACATCC
CTGCGCCAACATCCT
TGCGCCAACATCCTC
GCGCCAACATCCTCA
CGCCAACATCCTCAG
GCCAACATCCTCAGC
CCAACATCCTCAGCG
CAACATCCTCAGCGC
AACATCCTCAGCGCC
ACATCCTCAGCGCCG
CATCCTCAGCGCCGA
ATCCTCAGCGCCGAG
TCCTCAGCGCCGAGA
CCTCAGCGCCGAGAG
CTCAGCGCCGAGAGC
TCAGCGCCGAGAGCA
CAGCGCCGAGAGCAG
AGCGCCGAGAGCAGC
GCGCCGAGAGCAGCG
CGCCGAGAGCAGCGA
GCCGAGAGCAGCGAC
CCGAGAGCAGCGACT
CGAGAGCAGCGACTC
GAGAGCAGCGACTCC
AGAGCAGCGACTCCG
GAGCAGCGACTCCGA
AGCAGCGACTCCGAG
GCAGCGACTCCGAGG
CAGCGACTCCGAGGG
AGCGACTCCGAGGGG
GCGACTCCGAGGGGT
CGACTCCGAGGGGTT
GACTCCGAGGGGTTT
ACTCCGAGGGGTTTG
CTCCGAGGGGTTTGT
TCCGAGGGGTTTGTG
CCGAGGGGTTTGTGA
CGAGGGGTTTGTGAT
GAGGGGTTTGTGATC
AGGGGTTTGTGATCC
GGGGTTTGTGATCCA
WO 00/78341 WO 0078341PCT/AUOO/00693 -67-
GGGTTTGTGATCCAC
GGTTTGTGATCCACG
GTTTGTGATCCACGA
TTTGTGATCCACGAC
TTGTGATCCACGACG
TGTGATCCACGACGG
GTGATCCACGACGGC
TGATCCACGACGGCG
GATCCACGACGGCGA
ATCCACGACGGCGAG
TCCACGACGGCGAGT
CCACGACGGCGAGTG
CACGACGGCGAGTGC
ACGACGGCGAGTGCA
CGACGGCGAGTGCAT
GACGGCGAGTGCATG
ACGGCGAGTGCATGC
CGGCGAGTGCATGCA
GGCGAGTGCATGCAG
GCGAGTGCATGCAGG
CGAGTGCATGCAGGA
GAGTGCATGCAGGAG
AGTGCATGCAGGAGT
GTGCATGCAGGAGTG
TGCATGCAGGAGTGC
GCATGCAGGAGTGCC
CATGCAGGAGTGCCC
ATGCAGGAGTGCCCC
TGCAGGAGTGCCCCT
GCAGGAGTGCCCCTC
CAGGAGTGCCCCTCG
AGGAGTGCCCCTCGG
GGAGTGCCCCTCGGG
GAGTGCCCCTCGGGC
AGTGCCCCTCGGGCT
GTGCCCCTCGGGCTT
TGCCCCTCGGGCTTC
GCCCCTCGGGCTTCA
CCCCTCGGGCTTCAT
CCCTCGGGCTTCATC
CCTCGGGCTTCATCC
CTCGGGCTTCATCCG
TCGGGCTTCATCCGC
CGGGCTTCATCCGCA
GGGCTTCATCCGCAA
GGCTTCATCCGCAAC
GCTTCATCCGCAACG
CTTCATCCGCAACGG
TTCATCCGCAACGGC
TCATCCGCAACGGCA
CATCCGCAACGGCAG
ATCCGCAACGGCAGC
TCCGCAACGGCAGCC
CCGCAACGGCAGCCA
CGCAACGGCAGCCAG
GCAACGGCAGCCAGA
CAACGGCAGCCAGAG
AACGGCAGCCAGAGC
ACGGCAGCCAGAGCA
CGGCAGCCAGAGCAT
GGCAGCCAGAGCATG
GCAGCCAGAGCATGT
CAGCCAGAGCATGTA
AGCCAGAGCATGTAC
GCCAGAGCATGTACT
CCAGAGCATGTACTG
CAGAGCATGTACTGC
AGAGCATGTACTGCA
GAGCATGTACTGCAT
AGCATGTACTGCATC
GCATGTACTGCATCC
CATGTACTGCATCCC
ATGTACTGCATCCCT
TGTACTGCATCCCTT
GTACTGCATCCCTTG
TACTGCATCCCTTGT
ACTGCATCCCTTGTG
CTGCATCCCTTGTGA
TGCATCCCTTGTGAA
GCATCCCTTGTGAAG
CATCCCTTGTGAAGG
ATCCCTTGTGAAGGT
TCCCTTGTGAAGGTC
CCCTTGTGAAGGTCC
CCTTGTGAAGGTCCT
CTTGTGAAGGTCCTT
TTGTGAAGGTCCTTG
TGTGAAGGTCCTTGC
GTGAAGGTCCTTGCC
TGAAGGTCCTTGCCC
GAAGGTCCTTGCCCG
AAGGTCCTTGCCCGA
AGGTCCTTGCCCGAA
GGTCCTTGCCCGA.AG
GTCCTTGCCCGAAGG
TCCTTGCCCGAAGGT
CCTTGCCCGAAGGTC
CTTGCCCGAAGGTCT
TTGCCCGAAGGTCTG
TGCCCGAAGGTCTGT
GCCCGAAGGTCTGTG
CCCGAAGGTCTGTGA
CCGAAGGTCTGTGAG
CGAAGGTCTGTGAGG
GAAGGTCTGTGAGGA
AAGGTCTGTGAGGAA
AGGTCTGTGAGGAAG
GGTCTGTGAGGAAGA
GTCTGTGAGGAAGAA
TCTGTGAGGAAGAAA
CTGTGAGGAAGAAAA
TGTGAGGAAGAAAAG
GTGAGGAAGAAAAGA
TGAGGAAGAAAAGAA
GAGGAAGAAAAGAAA
AGGAAGAAAAGAAAA
GGAAGAAAAGAAAAC
GAAGAAAAGAAAACA
AAGAAAAGAAAACAA
AGAAAAGAAAACAAA
GAAAAGAAAACAAAG
AAAAGAAAACAAAGA
AAAGAAAACAAAGAC
AAGAAAACAAAGACC
AGAAA.ACAAAGACCA
GAAAACAAAGACCAT
AAAACAAAGACCATT
AAACAAAGACCATTG
AACAAAGACCATTGA
ACAAAGACCATTGAT
CAAAGACCATTGATT
AAAGACCATTGATTC
AAGACCATTGATTCT
AGACCATTGATTCTG
GACCATTGATTCTGT
ACCATTGATTCTGTT
CCATTGATTCTGTTA
CATTGATTCTGTTAC
ATTGATTCTGTTACT
TTGATTCTGTTACTT
TGATTCTGTTACTTC
GATTCTGTTACTTCT
ATTCTGTTACTTCTG
TTCTGTTACTTCTGC
TCTGTTACTTCTGCT
CTGTTACTTCTGCTC
TGTTACTTCTGCTCA
GTTACTTCTGCTCAG
TTACTTCTGCTCAGA
TACTTCTGCTCAGAT
ACTTCTGCTCAGATG
CTTCTGCTCAGATGC
TTCTGCTCAGATGCT
WO 00178341 WO 0078341PCT/AUOO/00693 68-
TCTGCTCAGATGCTC
CTGCTCAGATGCTCC
TGCTCAGATGCTCCA
GCTCAGATGCTCCAA
CTCAGATGCTCCAAG
TCAGATGCTCCAAGG
CAGATGCTCCAAGGA
AGATGCTCCAAGGAT
GATGCTCCAAGGATG
ATGCTCCAAGGATGC
TGCTCCAAGGATGCA
GCTCCAAGGATGCAC
CTCCAAGGATGCACC
TCCAAGGATGCACCA
CCAAGGATGCACCAT
CAAGGATGCACCATC
AAGGATGCACCATCT
AGGATGCACCATCTT
GGATGCACCATCTTC
GATGCACCATCTTCA
ATGCACCATCTTCAA
TGCACCATCTTCAAG
GCACCATCTTCAAGG
CACCATCTTCAAGGG
ACCATCTTCAAGGGC
CCATCTTCAAGGGCA
CATCTTCAAGGGCAA
ATCTTCAAGGGCAAT
TCTTCAAGGGCAATT
CTTCAAGGGCAATTT
TTCAAGGGCAATTTG
TCAAGGGCAATTTGC
CAAGGGCAATTTGCT
AAGGGCAATTTGCTC
AGGGCAATTTGCTCA
GGGCAATTTGCTCAT
GGCAATTTGCTCATT
GCAATTTGCTCATTA
CAATTTGCTCATTAA
AATTTGCTCATTAAC
ATTTGCTCATTAACA
TTTGCTCATTAACAT
TTGCTCATTAACATC
TGCTCATTAACATCC
GCTCATTAACATCCG
CTCATTAACATCCGA
TCATTAACATCCGAC
CATTAACATCCGACG
ATTAACATCCGACGG
TTAACATCCGACGG
TAACATCCGACGGGG
AACATCCGACGGGGG
ACATCCGACGGGGGA
CATCCGACGGGGGAA
ATCCGACGGGGGAAT
TCCGACGGGGGAATA
CCGACGGGGGAATAA
CGACGGGGGAATAAC
GACGGGGGAATAACA
ACGGGGGAATAACAT
CGGGGGAATAACATT
GGGGGAATAACATTG
GGGGAATAACATTGC
GGGAATAACATTGCT
GGAATAACATTGCTT
GAATAACATTGCTTC
AATAACATTGCTTC-A
ATAACATTGCTTCAG
TAACATTGCTTCAGA
AACATTGCTTCAGAG
ACATTGCTTCAGAGC
CATTGCTTCAGAGCT
ATTGCTTCAGAGCTG
TTGCTTCAGAGCTGG
TGCTTCAGAGCTGGA
GCTTCAGAGCTGGAG
CTTCAGAGCTGGAGA
TTCAGAGCTGGAGAA
TCAGAGCTGGAGAAC
CAGAGCTGGAGAACT
AGAGCTGGAGAACTT
GAGCTGGAGAACTTC
AGCTGGAGAACTTCA
GCTGGAGAACTTCAT
CTGGAGAACTTCATG
TGGAGAACTTCATGG
GGAGAACTTCATGG
GAGAACTTCATGGGG
AGAACTTCATGGGGC
GAACTTCATGGGGCT
AACTTCATGGGGCTC
ACTTCATGGGGCTCA
CTTCATGGGGCTCAT
TTCATGGGGCTCATC
TCATGGGGCTCATCG
CATGGGGCTCATCGA
ATGGGGCTCATCGAG
TGGGGCTCATCGAGG
GGGGCTCATCGAGGT
GGGCTCATCGAGGTG
GGCTCATCGAGGTGG
GCTCATCGAGGTGGT
CTCATCGAGGTGGTG
TCATCGAGGTGGTGA
CATCGAGGTGGTGAC
ATCGAGGTGGTGACG
TCGAGGTGGTGACGG
CGAGGTGGTGACGGG
GAGGTGGTGACGGGC
AGGTGGTGACGGGCT
GGTGGTGACGGGCTA
GTGGTGACGGGCTAC
TGGTGACGGGCTACG
GGTGACGGGCTACGT-
GTGACGGGCTACGTG
TGACGGGCTACGTGA
GACGGGCTACGTGAA
ACCGGCTACGTGAAG
CGGGCTACGTGAAGA
GGGCTACGTGAAGAT
GGCTACGTGAAGATC
GCTACGTGAAGATCC
CTACGTGAAGATCCG
TACGTGAAGATCCGC
ACGTGAAGATCCGCC
CGTGAAGATCCGCCA
GTGAAGATCCGCCAT
TGAAGATCCGCCATT
GAAGATCCGCCATTC
AAGATCCGCCATTCT
AGATCCGCCATTCTC
GATCCGCCATTCTCA
ATCCGCCATTCTCAT
TCCGCCATTCTCATG
CCGCCATTCTCATGC
CGCCATTCTCATGCC
GCCATTCTCATGCCT
CCATTCTCATGCCTT
CATTCTCATGCCTTG
ATTCTCATGCCTTGG
TTCTCATGCCTTGGT
TCTCATGCCTTGGTC
CTCATGCCTTGGTCT
TCATGCCTTGGTCTC
CATGCCTTGGTCTCC
ATGCCTTGGTCTCCT
TGCCTTGGTCTCCTT
GCCTTGGTCTCCTTG
CCTTGGTCTCCTTGT
CTTGGTCTCCTTGTC
TTGGTCTCCTTGTCC
TGGTCTCCTTGTCCT
GGTCTCCTTGTCCTT
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GTCTCCTTGTCCTTC
TCTCCTTGTCCTTCC
CTCCTTGTCCTTCCT
TCCTTGTCCTTCCTA
CCTTGTCCTTCCTAA
CTTGTCCTTCCTAAA
TTGTCCTTCCTAAAA
TGTCCTTCCTAAAAA
GTCCTTCCTAAAAAA
TCCTTCCTAAAAAAC
CCTTCCTAAAAAACC
CTTCCTAAAAAACCT
TTCCTAAAAAACCTT
TCCTAAAAAACCTTC
CCTAAAA.AACCTTCG
CTAAAAAACCTTCGC
TAAAAAACCTTCGCC
AAAAAACCTTCGCCT
AAAAACCTTCGCCTC
AAAACCTTCGCCTCA
AAACCTTCGCCTCAT
AACCTTCGCCTCATC
ACCTTCGCCTCATCC
CCTTCGCCTCATCCT
CTTCGCCTCATCCTA
TTCGCCTCATCCTAG
TCGCCTCATCCTAGG
CGCCTCATCCTAGGA
GCCTCATCCTAGGAG
CCTCATCCTAGGAGA
CTCATCCTAGGAGAG
TCATCCTAGGAGAGG
CATCCTAGGAGAGGA
ATCCTAGGAGAGGAG
TCCTAGGAGAGGAGC
CCTAGGAGAG7GAGCA
CTAGGAGAGGAGCAG
TAGGAGAGGAGCAGC
AGGAGAGGAGCAGCT
GGAGAGGAGCAGCTA
GAGAGGAGCAGCTAG
AGAGGAGCAGCTAGA
GAGGAGCAGCTAGAA
AGGAGCAGCTAGAAG
GGAGCAGCTAGAAGG
GAGCAGCTAGAAGGG
AGCAGCTAGAAGGGA
GcAGcTAGAAGGGAA
CAGCTAGAAGGGAAT
AGCTAGAAGGGAATT
GCTAGAAGGGAATTA
CTAGAAGGGAATTAC
TAGAAGGGAATTACT
AGAAGGGAATTACTC
GAAGGGAATTACTCC
AAGGGAATTACTCCT
AGGGAATTACTCCTT
GGGAATTACTCCTTC
GGAATTACTCCTTCT
GAATTACTCCTTCTA
AATTACTCCTTCTAC
ATTACTCCTTCTACG
TTACTCCTTCTACGT
TACTCCTTCTACGTC
ACTCCTTCTACGTCC
CTCCTTCTACGTCCT
TCCTTCTACGTCCTC
CCTTCTACGTCCTCG
CTTCTACGTCCTCGA
TTCTACGTCCTCGAC
TCTACGTCCTCGACA
CTACGTCCTCGACAA
TACGTCCTCGACAAC
ACGTCCTCGACAACC
CGTCCTCGACAACCA
GTCCTCGACAACCAG
TCCTCGACAACCAGA
CCTCGACAACCAGAA
CTCGACAACCAGAAC
TCGACAACCAGAACT
CGACAACCAGAACTT
GACAACCAGAACTTG
ACAACCAGAACTTGC
CAACCAGAACTTGCA
AACCAGAACTTGCAG
ACCAGAACTTGCAGC
CCAGAACTTGCAGCA
CAGAACTTGCAGCAA
AGAACTTGCAGCAAC
GAACTTGCAGCAACT
AACTTGCAGCAACTG
ACTTGCAGCAACTGT
CTTGCAGCAACTGTG
TTGCAGCAACTGTGG
TGCAGCAACTGTGGG
GCAGCAACTGTGGGA
CAGCAACTGTGGGAC
AGCAACTGTGGGACT
GCAACTGTGGGACTG
CAACTGTGGGACTGG
AACTGTGGGACTGGG
ACTGTGGGACTGGGA
CTGTGGGACTGGGAC
TGTGGGACTGGGACC
GTGGGACTGGGACCA
TGGGACTGGGACCAC
GGGACTGGGACCACC
GGACTGGGACCACCG
GACTGGGACCACCGC
ACTGGGACCACCGCA
CTGGGACCACCGCAA
TGGGACCACCGCAAC
GGGACCACCGCAACC
GGACCACCGCAACCT
GACCACCGCAACCTG
ACCACCGCAACCTGA
CCACCGCAACCTGAC
CACCGCAACCTGACC
ACCGCAACCTGACCA
CCGCAACCTGACCAT
CGCAACCTGACCATC
GCAACCTGACCATCA
CAACCTGACCATCAA
AACCTGACCATCAAA
ACCTGACCATCAAAG
CCTGAC CAT CAAAGC
CTGACCATCAAAGCA
TGACCATCAAAGCAG
GACCATCAAAGCAGG
ACCATCAAAGCAGGG
CCATCAAAGCAGGGA
CATCAAAGCAGGGAA
ATCAAAGCAGGGAAA
TCAAAGCAGGGAAAA
CAAAGCAGGGAAAAT
AAAGCAGGGAAAATG
AAGCAGGGAAAATGT
AGCAGGGAAAATGTA
GCAGGGAAAATGTAC
CAGGGAAAATGTACT
AGGGAAAATGTACTT
GGGAAAATGTACTTT
GGAAAATGTACTTTG
GAAAATGTACTTTGC
AAAATGTACTTTGCT
AAATGTACTTTGCTT
AATGTACTTTGCTTT
ATGTACTTTGCTTTC
TGTACTTTGCTTTCA
GTACTTT GCTTTCAA
TACTTTGCTTTCAAT
ACTTTGCTTTCAATC
CTTTGCTTTCAATCC
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TTTGCTTTCAATCCC
TTGCTTTCAATCCCA
TGCTTTCAATCCCAA
GCTTTCAATCCCAAA
CTTTCAATCCCAAAT
TTTCAATCCCAAATT
TTCAATCCCAAATTA
TCAATCCCAAATTAT
CAATCCCAAATTATG
AATCCCAAATTATGT
ATCCCAAATTATGTG
TCCCAAATTATGTGT
CCCAAATTATGTGTT
CCAAATTATGTGTTT
CAAATTATGTGTTTC
AAATTATGTGTTTCC
AATTATGTGTTTCCG
ATTATGTGTTTCCGA
TTATGTGTTTCCGAA
TATGTGTTTCCGAAA
ATGTGTTTCCGAAAT
TGTGTTTCCGAAATT
GTGTTTCCGAAATTT
TGTTTCCGAAATTTA
GTTTCCGAAATTTAC
TTTCCGAAATTTACC
TTCCGAAATTTACCG
TCCGAAATTTACCGC
CCGAAATTTACCGCA
CGAAATTTACCGCAT
GAAATTTACCGCATG
AAATTTACCGCATGG
AATTTACCGCATGGA
ATTTACCGCATGGAG
TTTACCGCATGGAGG
TTACCGCATGGAGGA
TACCGCATGGAGGAA
ACCGCATGGAGGAAG
CCGCATGGAGGAAGT
CGCATGGAGGAACTG
GCATGGAGGAAGTGA
CATGGAGGAAGTGAC
ATGGAGGAAGTGACG
TGGAGGAAGTGACGG
GGAGGAAGTGACGGG
GAGGAAGTGACGGGG
AGGAAGTGACGGGGA
GGAAGTGACGGGGAC
GAAGTGACGGGGACT
AAGTGACGGGGACTA
AGTGACGGGGACTAA
GTGACGGGGACTAAA
TGACGGGGACTAAAG
GACGGGGACTAAAGG
ACGGGGACTAAAGGG
CGGGGACTAAAGGGC
GGGGACTAAAGGGCG
GGGACTAAAGGGCGC
GGACTAAAGGGCGCC
GACTAAAGGGCGCCA
ACTAAAGGGCGCCAA
CTAAAGGGCGCCAAA
TAAAGGGCGCCAAAG
AAAGGGCGCCAAAGC
AAGGGCGCCAAAGCA
AGGGCGCCAAAGCAA
GGGCGCCAAAGCAAA
GGCGCCAAAGCAAAG
GCGCCAAAGCAAAGG
CGCCAAAGCAAAGGG
GCCAAAGCAAAGGGG
CCAAAGCAAAGGGGA
CAAAGCAAAGGGGAC
AAAGCAAAGGGGACA
AAGCAAAGGGGACAT
AGCAAAGGGGACATA
GCAAAGGGGACATAA
CAAAGGGGACATAAA
AAAGGGGACATAAAC
AAGGGGACATAAACA
AGGGGACATAAACAC
GGGGACATAAACACC
GGGACATAAACACCA
GGACATAAACACCAG
GACATAAACACCAGG
ACATAAACACCAGGA
CATAAACACCAGGAA
ATAAACACCAGGAAC
TAA.ACACCAGGAACA
AAACACCAGGAACAA
AACACCAGGAACAAC
ACACCAGGAACAACG
CACCAGGAACAACGG
ACCAGGAACAACGGG
CCAGGAACAACGGGG
CAGGAACAACGGGGA
AGGAACAACGGGGAG
GGAACAACGGGGAGA
GAACAACGGGGAGAG
AACAACGGGGAGAGA
ACAACGGGGAGAGAG
CAACGGGGAGAGAGC
AACGGGGAGAGAGCC
ACGGGGAGAGAGCCT
CGGGGAGAGAGCCTC
GGGGAGAGAGCCTCC
GGGAGAGAGCCTCCT
GGAGAGAGCCTCCTG
GAGAGAGCCTCCTGT
AGAGAGCCTCCTGTG
GAGAGCCTCCTGTGA
AGAGCCTCCTGTGAA
GAGCCTCCTGTGAAA
AGCCTCCTGTGAAAG
GCCTCCTGTGAAAGT
CCTCCTGTGAAAGTG
CTCCTGTGAAAGTGA
TCCTGTGAAAGTGAC
CCTGTGAAAGTGACG
CTGTGAAAGTGACGT
TGTGAAAGTGACGTC
GTGAAAGTGACGTCC
TGAAAGTGACGTCCT
GAAAGTGACGTCCTG
AAAGTGACGTCCTGC
AAGTGACGTCCTGCA
AGTGACGTCCTGCAT
GTGACGTCCTGCATT
TGACGTCCTGCATTT
GACGTCCTGCATTTC
ACGTCCTGCATTTCA
CGTCCTGCATTTCAC
GTCCTGCATTTCACC
TCCTGCATTTCACCT
CCTGCATTTCACCTC
CTGCATTTCACCTCC
TGCATTTCACCTCCA
GCATTTCACCTCCAC
CATTTCACCTCCACC
ATTTCACCTCCACCA
TTTCACCTCCACCAC
TTCACCTCCACCACC
TCACCTCCACCACCA
CACCTCCACCACCAC
ACCTCCACCACCACG
CCTCCACCACCACGT
CTCCACCACCACGTC
TCCACCACCACGTCG
CCACCACCACGTCGA
CACCACCACGTCGAA
ACCACCACGTCGAAG
CCACCACGTCGAAGA
CACCACGTCGAAGAA
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ACCACGTCGAAGAAT
CCACGTCGAAGAATC
CACGTCGAAGAATCG
ACGTCGAAGAATCGC
CGTCGAAGAATCGCA
GTCGAAGAATCGCAT
TCGAAGAATCGCATC
CGAAGAATCGCATCA
GAAGAATCGCATCAT
AAGAATCGCATCATC
AGAATCGCATCATCA
GAATCGCATCATCAT
AATCGCATCATCATA
ATCGCATCATCATAA
TCGCATCATCATAAC
CGCATCATCATAACC
GCATCATCATAACCT
CATCATCATAACCTG
ATCATCATAACCTGG
TCATCATAACCTGGC
CATCATAACCTGGCA
ATCATAACCTGGCAC
TCATAACCTGGCACC
CATAACCTGGCACCG
ATAACCTGGCACCGG
TAACCTGGCACCGGT
AACCTGGCACCGGTA
ACCTGGCACCGGTAC
CCTGGCACCGGTACC
CTGGCACCGGTACCG
TGGCACCGGTACCGG
GGCACCGGTACCGGC
GCACCGGTACCGGCC
CACCGGTACCGGCCC
ACCGGTACCGGCCCC
CCGGTACCGGCCCCC
CGGTACCGGCCCCCT
GGTACCGGCCCCCTG
GTACCGGCCCCCTGA
TACCGGCCCCCTGAC
ACCGGCCCCCTGACT
CCGGCCCCCTGACTA
CGGCCCCCTGACTAC
GGCCCCCTGACTACA
GCCCCCTGACTACAG
CCCCCTGACTACAGG
CCCCTGACTACAGGG
CCCTGACTACAGGGA
CCTGACTACAGGGAT
CTGACTACAGGGATC
TGACTACAGGGATCT
GACTACAGGGATCTC
ACTACAGGGATCTCA
CTACAGGGATCTCAT
TACAGGGATCTCATC
ACAGGGATCTCATCA
CAGGGATCTCATCAG
AGGGATCTCATCAGC
GGGATCTCATCAGCT
GGATCTCATCAGCTT
GATCTCATCAGCTTC
ATCTCATCAGCTTCA
TCTCATCAGCTTCAC
CTCATC!AGCTTCACC
TCATCAGCTTCACCG
CATCAGCTTCACCGT
ATCAGCTTCACCGTT
TCAGCTTCACCGTIT
CAGCTTCACCGTTTA
AGCTTCACCGTTTAC
GCTTCACCGTTTACT
CTTCACCGTTTACTA
TTCACCGTTTACTAC
TCACCGTTTACTACA
CACCGTTTACTACAA
ACCGTTTACTACAAG
CCGTTTACTACAAGG
CGTTTACTACAAGGA
GTTTACTACAAGGAA
TTTACTACAAGGAAG
TTACTACAAGGAAGC
TACTACAAGGAAGCA
ACTACAAGGAAGCAC
CTACAAGGAAGCACC
TACAAGGAAGCACCC
ACAAGGAAGCACCCT
CAAGGAAGCACCCTT
AAGGAAGCACCCTTT
AGGAAGCACCCTTTA
GGAAGCACCCTTTAA
GAAGCACCCTTTAAG
AAGCACCCTTTAAGA
AGCACCCTTTAAGAA
GCACCCTTTAAGAAT
CACCCTTTAAGAATG
ACCCTTTAAGAATGT
CCCTTTAAGAATGTC
CCTTTAAGAATGTCA
CTTTAAGAATGTCAC
TTTAAGAATGTCACA
TTAAGAATGTCACAG
TAAGAATGTCACAGA
AAGAATGTCACAGAG
AGAATGTCACAGAGT
GAATGTCACAGAGTA
AATGTCACAGAGTAT
ATGTCACAGAGTATG
TGTCACAGAGTATGA
GTCACAGAGTATGAT
TCACAGAGTATGATG
CACAGAGTATGATGG
ACAGAGTATGATGGG
CAGAGTATGATGGGC
AGAGTATGATGGGCA
GAGTATGATGGGCAG
AGTATGATGGGCAGG
GTATGATGGGCAGGA
TATGATGGGCAGGAT
ATGATGGGCAGGATG
TGATGGGCAGGATGC
GATGGGCAGGATGCC
ATGGGCAGGATGCCT
TGGGCAGGATGCCTG
GGGCAGGATGCCTGC
GGCAGGATGCCTGCG
GCAGGATGCCTGCGG
CAGGATGCCTGCGGC
AGGATGCCTGCGGCT
GGATGCCTGCGGCTC
GATGCCTGCGGCTCC
ATGCCTGCGGCTCCA
TGCCTGCGGCTCCAA
GCCTGCGGCTCCAAC
CCTGCGGCTCCAACA
CTGCGGCTCCAACAG
TGCGGCTCCAACAGC
GCGGCTCCAACAGCT
CGGCTCCAACAGCTG
GGCTCCAACAGCTGG
GCTCCAACAGCTGGA
CTCCAACAGCTGGAA
TCCAACAGCTGGAAC
CCAACAGCTGGAACA
CAACAGCTGGAACAT
AACAGCTGGAACATG
ACAGCTGGAACATGG
CAGCTGGAACATGGT
AGCTGGAACATGGTG
GCTGGAACATGGTGG
CTGGAACATGGTGGA
TGGAACATGGTGGAC
GGAACATGGTGGACG
GAACATGGTGGACGT
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AACATGGTGGACGTG
ACATGGTGGACGTGG
CATGGTGGACGTGGA
ATGGTGGACGTGGAC
TGGTGGACGTGGACC
GGTGGACGTGGACCT
GTGGACGTGGACCTC
TGGACGTGGACCTCC
GGACGTGGACCTCCC
GACGTGGACCTCCCG
ACGTGGACCTCCCGC
CGTGGACCTCCCGCC
GTGGACCTCCCGCCC
TGGACCTCCCGCCCA
GGACCTCCCGCCCAA
GACCTCCCGCCCAAC
ACCTCCCGCCCAACA
CCTCCCGCCCAACAA
CTCCCGCCCAACAAG
TCCCGCCCAACAAGG
CCCGCCCAACAAGGA
CCGCCCAACAAGGAC
CGCCCAACAAGGACG
GCCCAACAAGGACGT
CCCAACAAGGACGTG
CCAACAAGGACGTGG
CAACAAGGACGTGGA
AACAAGGACGTGGAG
ACAAGGACGTGGAGC
CAAGGACGTGGAGCC
AAGGACGTGGAGCCC
AGGACGTGGAGCCCG
GGACGTGGAGCCCGG
GACGTGGAGCCCGGC
ACGTGGAGCCCGGCA
CGTGGAGCCCGGCAT
GTGGAGCCCGGCATC
TGGAGCCCGGCATCT
GGAGCCCGGCATCTT
GAGCCCGGCATCTTA
AGCCCGGCATCTTAC
GCCCGGCATCTTACT
CCCGGCATCTTACTA
CCGGCATCTTACTAC
CGGCATCTTACTACA
GGCATCTTACTACAT
GCATCTTACTACATG
CATCTTACTACATGG
ATCTTACTACATGGG
TCTTACTACATGGGC
CTTACTACATGGGCT
TTACTACATGGGCTG
TACTACATGGGCTGA
ACTACATGGGCTGAA
CTACATGGGCTGAAG
TACATGGGCTGAAGC
ACATGGGCTGAAGCC
CATGGGCTGAAGCCC
ATGGGCTGAAGCCCT
TGGGCTGAAGCCCTG
GGGCTGAAGCCCTGG
GGCTGAAGCCCTGGA
GCTGAAGCCCTGGAC
CTGAAGCCCTGGACT
TGAAGCCCTGGACTC
GAAGCCCTGGACTCA
AAGCCCTGGACTCAG
AGCCCTGGACTCAGT
GCCCTGGACTCAGTA
CCCTGGACTCAGTAC
CCTGGACTCAGTACG
CTGGACTCAGTACGC
TGGACTCAGTACGCC
GGACTCAGTACGCCG
GACTCAGTACGCCGT
ACTCAGTACGCCGTT
CTCAGTACGCCGTTT
TCAGTACGCCGTTTA
CAGTACGCCGTTTAC
AGTACGCCGTTTACG
GTACGCCGTTTACGT
TACGCCGTTTACGTC
ACGCCGTTTACGTCA
CGCCGTTTACGTCAA
GCCGTTTACGTCAAG
CCGTTTACGTCAAGG
CGTTTACGTCAAGGC
GTTTACGTCAAGGCT
TTTACGTCAAGGCTG
TTACGTCAAGGCTGT
TACGTCAAGGCTGTG
ACGTCAAGGCTGTGA
CGTCAAGGCTGTGAC
GTCAAGGCTGTGACC
TCAAGGCTGTGACCC
CAAGGCTGTGACCCT
AAGGCTGTGACCCTC
AGGCTGTGACCCTCA
GGCTGTGACCCTCAC
GCTGTGACCCTCACC
CTGTGACCCTCACCA
TGTGACCCTCACCAT
GTGACCCTCACCATG
TGACCCTCACCATGG
GACCCTCACCATGGT
ACCCTCACCATGGTG
CCCTCACCATGGTGG
CCTCACCATGGTGGA
CTCACCATGGTGGAG
TCACCATGGTGGAGA
CACCATGGTGGAGAA
ACCATGGTGGAGAAC
CCATGGTGGAGAACG
CATGGTGGAGAACGA
ATGGTGGAGAACGAC
TGGTGGAGAACGACC
GGTGGAGAACGACCA
GTGGAGAACGACCAT
TGGAGAACGACCATA
GGAGAACGACCATAT
GAGAACGACCATATC
AGAACGACCATATCC
GAACGACCATATCCG
AACGACCATATCCGT
ACGACCATATCCGTG
CGACCATATCCGTGG
GACCATATCCGTGGG
ACCATATCCGTGGGG
CCATATCCGTGGGGC
CATATCCGTGGGGCC
ATATCCGTGGGGCCA
TATCCGTGGGGCCAA
ATCCGTGGGGCCAAG
TCCGTGGGGCCAAGA
CCGTGGGGCCAAGAG
CGTGGGGCCAAGAGT
GTGGGGCCAAGAGTG
TGGGGCCAAGAGTGA
GGGGCCAAGAGTGAG
GGGCCAAGAGTGAGA
GGCCAAGAGTGAGAT
GCCAAGAGTGAGATC
CCAAGAGTGAGATCT
CAAGAGTGAGATCTT
AAGAGTGAGATCTTG
AGAGTGAGATCTTGT
GAGTGAGATCTTGTA
AGTGAGATCTTGTAC
GTGAGATCTTGTACA
TGAGATCTTGTACAT
GAGATCTTGTACATT
AGATCTTGTACATTC
GATCTTGTACATTCG
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ATCTTGTACATTCGC
TCTTGTACATTCGCA
CTTGTACATTCGCAC
TTGTACATTCGCACC
TGTACATTCGCACCA
GTACATTCGCACCAA
TACATTCGCACCAAT
ACATTCGCACCAATG
CATTCGCACCAATGC
ATTCGCACCAATGCT
TTCGCACCAATGCTT
TCGCACCAATGCTTC
CGCACCAATGCTTCA
GCACCAATGCTTCAG
CACCAATGCTTCAGT
ACCAATGCTTCAGTT
CCAATGCTTCAGTTC
CAATGCTTCAGTTCC
AATGCTTCAGTTCCT
ATGCTTCAGTTCCTT
TGCTTCAGTTCCTTC
GCTTCAGTTCCTTCC
CTTCAGTTCCTTCCA
TTCAGTTCCTTCCAT
TCAGTTCCTTCCATT
CAGTTCCTTCCATTC
AGTTCCTTCCATTCC
GTTCCTTCCATTCCC
TTCCTTCCATTCCCT
TCCTTCCATTCCCTT
CCTTCCATTCCCTTG
CTTCCATTCCCTTGG
TTCCATTCCCTTGGA
TCCATTCCCTTGGAC
CCATTCCCTTGGACG
CATTCCCTTGGACGT
ATTCCCTTGGACGTT
TTCCCTTGGACGTTC
TCCCTTGGACGTTCT
CCCTTGGACGTTCTT
CCTTGGACGTTCTTT
CTTGGACGTTCTTTC
TTGGACGTTCTTTCA
TGGACGTTCTTTCAG
GGACGTTCTTTCAGC
GACGTTCTTTCAGCA
ACGTTCTTTCAGCAT
CGTTCTTTC-AGCATC
GTTCTTTCAGCATCG
TTCTTTCAGCATCGA
TCTTTCAGCATCGAA
CTTTCAGCATCGAAC
TTTCAGCATCGAACT
TTCAGCATCGAACTC
TCAGCATCGAACTCC
CAGCATCGAACTCCT
AGCATCGAACTCCTC
GCATCGAACTCCTCT
CATCGAACTCCTCTT
ATCGAACTCCTCTTC
TCGAACTCCTCTTCT
CGAACTCCTCTTCTC
GAACTCCTCTTCTCA
AACTCCTCTTCTCAG
ACTCCTCTTCTCAGT
CTCCTCTTCTCAGTT
TCCTCTTCTCAGTTA
CCTCTTCTCAGTTAA
CTCTTCTCAGTTAAT
TCTTCTCAGTTAATC
CTTCTCAGTTAATCG
TTCTCAGTTAATCGT
TCTCAGTTAATCGTG
CTCAGTTAATCGTGA
TCAGTTAATCGTGAA
CAGTTAATCGTGAAG
AGTTAATCGTGAAGT
GTTAATCGTGAAGTG
TTAATCGTGAAGTGG
TAATCGTGAAGTGGA
AATCGTGAAGTGGAA
ATCGTGAAGTGGAAC
TCGTGAAGTGGAACC
CGTGAAGTGGAACCC
GTGAAGTGGAACCCT
TGAAGTGGAACCCTC
GAAGTGGAACCCTCC
AAGTGGAACCCTCCC
AGTGGAACCCTCCCT
GTGGAACCCTCCCTC
TGGAACCCTCCCTCT
GGAACCCTCCCTCTC
GAACCCTCCCTCTCT
AACCCTCCCTCTCTG
ACCCTCCCTCTCTGC
CCCTCCCTCTCTGCC
CCTCCCTCTCTGCCC
CTCCCTCTCTGCCCA
TCCCTCTCTGCCCAA
CCCTCTCTGCCCAAC
CCTCTCTGCCCAACG
CT CT CTGCCCAACGG
TCTCTGCCCAACGGC
CTCTGCCCAACGGCA
TCTGCCCAACGGCAA
CTGCCCAACGGCAAC
TGCCCAACGGCAACC
GCCCAACGGCAACCT
CCCAACGGCAACCTG
CCAACGGCAACCTGA
CAACGGCAACCTGAG
AACGGCAACCTGAGT
ACGGCAACCTGAGTT
CGGCAACCTGAGTTA
GGCAACCTGAGTTAC
CCAACCTGAGTTACT
CAACCTGAGTTACTA
AACCTGAGTTACTAC
ACCTGAGTTACTACA
CCTGAGTTACTACAT
CTGAGTTACTACATT
TGAGTTACTACATTG
GAGTTACTACATTGT
AGTTACTACATTGTG
GTTACTACATTGTGC
TTACTACATTGTGCG
TACTACATTGTGCGC
ACTACATTGTGCGCT
CTACATTGTGCGCTG
TACATTGTGCGCTGG
ACATTGTGCGCTGGC
CATTGTGCGCTGGCA
ATTGTGCGCTGGCAG
TTGTGCGCTGGCAGC
TGTGCGCTGGCAGCG
GTGCGCTGGCAGCGG
TGCGCTGGCAGCGGC
GCGCTGGCAGCGGCA
CGCTGGCAGCGGCAG
GCTGGCAGCGGCAGC
CTGGCAGCGGCAGCC
TGGCAGCGGCAGCCT
GGCAGCGGCAGCCTC
GCAGCGGCAGCCTCA
CAGCGGCAGCCTCAG
AGCGGCAGCCTCAGG
GCGGCAGCCTCAGGA
CGGCAGCCTCAGGAC
GGCAGCCTCAGGACG
GCAGCCTCAGGACGG
CAGCCTCAGGACGGC
AGCCTCAGGACGGCT
GCCTCAGGACGGCTA
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CCTCAGGACGGCTAC
CTCAGGACGGCTACC
TCAGGACGGCTACCT
CAGGACGGCTACCTT
AGGACGGCTACCTTT
GGACGGCTACCTTTA
GACGGCTACCTTTAC
ACGGCTACCTTTACC
CGGCTACCTTTACCG
GGCTACCTTTACCGG
GCTACCTTTACCGGC
CTACCTTTACCGGCA
TACCTTTACCGGCAC
ACCTTTACCGGCACA
CCTTTACCGGCACAA
CTTTACCGGCACAAT
TTTACCGGCACAATT
TTACCGGCACAATTA
TACCGGCACAATTAC
ACCGGCACAATTACT
CCGGCACAATTACTG
CGGCACAATTACTGC
GGCACAATTACTGCT
GCACAATTACTGCTC
CACAATTACTGCTCC
ACAATTACTGCTCCA
CAATTACTGCTCCAA
AATTACTGCTCCAAA
ATTACTGCTCCAAAG
TTACTGCTCCAAAGA
TACTGCTCCAAAGAC
ACTGCTCCAAAGACA
CTGCTCCAAAGACAA
TGCTCCAAAGACAAA
GCTCCAAAGACAAAA
CTCCAAAGACAAAAT
TCCAAAGACAAAATC
CCAAAGACAAAATC C CAAAGACAAAAT CC C AAAGAcAAAATCCCC
AAGACAAAATCCCCA
AGACAAAATCCCCAT
GACAAAATCCCCATC
ACAAAATCCCCATCA
CAAAATCCCCATCAG
AAAATCCCCATCAGG
AAATCCCCATCAGGA
AATCCCCATCAGGAA
AT CCC CATCAGGAAG
TCCCCATCAGGAAGT
CCC CATCAGGAAGTA
CCCATCAGGAAGTAT
CCATCAGGAAGTATG
CATCAGGAAGTATGC
ATCAGGAAGTATGCC
TCAGGAAGTATGCCG
CAGGAAGTATGCCGA
AGGAAGTATGCCGAC
GGAAGTATGCCGACG
GAAGTATGCCGACGG
AAGTATGCCGACGGC
AGTATGCCGACGGCA
GTATGCCGACGGCAC
TATGCCGACGGCACC
ATGCCGACGGCACCA
TGCCGACGGCACCAT
GCCGACGGCACCATC
CCGACGGCACCATCG
CGACGGCACCATCGA
GACGGCACCATCGAC
ACGGCACCATCGACA
CGGCACCATCGACAT
GGCACCATCGACATT
GCACCATCGACATTG
CACCATCGACATTGA
ACCATCGACATTGAG
CCATCGACATTGAGG
CATCGACATTGAGGA
ATCGACATTGAGGAG
TCGACATTGAGGAGG
CGACATTGAGGAGGT
GACATTGAGGAGGTC
ACATTGAGGAGGTCA
CATTGAGGAGGTCAC
ATTGAGGAGGTCACA
TTGAGGAGGT CACAG
TGAGGAGGTCACAGA
GAGGAGGTCACAGAG
AGGAGGTCACAGAGA
GGAGGTCACAGAGAA
GAGGTCACAGAGAAC
AGGTCACAGAGAACC
GGTCACAGAGAACCC
GTCACAGAGAACCCC
TCACAGAGAACCCCA
CACAGAGAACCCCAA
ACAGAGAACCCCAAG
CAGAGAACCCCAAGA
AGAGAACCCCAAGAC
GAGAACCCCAAGACT
AGAACCCCAAGACTG
GAACCCCAAGACTGA
AACCCCAAGACTGAG
ACCCCAAGACTGAOG
CCCCAAGACTGAGGT
CCCAAGACTGAGGTG
CCAAGACTGAGGTGT
CAAGACTGAGGTGTG
AAGACTGAGGTGTGT
AGACTGAGGTGTGTG
GACTGAGGTGTGTGG
ACTGAGGTGTGTGGT
CTGAGGTGTGTGGTG
TGAGGTGTGTGGTGG
GAGGTGTGTGGTGGG
AGGTGTGTGGTGGGG
GGTGTGTGGTGGGGA
GTGTGTGGTGGGGAG
TGTGTGGTGGGGAGA
GTGTGGTGGGGAGAA
TGTGGTGGGGAGAAA
GTGGTGGGGAGAAAG
TGGTGGGGAGAAAGG
GGTGGGGAGAAAGGG
GTGGGGAGAAAGGGC
TGGGGAGAAAGGGCC
GGGGAGAAAGGGCCT
GGGAGAAAGGGCCTT
GGAGAAAGGGCCTTG
GAGAAAGGGCCTTGC
AGAAAGGGCCTTGCT
GAAAGGGCCTTGCTG
AAAGGGCCTTGCTGC
AAGGGCCTTGCTGCG
AGGGCCTTGCTGCGC
GGGCCTTGCTGCGCC
GGCCTTGCTGCGCCT
GCCTTGCTGCGCCTG
CCTTGCTGCGCCTGC
CTTGCTGCGCCTGCC
TTGCTGCGCCTGCCC
TGCTGCGCCTGCCCC
GCTGCGCCTGCCCCA
CTGCGCCTGCCCCAA
TGCGCCTGCCCCAAA
GCGCCTGCCCCAAAA
CGCCTGCCCCAAAAC
GCCTGCCCCAAAACT
CCTGCCCCAAAACTG
CTGCCCCAAAACTGA
TGCCCCAAAACTGAA
GCCCCAAAACTGAAG
CCCCAAAACTGAAGC
WO 00/78341 WO 0078341PCT/AUOO/00693 75
CCCAAAACTGAAGCC
CCAAAACTGAAGCCG
CAAAACTGAAGCCGA
AAAACTGAAGCCGAG
AAACTCAAGCCGAGA
AACTGAAGCCGAGAA
ACTGAAGCCGAGAAG
CTGAAGCCGAGAAGC
TGAAGCCGAGAAGCA
GAAGCCGAGAAGCAG
AAGCCGAGAAGCAGG
AGCCGAGAAGCAGGC
GCCGAGAAGCAGGCC
CCGAGAAGCAGGCCG
CGAGAAGCAGGCCGA
GAGAAGCAGGCCGAG
AGAAGCAGGCCGAGA
GAAGCAGGCCGAGAA
AAGCAGGCCGAGAAG
AGCAGGCCGAGAAGG
GCAGGCCGAGAAGGA
CAGGCCGAGAAGGAG
AGGCCGAGAAGGAGG
GGCCGAGAAGGAGGA
GCCGAGAAGGAGGAG
CCGAGAAGGAGGAGG
CGAGAAGGAGGAGGC
GAGAAGGAGGAGGCT
AGAAGGAGGAGGCTG
GAAGGAGGAGGCTGA
AAGGAGGAGGCTGAA
AGGAGGAGGCTGAAT
GGAGGAGGCTGAATA
GAGGAGGCTGAATAC
AGGAGGCTGAATACC
GGAGGCTGAATACCG
GAGGCTGAATACCGC
AGGCTGAATACCGCA
GGCTGAATACCGCAA
GCTGAATACCGCAAA
CTGAATACCGCAAAG
TGAATACCGCAAAGT
GAATACCGCAAAGTC
AATACCGCAAAGTCT
ATACCGCAAAGTCTT
TACCGCAAAGTCTTT
ACCGCAAAGTCTTTG
CCGCAAAGTCTTTGA
CGCAAAGTCTTTGAG
GCAAAGTCTTTGAGA
CAAAGTCTTTGAGAA
AAAGTCTTTGAGAAT
AAGTCTTTGAGAATT
AGTCTTTGAGAATTT
GTCTTTGAGAATTTC
TCTTTGAGAATTTCC
CTTTGAGAATTTCCT
TTTGAGAATTTCCTG
TTGAGAATTTCCTC
TGAGAATTTCCTGCA
GAGAATTTCCTGCAC
AGAATTTCCTGCACA
GAATTTCCTGCACAA
AATTTCCTGCACAAC
ATTTCCTGCACAACT
TTTCCTGCACAACTC
TTCCTGCACAACTCC
TCCTGCACAACTCCA
CCTGCACAACTCCAT
CTGCACAACTCCATC
TGCACAACTCCATCT
GCACAACTCCATCTT
CACAACTCCATCTTC
ACAACTCCATCTTCG
CAACTCCATCTTCGT
AACTCCATCTTCGTG
ACTCCATCTTCGTGC
CT CCATCTTCGTG CC
TCCATCTTCGTGCCC
CCATCTTCGTGCCCA
CATCTTCGTGCCCAG
ATCTTCGTGCCCAGA
TCTTCGTGCCCAGAC
CTTCGTGCCCAGACC
TTCGTGCCCAGACCT
TCGTGCCCAGACCTG
CGTGCCCAGACCTGA
GTGCCCAGACCTGAA
TGCCCAGACCTGAAA
GCCCAGACCTGAAAG
CCCAGACCTGAAAGG
CCAGACCTGAAAGGA
CAGACCTGAAAGGAA
AGACCTGAAAGGAAG
GACCTGAAAGGAAGC
ACCTGAAAGGAAGCG
CCTGAAAGGAAGCGG
CTGAAAGGAAGCGGA
TGAAAGGAAGCGGAG
GAAAGGAAGCGGAGA
AAAGGAAGCGGAGAG
AAGGAAGCGGAGAGA
AGGAAGCGGAGAGAT
GGAAGCGGAGAGATG
GAAGCGGAGAGATGT
AAGCGGAGAGATGTC
AGCGGAGAGATGTCA
GCGGAGAGATGTCAT
CGGAGAGATGTCATG
GGAGAGATGTCATGC
GAGAGATGTCATGCA
AGAGATGTCATGCAA
GAGATGTCATGCAAG
AGATGTCATGCAAGT
GATGTCATGCAAGTG
ATGTCATGCAAGTGG
TGTCATGCAAGTGGC
GTCATGCAAGTGGCC
TCATGCAAGTGGCCA
CATGCAAGTGGCCAA
ATGCAAGTGGCCAAC
TGCAAGTGGCCAACA
GCAAGTGGCCAACAC
CAAGTGGCCAACACC
AAGTGGCCAACACCA
AGTGGCCAACACCAC
GTGGCCAACACCACC
TGGCCAACACCACCA
GGCCAACACCACCAT
GCCAACACCACCATG
CCAACACCACCATGT
CAACACCACCATGTC
AACACCACCATGTCC
ACACCACCATGTCCA
CACCACCATGTCCAG
ACCACCATGTCCAGC
CCACCATGTCCAGCC
CACCATGTCCAGCCG
ACCATGTCCAGCCGA
CCATGTCCAGCCGAA
CATGTCCAGCCGAAG
ATGTCCAGCCGAAGC
TGTCCAGCCGAAGCA.
GTCCAGCCGAAGCAG
TCCAGCCGAAGCAGG
CCAGCCGAAGCAGGA
CAGCCGAAGCAGGAA
AGCCGAAGCAGGAAC
GCCGAAGCAGGAACA
CCGAAGCAGGAACAC
CGAAGCAGGAACACC
GAAGCAGGAACACCA
AAGCAGGAACACCAC
WO 00/78341 WO 0078341PCT/AUOO/00693 76
AGCAGGAACACCACG
GCAGGAACACCACGG
CAGGAACACCACGGC
AGGAACACCACGGCC
GGAACACCACGGCCG
GAACACCACGGCCGC
AACACCACGGCCGCA
ACACCACGGCCGCAG
CACCACGGCCGCAGA
ACCACGGCCGCAGAC
CCACGGCCGCAGACA
CACGGCCGCAGACAC
ACGGCCGCAGACACC
CGGCCGCAGACACCT
GGCCGCAGACACCTA
GCCGCAGACACCTAC
CCGCAGACACCTACA
CGCAGACACCTACAA
GCAGACACCTACAAC
CAGACACCTACAACA
AGACACCTACAACAT
GACACCTACAACATC
ACACCTACAACATCA
CACCTACAACATCAC
ACCTACAACATCACC
CCTACAACATCACCG
CTACAACATCACCGA
TACAACATCACCGAC
ACAACATCACCGACC
CAACATCACCGACCC
AACATCACCGACCCG
ACATCACCGACCCGG
CATCACCGACCCGGA
ATCACCGACCCGGAA
TCACCGACCCGGAAG
CACCGACCCGGAAGA
ACCGACCCGGAAGAG
CCGACCCGGAAGAGC
CGACCCGGAAGAGCT
GACCCGGAAGAGCTG
ACCCGGAAGAGCTGG
CCCGGAAGAGCTGGA
CCGGAAGAGCTGGAG
CGGAAGAGCTGGAGA
GGAAGAGCTGGAGAC
GAAGAGCTGGAGACA
AAGAGCTGGAGACAG
AGAGCTGGAGACAGA
GAGCTGGAGACAGAG
AGCTGGAGACAGAGT
GCTGGAGACAGAGTA
CTGGAGACAGAGTAC
TGGAGACAGAGTACC
GGAGACAGAGTACCC
GAGACAGAGTAC CCT
AGACAGAGTACCCTT
GACAGAGTACCCTTT
ACAGAGTACCCTTTC
CAGAGTACCCTTTCT
AGAGTACCCTTTCTT
GAGTACCCTTTCTTT
AGTACCCTTTCTTTG
GTACCCTTTCTTTGA
TACCCTTTCTTTGAG
ACCCTTTCTTTGAGA
CCCTTTCTTTGAGAG
CCTTTCTTTGAGAGC
CTTTCTTTGAGAGCA
TTTCTTTGAGAGCAG
TTCTTTGAGAGCAGA
TCTTTGAGAGCAGAG
CTTTGAGAGCAGAGT
TTTGAGAGCAGAGTG
TTGAGAGCAGAGTGG
TGAGAGCAGAGTGGA
GAGAGCAGAGTGGAT
AGAGCAGAGTGGATA
GAGCAGAGTGGATAA
AGCAGAGTGGATAAC
GCAGAGTGGATAACA
CAGAGTGGATAACAA
AGAGTGGATAACAAG
GAGTGGATAACAAGG
AGTGGATAACAAGGA
GTGGATAACAAGGAG
TGGATAACAAGGAGA
GGATAACAAGGAGAG
GATAACAAGGAGAGA
ATAACAAGGAGAGAA
TAACAAGGAGAGAAC
AACAAGGAGAGAACT
ACAAGGAGAGAACTG
CAAGGAGAGAACTGT
AAGGAGAGAACTGTC
AGGAGAGAACTGTCA
GGAGAGAACTGTCAT
GAGAGAACTGTCATT
AGAGAACTGTCATTT
GAGAACTGTCATTTC
AGAACTGTCATTTCT
GAACTGTCATTTCTA
AACTGTCATTTCTAA
ACTGTCATTTCTAAC
CTGTCATTTCTAACC
TGTCATTTCTAACCT
GTCATTTCTAACCTT
TCATTTCTAACCTTC
CATTTCTAACCTTCG
ATTTCTAACCTTCGG
TTTCTAACCTTCGGC
TTCTAACCTTCGGCC
TCTAACCTTCGGCCT
CTAACCTTCGGCCTT
TAACCTTCGGCCTTT
AACCTTCGGCCTTTC
ACCTTCGGCCTTTCA
CCTTCGGCCTTTCAC
CTTCGGCCTTTCACA
TTCGGCCTTTCACAT
TCGGCCTTTCACATT
CGGCCTTTCACATTG
GGCCTTTCACATTGT
GCCTTTCACATTGTA
CCTTTCACATTGTAC
CTTTCACATTGTACC
TTTCACATTGTACCG
TTCACATTGTACCGC
TCACATTGTACCGCA
CACATTGTACCGCAT
ACATTGTACCGCATC
CATTGTACCGCATCG
ATTGTACCGCATCGA
TTGTACCGCATCGAT
TGTACCGCATCGATA
GTACCGCATCGATAT
TACCGCATCGATATC
ACCGCATCGATATCC
CCGCATCGATATCCA
CGCATCGATATCCAC
GCATCGATATCCACA
CATCGATATCCACAG
ATCGATATCCACAGC
TCGATATCCACAGCT
CGATATCCACAGCTG
GATATCCACAGCTGC
ATATCCACAGCTGCA
TATCCACAGCTGCAA
ATCCACAGCTGCAAC
TCCACAGCTGCAACC
CCACAGCTGCAACCA
CACAGCTGCAACCAC
ACAGCTGCAACCACG
CAGCTGCAACCACGA
WO 00/78341 WO 00/834 1PCT/AUOO/00693 -77-
AGCTGCAACCACGAG
GCTGCAACCACGAGG
CTGCAACCACGAGGC
TGCAACCACGAGGCT
GCAACCACGAGGCTG
CAACCACGAGGCTGA
AACCACGAGGCTGAG
ACCACGAGGCTGAGA
CCACGAGGCTGAGAA
CACGAGGCTGAGAAG
ACGAGGCTGAGAAGC
CGAGGCTGAGAAGCT
GAGGCTGAGAAGCTC
AGGCTGAGAAGCTGG
GGCTGAGAAGCTGGG
GCTGAGAAGCTGGGC
CTGAGAAGCTGGGCT
TGAGAAGCTGGGCTG
GAGAAGCTGGGCTGC
AGAAGCTGGGCTGCA
GAAGCTGGGCTGCAG
AAGCTGGGCTGCAGC
AGCTGGGCTGCAGCG
GCTGGGCTGCAGCGC
CTGGGCTGCAGCGCC
TGGGCTGCAGCGCCT
GGGCTGCAGCGCCTC
GGCTGCAGCGCCTCC
GCTGCAGCGCCTCCA
CTGCAGCGCCTCCAA
TGCAGCGCCTCCAAC
GCAGCGCCTCCAACT
CAGCGCCTCCAACTT
AGCGCCTCCAACTTC
GCGCCTCCAACTTCG
CGCCTCCAACTTCGT
GCCTCCAACTTCGTC
CCTCCAACTTCGTCT
CTCCAACTTCGTCTT
TCCAACTTCGTCTTT
CCAACTTCGTCTTTG
CAACTTCGTCTTTGC
AACTTCGTCTTTGCA
ACTTCGTCTTTGCAA
CTTCGTCTTTGCAAG
TTCGTCTTTGCAAGG
TCGTCTTTGCAAGGA
CGTCTTTGCAAGGAC
GTCTTTGCAAGGACT
TCTTTGCAAGGACTA
CTTTGCAAGGACTAT
TTTGCAAGGACTATG
TTGCAAGGACTATGC
TGCAAGGACTATGCC
GCAAGGACTATGCCC
CAAGGACTATGCCCG
AAGGACTATGCCCGC
AGGACTATGCCCGCA
GGACTATGCCCGCAG
GACTATGCCCGCAGA
ACTATGCCCGCAGAA
CTATGCCCGCAGAAG
TATGCCCGCAGAAGG
ATGCCCGCAGAAGGA
TGCCCGCAGAAGGAG
GCCCGCAGAAGGAGC
CCCGCAGAAGGAGCA
CCGCAGAAGGAGCAG
CGCAGAAGGAGCAGA
GCAGAAGGAGCAGAT
CAGAAGGAGCAGATG
AGAAGGAGCAGATGA
GAAGGAGCAGATGAC
AAGGAGCAGATGACA
AGGAGCAGATGACAT
GGAGCAGATGACATT
GAGCAGATGACATTC
AGCAGATGACATTCC
GCAGATGACATTCCT
CAGATGACATTCCTG
AGATGACATTCCTGG
GATGACATTCCTGGG
ATGACATTCCTGGGC
TGACATTCCTGGGCC
GACATTCCTGGGCCA
ACATTCCTGGGCCAG
CATTCCTGGGCCAGT
ATTCCTGGGCCAGTG
TTCCTGGGCCAGTGA
TCCTGGGCCAGTGAC
CCTGGGCCAGTGACC
CTGGGCCAGTGACCT
TGGGCCAGTGACCTG
GGGCCAGTGACCTGG
GGCCAGTGACCTGGG
GCCAGTGACCTGGGA
CCAGTGACCTGGGAG
CAGTGACCTGGGAGC
AGTGACCTGGGAGCC
GTGACCTGGGAGCCA
TGACCTGGGAGCCAA
GACCTGGGAGCCAAG
ACCTGGGAGCCAAGG
CCTGGGAGCCAAGGC
CTGGGAGCCAAGGCC
TGGGAGCCAAGGCCT
GGGAGCCAAGGCCTG
GGAGCCAAGGCCTGA
GAGCCAAGGCCTGAA
AGCCAAGGCCTGAAA
GCCAAGGCCTGAAAA
CCAAGGCCTGAAAAC
CAAGGCCTGAAAACT
AAGGCCTGAAAACTC
AGGCCTGAAAACTCC
GGCCTGAAAACTCCA
GCCTGAAAACTCCAT
CCTGAAAACTCCATC
CTGAAAACTCCATCT
TGAAAACTCCATCTT
GAAAACTCCATCTTT
AAAACTCCATCTTTT
AAACTCCATCTTTTT
AACTCCATCTTTTTA
ACTCCATCTTTTTAA
CTCCATCTTTTTAAA
TCCATCTTTTTAAAG
CCATCTTTTTAAAGT
CAT CTTTTTAAAGTG
ATCTTTTTAAAGTGG
TCTTTTTAAAGTGGC
CTTTTTAAAGTGGCC
TTTTTAAAGTGGCCG
TTTTAAAGTGGCCGG
TTTAAAGTGGCCGGA
TTAAAGTGGCCGGAA
TAAAGTGGCCGGAAC
AAAGTGGCCGGAACC
AAGTGGCCGGAACCT
AGTGGCCGGAACCTG
GTGGCCGGAACCTGA
TGGCCGGAACCTGAG
GGCCGGAACCTGAGA
GCCGGAACCTGAGAA
CCGGAACCTGAGAAT
CGGAACCTGAGAATC
GGAACCTGAGAATCC
GAACCTGAGAATCCC
AACCTGAGAATCCCA
ACCTGAGAATCCCAA
CCTGAGAATCCCAAT
CTGAGAATCCCAATG
TGAGAATCCCAATGG
WO 00/78341 WO 0078341PCT/AUOO/00693 78
GAGAATCCCAATGGA
AGAATCCCAATGGAT
GAATCCCAATGGATT
AATCCCAATGGATTG
ATCCCAATGGATTGA
TCCCAATGGATTGAT
CCCAATGGATTGATT
CCAATGGATTGATTC
CAATGGATTGATTCT
AATGGATTGATTCTA
ATGGATTGATTCTAA
TGGATTGATTCTAAT
GGATTGATTCTAATG
GATTGATTCTAATGT
ATTGATTCTAATGTA
TTGATTCTAATGTAT
TGATTCTAATGTATG
GATTCTAATGTATGA
ATTCTAATGTATGAA
TTCTAATGTATGAAA
TCTAATGTATGAAAT
CTAATGTATGAAATA
TAATGTATGAAATAA
AATGTATGAAATAAA
ATGTATGAAATAAAA
TGTATGAAATAAAAT
GTATGAAATAAAATA
TATGAA.ATAAAATAC
ATGAAATAAAATACG
TGAAATAAAATACGG
GAAATAAAATACGGA
AAATAAAATACGGAT
AATAAAATACGGATC
ATAAAATACGGATCA
TAAAATACGGATCAC
AAAATACGGATCACA
AAATACGGATCACAA
AATACGGATCACAAG
ATACGGATCACAAGT
TACGGATC-ACAAGTT
ACGGATCACAAGTTG
CGGATCACAAGTTGA
GGATCACAAGTTGAG
GATCACAAGTTGAGG
ATCACAAGTTGAGGA
TCACAAGTTGAGGAT
CACAAGTTGAGGATC
ACAAGTTGAGGATCA
CAAGTTGAGGATCAG
AAGTTGAGGATCAGC
AGTTGAGGATCAGCG
GTTGAGGATCAGCGA
TTGAGGATCAGCGAG
TGAGGATCAGCGAGA
GAGGATCAGCGAGAA
AGGATCAGCGAGAAT
GGATCAGCGAGAATG
GATCAGCGAGAATGT
ATCAGCGAGAATGTG
TCAGCGAGAATGTGT
CAGCGAGAATGTGTG
AGCGAGAATGTGTGT
GCGAGAATGTGTGTC
CGAGAATGTGTGTCC
GAGAATGTGTGTCCA
AGAATGTGTGTCCAG
GAATGTGTGTCCAGA
AATGTGTGTCCAGAC
ATGTGTGTCCAGACA
TGTGTGTCCAGACAG
GTGTGTCCAGACAGG
TGTGTCCAGACAGGA
GTGTCCAGACAGGAA
TGTCCAGACAGGAAT
GTCCAGACAGGAATA
TCCAGACAGGAATAC
CCAGACAGGAATACA
CAGACAGGAATACAG
AGACAGGAATACAGG
GACAGGAATACAGGA
ACAGGAATACAGGAA
CAGGAATACAGGAAG
AGGAATACAGGAAGT
GGAATACAGGAAGTA
GAATACAGGAAGTAT
AATACAGGAAGTATG
ATACAGGAAGTATGG
TACAGGAAGTATGGA
ACAGGAAGTATGGAG
CAGGAAGTATGGAGG
AGGAAGTATGGAGGG
GGAAGTATGGAGGGG
GAAGTATGGAGGGGC
AAGTATGGAGGGGCC
AGTATGGAGGGGCCA
GTATGGAGGGGCCAA
TATGGAGGGGCCAAG
ATGGAGGGGCCAAGC
TGGAGGGGCCAAGCT
GGAGGGGCCAAGCTA
GAGGGGCCAAGCTAA
AGGGGCCAAGCTAAA
GGGGCCAAGCTAAAC
GGGCCAAGCTAAACC
GGCCAAGCTAAACCG
GCCAAGCTAAACCGG
CCAAGCTAAACCGGC
CAAGCTAAACCGGCT
AAGCTAAACCGGCTA
AGCTAAACCGGCTAA
GCTAAACCGGCTAAA
CTAAACCGGCTAAAC
TAAACCGGCTAAACC
AAACCGGCTAAACCC
AACCGGCTAAACCCG
ACCGGCTAAACCCGG
CCGGCTAAACCCGGG
CGGCTAAACCCGGGG
GGCTAAACCCGGGGA
GCTAAACCCGGGGAA
CTAAACCCGGGGAAC
TAAACCCGGGGAACT
AAACCCGGGGAACTA
AACCCGGGGAACTAC
ACCCGGGGAACTACA
CCCGGGGAACTACAC
CCGGGGAACTACACA
CGGGGAACTACACAG
GGGGAACTACACAGC
GGGAACTACACAGCC
GGAACTACACAGCCC
GAACTACACAGCCCG
AACTACACAGCCCGG
ACTACACAGCCCGGA
CTACACAGCCCGGAT
TACACAGCCCGGATT
ACACAGCCCGGATTC
CACAGCCCGGATTCA
ACAGCCCGGATTCAG
CAGCCCGGATTCAGG
AGCCCGGATTCAGGC
GCCCGGATTCAGGCC
CCCGOATTCAGGCCA
CCGGATTCAGGCCAC
CGGATTCAGGCCACA
GGATTCAGGCCACAT
GATTCAGGCCACATC
ATTCAGGCCACATCT
TTCAGGCCACATCTC
TCAGGCCACATCTCT
CAGGCCACATCTCTC
AGGCCACATCTCTCT
GGCCACATCTCTCTC
WO 00/78341 WO 00/834 1PCT/AUOO/00693 79
GCCACATCTCTCTCT
CCACATCTCTCTCTG
CACATCTCTCTCTGG
ACATCTCTCTCTGGG
CATCTCTCTCTGGGA
ATCTCTCTCTGGGAA
TCTCTCTCTGGGAAT
CTCTCTCTGGGAATG
TCTCTCTGGGAATGG
CTCTCTGGGAATGGG
TCTCTGGGAATGGGT
CTCTGGGAATGGGTC
TCTGGGAATGGGTCG
CTGGGAATGGGTCGT
TGGGAATGGGTCGTG
GGGAATGGGTCGTGG
GGAATGGGTCGTGGA
GAATGGGTCGTGGAC
AATGGGTCGTGGACA
ATGGGTCGTGGACAG
TGGGTCGTGGACAGA
GGGTCGTGGACAGAT
GGTCGTGGACAGATC
GTCGTGGACAGATCC
TCGTGGACAGATCCT
CGTGGACAGATCCTG
GTGGACAGATCCTGT
TGGACAGATCCTGTG
GGACAGATCCTGTGT
GACAGATCCTGTGTT
ACAGATCCTGTGTTC
CAGATCCTGTGTTCT
AGATCCTGTGTTCTT
GATCCTGTGTTCTTC
ATCCTGTGTTCTTCT
TCCTGTGTTCTTCTA
CCTGTGTTCTTCTAT
CTGTGTTCTTCTATG
TGTGTTCTTCTATGT
GTGTTCTTCTATGTC
TGTTCTTCTATGTCC
GTTCTTCTATGTCCA
TTCTTCTATGTCCAG
TCTTCTATGTCCAGG
CTTCTATGTCCAGGC
TTCTATGTCCAGGCC
TCTATGTCCAGGCCA
CTATGTCCAGGCCAA
TATGTCCAGGCCAAA
ATGTCCAGGCCAAAA
TGTCCAGGCCAAAAC
GTCCAGGCCAAAACA
TCCAGGCCAAAACAG
CCAGGCCAAAACAGG
CAGGCCAAAACAGGA
AGGCCAAAACAGGAT
GGCCAAAACAGGATA
GCCAAAACAGGATAT
CCAAAACAGGATATG
CAAAACAGGATATGA
AAAACAGGATATGAA
AAACAGGATATGAAA
AACAGGATATGAAAA
ACAGGATATGAAAAC
CAGGATATGAAAACT
AGGATATGAA.AACTT
GGATATGAAAACTTC
GATATGAAAACTTC-A
ATATGAAAACTTCAT
TATGAAAACTTCATC
ATGAAAACTTCATCC
TGAAAACTTCATCCA
GAAAACTTCATCCAT
AAAACTTCATCCATC
AAACTTCATCCATCT
AACTTCATCCATCTG
ACTTCATCCATCTGA
CTTCATCCATCTGAT
TTCATCCATCTGATC
TCATCCATCTGATCA
CATCCATCTGATCAT
ATCCATCTGATCATC
TCCATCTGATCATCG
CCATCTGATCATCGC
CATCTGATCATCGCT
ATCTGATCATCGCTC
TCTGATCATCGCTCT
CTGATCATCGCTCTG
TGATCATCGCTCTGC
GATCATCGCTCTGCC
ATCATCGCTCTGCCC
TCATCGCTCTGCCCG
CATCGCTCTGCCCGT
ATCGCTCTGCCCGTC
TCGCTCTGCCCGTCG
CGCTCTGCCCGTCGC
GCTCTGCCCGTCGCT
CTCTGCCCGTCGCTG
TCTGCCCGTCGCTGT
CTGCCCGTCGCTGTC
TGCCCGTCGCTGTCC
GCCCGTCGCTGTCCT
CCCGTCGCTGTCCTG
CCGTCGCTGTCCTGT
CGTCGCTGTCCTGTT
GTCGCTGTCCTGTTG
TCGCTGTCCTGTTGA
CGCTGTCCTGTTGAT
GCTGTCCTGTTGATC
CTGTCCTGTTGATCG
TGTCCTGTTGATCGT
GTCCTGTTGATCGTG
TCCTGTTGATCGTGG
CCTGTTGATCGTGGG
CTGTTGATCGTGGGA
TGTTGATCGTGGGAG
GTTGATCGTGGGAGG
TTGATCGTGGGAGGG
TGATCGTGGGAGGGT
GATCGTGGGAGGGTT
ATCGTGGGAGGGTTG
TCGTGGGAGGGTTGG
CGTGGGAGGGTTGGT
GTGGGAGGGTTGGTG
TGGGAGGGTTGGTGA
GGGAGGGTTGGTGAT
GGAGGGTTGGTGATT
GAGGGTTGGTGATTA
AGGGTTGGTGATTAT
GGGTTGGTGATTATG
GGTTGGTGATTATGC
GTTGGTGATTATGCT
TTGGTGATTATGCTG
TGGTGATTATGCTGT
GGTGATTATGCTGTA
GTGATTATGCTGTAC
TGATTATGCTGTACG
GATTATGCTGTACGT
ATTATGCTGTACGTC
TTATGCTGTACGTCT
TATGCTGTACGTCTT
ATGCTGTACGTCTTC
TGCTGTACGTCTTCC
GCTGTACGTCTTCCA
CTGTACGTCTTCCAT
TGTACGTCTTCCATA
GTACGTCTTCCATAG
TACGTCTTCCATAGA
ACGTCTTCCATAGAA
CGTCTTCCATAGAAA
GTCTTCCATAGAAAG
TCTTCCATAGAAAGA
CTTCCATAGAAAGAG
WO 00/78341 WO 0078341PCT/AUOO/00693 80
TTCCATAGAAAGAGA
TCCATAGAAAGAGAA
CCATAGAAAGAGAAA
CATAGAAAGAGAAAT
ATAGAAAGAGAAATA
TAGAAAGAGAAATAA
AGAAAGAGAAATAAC
GAAAGAGAAATAACA
AAAGAGAAATAACAG
AAGAGAAATAACAGC
AGAGAAATAACAGCA
GAGAAATAACAGCAG
AGAAATAACAGCAGG
GAAATAACAGCAGGC
AAATAACAGCAGCCT
AATAACAGCAGGCTG
ATAACAGCAGGCTGG
TAACAGCAGGCTGGG
AACAGCAGGCTGGGG
ACAGCAGGCTGGGGA
CAGCAGGCTGGGGAA
AGCAGGCTGGGGAAT
GCAGGCTGGGGAATG
CAGGCTGGGGAATGG
AGGCTGGGGAATGGA
GGCTGGGGAATGGAG
GCTGGGGAATGGAGT
CTGGGGAATGGAGTG
TGGGGAATGGAGTGC
GGGGAATGGAGTGCT
GGGAATGGAGTGCTG
GGAATGGAGTGCTGT
GAATGGAGTGCTGTA
AATGGAGTGCTGTAT
ATGGAGTGCTGTATG
TGGAGTGCTGTATGC
GGAGTGCTGTATGCC
GAGTGCTGTATGCCT
AGTGCTGTATGCCTC
GTGCTGTATGCCTCT
TGCTGTATGCCTCTC
GCTGTATGCCTCTGT
CTGTATGCCTCTGTG
TGTATGCCTCTGTGA
GTATGCCTCTGTGAA
TATGCCTCTGTGAAC
ATGCCTCTGTGAACC
TGCCTCTGTGAACCC
GCCTCTGTGAACCCG
CCTCTGTGAACCCGG
CTCTGTGAACCCGGA
TCTGTGAACCCGGAG
CTGTGAACCCGGAGT
TGTGAACCCGGAGTA
GTGAACCCGGAGTAC
TGAACCCGGAGTACT
GAACCCGGAGTACTT
AACCCGGAGTACTTC
ACCCGGAGTACTTCA
CCCGGAGTACTTCAG
CCGGAGTACTTCAGC
CGGAGTACTTCAGCG
GGAGTACTTCAGCGC
GAGTACTTCAGCGCT
AGTACTTCAGCGCTG
GTACTTCAGCGCTGC
TACTTCAGCGCTGCT
ACTTCAGCGCTGCTG
CTTCAGCGCTGCTGA
TTCAGCGCTGCTGAT
TCAGCGCTGCTGATG
CAGCGCTGCTGATGT
AGCGCTGCTGATGTG
GCGCTGCTGATGTGT
CGCTGCTGATGTGTA
GCTGCTGATGTGTAC
CTGCTGATGTGTACG
TGCTGATGTGTACGT
GCTGATGTGTACGTT
CTGATGTGTACGTTC
TGATGTGTACGTTCC
GATGTGTACGTTCCT
ATGTGTACGTTCCTG
TGTGTACGTTCCTGA
GTGTACGTTCCTGAT
TGTACGTTCCTGATG
GTACGTTCCTGATGA
TACGTTCCTGATGAG
ACGTTCCTGATGAGT
CGTTCCTGATGAGTG
GTTCCTGATGAGTGG
TTCCTGATGAGTGGG
TCCTGATGAGTGGGA
CCTGATGAGTGGGAG
CTGATGAGTGGGAGG
TGATGAGTGGGAGGT
GATGAGTGGGAGGTG
ATGAGTGGGAGGTGG
TGAGTQGGAGGTGGC
GAGTGGGAGGTGGCT
AGTGGGAGGTGGCTC
GTGGGAGGTGGCTCG
TGGGAGGTGGCTCGG
GGGAGGTGGCTCGGG
GGAGGTGGCTCGGGA
GAGGTGGCTCGGGAG
AGGTGGCTCGGGAGA
GGTGGCTCGGGAGAA
GTGGCTCGGGAGAAG
TGGCTCGGGAGAAGA
GGCTCGGGAGAAGAT
GCTCGGGAGAAGATC
CTCGGGAGAAGATCA
TCGGGAGAAGATCAC
CGGGAGAAGATCACC
GGGAGAAGATCACCA
GGAGAAGAT CAC CAT
GAGAAGATCACCATG
AGAAGATCACCATGA
GAAGATCACCATGAG
AAGATCACCATGAGC
AGATCACCATGAGCC
GATCACCATGAGCCG
ATCACCATGAGCCGG
TCACCATGAGCCGGG
CACCATGAGCCGGGA
ACCATGAGCCGGGAA
CCATGAGCCGGGAAC
CATGAGCCGGGAACT
ATGAGCCGGGAACTT
TGAGCCGGGAACTTG
GAGCCGGGAACTTGG
AGCCGGGAACTTGGG
GCCGGGAACTTGGGC
CCGGGAACTTGGGCA
CGGGAACTTGGGCAG
GGGAACTTGGGCAGG
GGAACTTGGGCAGGG
GAACTTGGGCAGGGG
AACTTGGGCAGGGGT
ACTTGGGCAGGGGTC
CTTGGGCAGGGGTCG
TTGGGCAGGGGTCGT
TGGGCAGGGGTCGTT
GGGCAGGGGTCGTTT
GGCAGGGGTCGTTTG
GCAGGGGTCGTTTGG
CAGGGGTCGTTTGGG
AGGGGTCGTTTGGGA
GGGGTCGTTTGGGAT
GGGTCGTTTGGGATG
GGTCGTTTGGGATGG
GTCGTTTGGGATGGT
WO 00/78341 WO 0078341PCT/AUOO/00693 -81-
TCGTTTGGGATGGTC
CGTTTGGGATGGTCT
GTTTGGGATGGTCTA
TTTGGGATGGTCTAT
TTGGGATGGTCTATG
TGGGATGGTCTATGA
GGGATGGTCTATGAA
GGATGGTCTATGAAG
GATGGTCTATGAAGG
ATGGTCTATGAAGGA
TGGTCTATGAAGGAG
GGTCTATGAAGGAGT
GTCTATGAAGGAGTT
TCTATGAAGGAGTTG
CTATGAAGGAGTTGC
TATGAAGGAGTTGCC
ATGAAGGAGTTGCCA
TGAAGGAGTTGCCAA
GAAGGAGTTGCCAAG
AAGGAGTTGCCAAGG
AGGAGTTGCCAAGGG
GGAGTTGCCAAGGGT
GAGTTGCCAAGGGTG
AGTTGCCAAGGGTGT
GTTGCCAAGGGTGTG
TTGCCAAGGGTGTGG
TGCCAAGGGTGTGGT
GCCAAGGGTGTGGTG
CCAAGGGTGTGGTGA
CAAGGGTGTGGTGAA
AAGGGTGTGGTGAAA
AGGGTGTGGTGAAAG
GGGTGTGGTGAAAGA
GGTGTGGTGAAAGAT
GTGTGGTGAAAGATG
TGTGGTGAAAGATGA
GTGGTGAAAGATGAA
TGGTGAAAGATGAAC
GGTGAAAGATGAACC
GTGAAAGATGAACCT
TGAAAGATGAACCTG
GAAAGATGAACCTGA
AAAGATGAACCTGAA
AAGATGAACCTGAAA
AGATGAACCTGAAAC
GATGAACCTGAAACC
ATGAACCTGAAACCA
TGAACCTGAAACCAG
GAACCTGAAACCAGA
AACCTGAAACCAGAG
ACCTGAAACCAGAGT
CCTGAAACCAGAGTG
CTGAAACCAGAGTGG
TGAALACCAGAGTGGC
GAAACCAGAGTGGCC
AAACCAGAGTGGCCA
AACCAGAGTGGCCAT
ACCAGAGTGGCCATT
CCAGAGTGGCCATTA
CAGAGTGGCCATTAA
AGAGTGGCCATTAAA
GAGTGGCCATTAAAA
AGTGGCCATTAAAAC
GTGGCCATTAAAACA
TGGCCATTAAAACAG
GGCCATTAAAACAGT
GCCATTAAAACAGTG
CCATTAAAACAGTGA
CATTAAAACAGTGAA
ATTAAAACAGTGAAC
TTAAAACAGTGAACG
TAAAACAGTGAACGA
AAAACAGTGAACGAG
AAACAGTGAACGAGG
AACAGTGAACGAGGC
ACAGTGAACGAGGCC
CAGTGAACGAGGCCG
AGTGAACGAGGCCGC
GTGAACGAGGCCGCA
TGAACGAGGCCGCAA
GAACGAGGCCGCAAG
AACGAGGCCGCAAGC
ACGAGGCCGCAAGCA
CGAGGCCGCAAGCAT
GAGGCCGCAAGCATG
AGGCCGCAAGCATGC
GGCCGCAAGCATGCG
GCCGCAAGCATGCGT
CCGCAAGCATGCGTG
CGCAAGCATGCGTGA
GCAAGCATGCGTGAG
CAAGCATGCGTGAGA
AAGCATGCGTGAGAG
AGCATGCGTGAGAGG
GCATGCGTGAGAGGA
CATGCGTGAGAGGAT
ATGCGTGAGAGGATT
TGCGTGAGAGGATTG
GCGTGAGAGGATTGA
CGTGAGAGGATTGAG
GTGAGAGGATTGAGT
TGAGAGGATTGAGTT
GAGAGGATTGAGTTT
AGAGGATTGAGTTTC
GAGGATTGAGTTTCT
AGGATTGAGTTTCTC
GGATTGAGTTTCTCA
GATTGAGTTTCTCAA
ATTGAGTTTCTCAAC
TTGAGTTTCTCAACG
TGAGTTTCTCAACGA
GAGTTTCTCAACGAA
AGTTTCTCAACGAAG
GTTTCTCAACGAAGC
TTTCTCAACGAAGCT
TTCTCAACGAAGCTT
TCTCAACGAAGCTTC
CTCAACGAAGCTTCT
TCAACGAAGCTTCTG
CAACGAAGCTTCTGT
AACGAAGCTTCTGTG
ACGAAGCTTCTGTGA
CGAAGCTTCTGTGAT
GAAGCTTCTGTGATG
AAGCTTCTGTGATGA
AGCTTCTGTGATGAA
GCTTCTGTGATGAAG
CTTCTGTGATGAAGG
TTCTGTGATGAAGGA
TCTGTGATGAAGGAG
CTGTGATGAAGGAGT
TGTGATGAAGGAGTT
GTGATGAAGGAGTTC
TGATGAAGGAGTTCA
GATGAAGGAGTTCAA
ATGAAGGAGTTCAAT
TGAAGGAGTTCAATT
GAAGGAGTTCAATTG
AAGGAGTTCAATTGT
AGGAGTTCAATTGTC
GGAGTTCAATTGTCA
GAGTTCAATTGTCAC
AGTTCAATTGTCACC
GTTCAATTGTCACCA
TTCAATTGTCAC CAT
TCAATTGTCACCATG
CAATTGTCACCATGT
AATTGTCACCATGTG
ATTGTCACCATGTGG
TTGTCACCATGTGGT
TGTCACCATGTGGTG
GTCACCATGTGGTGC
TCACCATGTGGTGCG
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CACCATGTGGTGCGA
ACCATGTGGTGCGAT
CCATGTGGTGCGATT
CATGTGGTGCGATTG
ATGTGGTGCGATTGC
TGTGGTGCGATTGCT
GTGGTGCGATTGCTG
TGGTGCGATTGCTGG
GGTGCGATTGCTGGG
GTGCGATTGCTGGGT
TGCGATTGCTGGGTG
GCGATTGCTGGGTGT
CGATTGCTGGGTGTG
GATTGCTGGGTGTGG
ATTGCTGGGTGTGGT
TTGCTGGGTGTGGTG
TGCTGGGTGTGGTGT
GCTGGGTGTGGTGTC
CTGGGTGTGGTGTCC
TGGGTGTGGTGTCCC
GGGTGTGGTGTCCCA
GGTGTGGTGTCCCAA
GTGTGGTGTCCCAAG
TGTGGTGTCCCAAGG
GTGGTGTCCCAAGGC
TGGTGTCCCAAGGCC
GGTGTCCCAAGGCCA
GTGTCCCAAGGCCAG
TGTCCCAAGGCCAGC
GTCCCAAGGCCAGCC
TCCCAAGGCCAGCCA
CCCAAGGCCAGCCAA
CCAAGGCCAGCCAAC
CAAGGCCAGCCAACA
AAGGCCAGCCAACAC
AGGCCAGCCAACACT
GGCCAGCCAACACTG
GCCAGCCAACACTGG
CCAGCCAACACTGGT
CAGCCAACACTGGTC
AGCCAACACTGGTCA
GCCAACACTGGTCAT
CCAACACTGGTCATC
CAACACTGGTCATCA
AACACTGGTCATCAT
ACACTGGTCATCATG
CACTGGTCATCATGG
ACTGGTCATCATGGA
CTGGTCATCATGGAA
TGGTCATCATGGAAC
GGTCATCATGGAACT
GTCATCATGGAACTG
TCATCATGGAACTGA
CATCATGGAACTGAT
ATCATGGAACTGATG
TCATGGAACTGATGA
CATGGAACTGATGAC
ATGGAACTGATGACA
TGGAACTGATGACAC
GGAACTGATGACACG
GAACTGATGACACGG
AACTGATGACACGGG
ACTGATGACACGGGG
CTGATGACACGGGGC
TGATGACACGGGGCG
GATGACACGGGGCGA
ATGACACGGGGCGAT
TGACACGGGGCGATC
GACACGGGGCGATCT
ACACGGGGCGATCTC
CACGGGGCGATCTCA
ACGGGGCGATCTCAA
CGGGGCGATCTCAAA
GGGGCGATCTCAAAA
GGGCGATCTCAAAAG
GGCGATCTCAAAAGT
GCGATCTCAAAAGTT
CGATCTCAAAAGTTA
GATCTCAAAAGTTAT
ATCTCAAAAGTTATC
TCTCAAAAGTTATCT
CTCAAAAGTTATCTC
TCAAAAGTTATCTCC
CAAAAGTTATCTCCG
AAAAGTTATCTCCGG
AAAGTTATCTCCGGT
AAGTTATCTCCGGTC
AGTTATCTCCGGTCT
GTTATCTCCGGTCTC
TTATCTCCGGTCTCT
TATCTCCGGTCTCTG
ATCTCCGGTCTCTGA
TCTCCGGTCTCTGAG
CTCCGGTCTCTGAGG
TCCGGTCTCTGAGGC
CCGGTCTCTGAGGCC
CGGTCTCTGAGGCCA
GGTCTCTGAGGCCAG
GTCTCTGAGGCCAGA
TCTCTGAGGCCAGAA
CTCTGAGGCCAGAAA
TCTGAGGCCAGAAAT
CTGAGGCCAGAAATG
TGAGGCCAGAAATGG
GAGGCCAGAAATGGA
AGGCCAGAAATGGAG
GGCCAGAAATGGAGA
GCCAGAAATGGAGAA
CCAGAAATGGAGAAT
CAGAAATGGAGAATA
AGAAATGGAGAATAA
GAAATGGAGAATAAT
AAATGGAGAATAATC
AATGGAGAATAATCC
ATGGAGAATAATCCA
TGGAGAATAATCCAG
GGAGAATAATCCAGT
GAGAATAATCCAGTC
AGAATAATCCAGTCC
GAATAATCCAGTCCT
AATAATCCAGTCCTA
ATAATCCAGTCCTAG
TAATCCAGTCCTAGC
AATCCAGTCCTAGCA
ATCCAGTCCTAGCAC
TCCAGTCCTAGCACC
CCAGTCCTAGCACCT
CAGTCCTAGCACCTC
AGTCCTAGCACCTCC
GTCCTAGCACCTCCA
TCCTAGCACCTCCAA
CCTAGCACCTCCAAG
CTAGCACCTCCAAGC
TAGCACCTCCAAGCC
AGCACCTCCAAGCCT
GCACCTCCAAGCCTG
CACCTCCAAGCCTGA
ACCTCCAAGCCTGAG
CCTCCAAGCCTGAGC
CTCCAAGCCTGAGCA
TCCAAGCCTGAGCAA
CCAAGCCTGAGCAAG
CAAGCCTGAGCAAGA
AAGCCTGAGCAAGAT
AGCCTGAGCAAGATG
GCCTGAGCAAGATGA
CCTGAGCAAGATGAT
CTGAGCAAGATGATT
TGAGCAAGATGATTC
GAGCAAGATGATTCA
AGCAAGATGATTCAG
GCAAGATGATTCAGA
CAAGATGATTCAGAT
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AAGATGATTCAGATG
AGATGATTCAGATGG
GATGATTCAGATGGC
ATGATTCAGATGGCC
TGATTCAGATGGCCG
GATTCAGATGGCCGG
ATTCAGATGGCCGGA
TTCAGATGGCCGGAG
TCAGATGGCCGGAGA
CAGATGGCCGGAGAG
AGATGGCCGGAGAGA
GATGGCCGGAGAGAT
ATGGCCGGAGAGATT
TGGCCGGAGAGATTG
GGCCGGAGAGATTGC
GCCGGAGAGATTGCA
CCGGAGAGATTGCAG
CGGAGAGATTGCAGA
GGAGAGATTGCAGAC
GAGAGATTGCAGACG
AGAGATTGCAGACGG
GAGATTGCAGACGGC
AGATTGCAGACGGCA
GATTGCAGACGGCAT
ATTGCAGACGGCATG
TTGCAGACGGCATGG
TGCAGACGGCATGGC
GCAGACGGCATGGCA
CAGACGGCATGGCAT
AGACGGCATGGCATA
GACGGCATGGCATAC
ACGGCATGGCATACC
CGGCATGGCATACCT
GGCATGGCATACCTC
GCATGGCATACCTCA
CATGGCATACCTCAA
ATGGCATACCTCAAC
TGGCATACCTCAACG
GGCATACCTCAACGC
GCATACCTCAACGCC
CATACCTCAACGCCA
ATACCTCAACGCCAA
TACCTCAACGCCAAT
ACCTCAACGCCAATA
CCTCAACGCCAATAA
CTCAACGCCAATAAG
TCAACGCCAATAAGT
CAACGCCAATAAGTT
AACGC CAATAAGTTC
ACGCCAATAAGTTCG
CGCCAATAAGTTCGT
GCCAATAAGTTCGTC
CCAATAAGTTCGTCC
CAATAAGTTCGTCCA
AATAAGTTCGTCCAC
ATAAGTTCGTCCACA
TAAGTTCGTCCACAG
AAGTTCGTCCACAGA
AGTTCGTCCACAGAG
GTTCGTCCACAGAGA
TTCGTCCACAGAGAC
TCGTCCACAGAGACC
CGTCCACAGAGACCT
GTCCACAGAGACCTT
TCCACAGAGACCTTG
CCACAGAGACCTTGC
CACAGAGACCTTGCT
ACAGAGACCTTGCTG
CAGAGACCTTGCTGC
AGAGACCTTGCTGCC
GAGACCTTGCTGCCC
AGACCTTGCTGCCCG
GACCTTGCTGCCCGG
ACCTTGCTGCCCGGA
CCTTGCTGCCCGGAA
CTTGCTGCCCGGAAT
TTGCTGCCCGGAATT
TGCTGCCCGGAATTG
GCTGCCCGGAATTGC
CTGCCCGGAATTGCA
TGCCCGGAATTGCAT
GCCCGGAATTGCATG
CCCGGAATTGCATGG
CCGGAATTGCATGGT
CGGAATTGCATGGTA
GGAATTGCATGGTAG
GAATTGCATGGTAGC
AATTGCATGGTAGCC
ATTGCATGGTAGCCG
TTGCATGGTAGCCGA
TGCATGGTAGCCGAA
GCATGGTAGCCGAAG
CATGGTAGCCGAAGA
ATGGTAGCCGAAGAT
TGGTAGCCGAAGATT
GGTAGCCGAAGATTT
GTAGCCGAAGATTTC
TAGCCGAAGATTTCA
AGCCGAAGATTTCAC
GCCGAAGATTTCACA
CCGAAGATTTCACAG
CGAAGATTTCACAGT
GAAGATTTCACAGTC
AAGATTTCACAGTCA
AGATTTCACAGTCAA
GATTTCACAGTCAAA
ATTTCACAGTCAAAA
TTTCACAGTCAAAAT
TTCACAGTCAAAATC
TCACAGTCAAAATCG
CACAGTCAAAATCGG
ACAGTCAAAATCGGA
CAGTCAAAATCGGAG
AGTCAAAATCGGAGA
GTCAAAATCGGAGAT
TCAAAATCGGAGATT
CAAAATCGGAGATTT
AAAATCGGAGATTTT
AAATCGGAGATTTTG
AATCGGAGATTTTGG
ATCGGAGATTTTGGT
TCGGAGATTTTGGTA
CGGAGATTTTGGTAT
GGAGATTTTGGTATG
GAGATTTTGGTATGA
AGATTTTGGTATGAC
GATTTTGGTATGACG
ATTTTGGTATGACGC
TTTTGGTATGACGCG
TTTGGTATGACGCGA
TTGGTATGACGCGAG
TGGTATGACGCGAGA
GGTATGACGCGAGAT
GTATGACGCGAGATA
TATGACGCGAGATAT
ATGACGCGAGATATC
TGACGCGAGATATCT
GACGCGAGATATCTA
ACGCGAGATATCTAT
CGCGAGATATCTATG
GCGAGATATCTATGA
CGAGATATCTATGAG
GAGATATCTATGAGA
AGATATCTATGAGAC
GATATCTATGAGACA
ATATCTATGAGACAG
TATCTATGAGACAGA
ATCTATGAGACAGAC
TCTATGAGACAGACT
CTATGAGACAGACTA
TATGAGACAGACTAT
ATGAGACAGACTATT
TGAGACAGACTATTA
WO 00/78341 WO 00/834 1PCT/AUOO/00693 84
GAGACAGACTATTAC
AGACAGACTATTACC
GACAGACTATTACCG
ACAGACTATTACCGG
CAGACTATTACCGGA
AGACTATTACCGGAA
GACTATTACCGGAAA
ACTATTACCGGAAAG
CTATTACCGGAAAGG
TATTACCGGAAAGGA
ATTACCGGAAAGGAG
TTACCGGAAAGGAGG
TACCGGAAAGGAGGC
ACCGGAAAGGAGGCA
CCGGAAAGGAGGCAA
CGGAAAGGAGGCAAA
GGAAAGGAGGCAAAG
GAAAGGAGGCAAAGG
AAAGGAGGCAAAGGG
AAGGAGGCAAAGGGC
AGGAGGCAAAGGGCT
GGAGGCAAAGGGCTG
GAGGCAAAGGGCTGC
AGGCAAAGGGCTGCT
GGCAAAGGGCTGCTG
GCAAAGGGCTGCTGC
CAAAGGGCTGCTGCC
AAAGGGCTGCTGCCC
AAGGGCTGCTGCCCG
AGGGCTGCTGCCCGT
GGGCTGCTGCCCGTG
GGCTGCTGCCCGTGC
GCTGCTGCCCGTGCG
CTGCTGCCCGTGCGC
TGCTGCCCGTGCGCT
GCTGCCCGTGCGCTG
CTGCCCGTGCGCTGG
TGCCCGTGCGCTGGA
GCCCGTGCGCTGGAT
CCCGTGCGCTGGATG
CCGTGCGCTGGATGT
CGTGCGCTGGATGTC
GTGCGCTGGATGTCT
TGCGCTGGATGTCTC
GCGCTGGATGTCTCC
CGCTGGATGTCTCCT
GCTGGATGTCTCCTG
CTGGATGTCTCCTGA
TGGATGTCTCCTGAG
GGATGTCTCCTGAGT
GATGTCTCCTGAGTC
ATGTCTCCTGAGTCC
TGTCTCCTGAGTCCC
GTCTCCTGAGTCCCT
TCTCCTGAGTCCCTC
CTCCTGAGTCCCTCA
TCCTGAGTCCCTCAA
CCTGAGTCCCTCA-AG
CTGAGTCCCTCAAGG
TGAGTCCCTCAAGGA
GAGTCCCTCAAGGAT
AGTCCCTCAAGGATG
GTCCCTCAAGGATGG
TCCCTCAAGGATGGA
CCCTCAAGGATGGAG
CCTCAAGGATGGAGT
CTCAAGGATGGAGTC
TCAAGGATGGAGTCT
CAAGGATGGAGTCTT
AAGGATGGAGTCTTC
AGGATGGAGTCTTCA
GGATGGAGTCTTCAC
GATGGAGTCTTCACC
ATGGAGTCTTCACCA
TGGAGTCTTCACCAC
GGAGTCTTCACCACT
GAGTCTTCACCACTT
AGTCTTCACCACTTA
GTCTTCACCACTTAC
TCTTCACCACTTACT
CTTCACCACTTACTC
TTCACCACTTACTCG
TCACCACTTACTCGG
CACCACTTACTCGGA
ACCACTTACTCGGAC
CCACTTACTCGGACG
CACTTACTCGGACGT
ACTTACTCGGACGTC
CTTACTCGGACGTCT
TTACTCGGACGTCTG
TACTCGGACGTCTGG
ACTCGGACGTCTGGT
CTCGGACGTCTGGTC
TCGGACGTCTGGTCC
CGGACGTCTGGTCCT
GGACGTCTGGTCCTT
GACGTCTGGTCCTTC
ACGTCTGGTCCTTCG
CGTCTGGTCCTTCGG
GTCTGGTCCTTCGGG
TCTGGTCCTTCGGGG
CTGGTCCTTCGGGGT
TGGTCCTTCGGGGTC
GGTCCTTCGGGGTCG
GTCCTTCGGGGTCGT
TCCTTCGGGGTCGTC
CCTTCGGGGTCGTCC
CTTCGGGGTCGTCCT
TTCGGGGTCGTCCTC
TCGGGGTCGTCCTCT
CGGGGTCGTCCTCTG
GGGGTCGTCCTCTGG
GGGTCGTCCTCTGGG
GGTCGTCCTCTGGGA
GTCGTCCTCTGGGAG
TCGTCCTCTGGGAGA
CGTCCTCTGGGAGAT
GTCCTCTGGGAGATC
TCCTCTGGGAGATCG
CCTCTGGGAGATCGC
CTCTGGGAGATCGCC
TCTGGGAGATCGCCA
CTGGGAGATCGCCAC
TGGGAGATCGCCACA
GGGAGATCGCCACAC
GGAGATCGCCACACT
GAGATCGCCACACTG
AGATCGCCACACTGG
GATCGCCACACTGGC
ATCGCCACACTGGCC
TCGCCACACTGGCCG
CGCCACACTGGCCGA
GCCACACTGGCCGAG
CCACACTGGCCGAGC
CACACTGGCCGAGCA
ACACTGGCCGAGCAG
CACTGGCCGAGCAGC
ACTGGCCGAGCAGCC
CTGGCCGAGCAGCCC
TGGCCGAGCAGCCCT
GGCCGAGCAGCCCTA
GCCGAGCAGCCCTAC
CCGAGCAGCCCTACC
CGAGCAGCCCTACCA
GAGCAGCCCTACCAG
AGCAGCCCTACCAGG
GCAGCCCTACCAGGG
CAGCCCTACCAGGGC
AGCCCTACCAGGGCT
GCCCTACCAGGGCTT
CCCTACCAGGGCTTG
CCTACCAGGGCTTGT
CTACCAGGGCTTGTC
WO 00/78341 WO 0078341PCT/AUOO/00693
TACCAGGGCTTGTCC
ACCAGGGCTTGTCCA
CCAGGGCTTGTCCAA
CAGGGCTTGTCCAAC
AGGGCTTGTCCAACG
GGGCTTGTCCAACGA
GGCTTGTCCAACGAG
GCTTGTCCAACGAGC
CTTGTCCAACGAGCA
TTGTCCAACGAGCAA
TGTCCAACGAGCAAG
GTCCAACGAGCAAGT
TCCAACGAGCAAGTC
CCAACGAGCAAGTCC
CAACGAGCAAGTCCT
AACGAGCAAGTCCTT
ACGAGCAAGTCCTTC
CGAGCAAGTCCTTCG
GAGCAAGTCCTTCGC
AGCAAGTCCTTCGCT
GCAAGTCCTTCGCTT
CAAGTCCTTCGCTTC
AAGTCCTTCGCTTCG
AGTCCTTCGCTTCGT
GTCCTTCGCTTCGTC
TCCTTCGCTTCGTCA
CCTTCGCTTCGTCAT
CTTCGCTTCGTCATG
TTCGCTTCGTCATGG
TCGCTTCGTCATGGA
CGCTTCGTCATGGAG
GCTTCGTCATGGAGG
CTTCGTCATGGAGGG
TTCGTCATGGAGGGC
TCGTCATGGAGGGCG
CGTCATGGAGGGCGG
GTCATGGAGGGCGGC
TCATGGAGGGCGGCC
CATGGAGGGCGGCCT
ATGGAGGGCGGCCTT
TGGAGGGCGGCCTTC
GGAGGGCGGCCTTCT
GAGGGCGGCCTTCTG
AGGGCGGCCTTCTGG
GGGCGGCCTTCTGGA
GGCGGCCTTCTGGAC
GCGGCCTTCTGGACA
CGGCCTTCTGGACAA
GGCCTTCTGGACAAG
GCCTTCTGGACAAGC
CCTTCTGGACAAGCC
CTTCTGGACAAGCCA
TTCTGGACAAGCCAG
TCTGGACAAGCCAGA
CTGGACAAGCCAGAC
TGGACAAGCCAGACA
GGACAAGCCAGACAA
GACAAGCCAGACAAC
ACAAGCCAGACAACT
CAAGCCAGACAACTG
AAGCCAGACAACTGT
AGCCAGACAACTGTC
GCCAGACAACTGTCC
CCAGACAACTGTCCT
CAGACAACTGTCCTG
AGACAACTGTCCTGA
GACAACTGTCCTGAC
ACAACTGTCCTGACA
CAACTGTCCTGACAT
AACTGTCCTGACATG
ACTGTCCTGACATC
CTGTCCTGACATGCT
TGTCCTGACATGCTG
GTCCTGACATGCTGT
TCCTGACATGCTGTT
CCTGACATGCTGTTT
CTGACATGCTGTTTG
TGACATGCTGTTTGA
GACATGCTGTTTGAA
ACATGCTGTTTGAAC
CATGCTGTTTGAACT
ATGCTGTTTGAACTG
TGCTGTTTGAACTGA
GCTGTTTGAACTGAT
CTGTTTGAACTGATG
TGTTTGAACTGATGC
GTTTGAACTGATGCG
TTTGAACTGATGCGC
TTGAACTGATGCGCA
TGAACTGATGCGCAT
GAACTGATGCGCATG
AACTGATGCGCATGT
ACTGATGCGCATGTG
CTGATGCGCATGTGC
TGATGCGCATGTGCT
GATGCGCATGTGCTG
ATGCGCATGTGCTGG
TGCGCATGTGCTGGC
GCGCATGTGCTGGCA
CGCATGTGCTGGCAG
GCATGTGCTGGCAGT
CATGTGCTGGCAGTA
ATGTGCTGGCAGTAT
TGTGCTGGCAGTATA
GTGCTGGCAGTATAA
TGCTGGCAGTATAAC
GCTGGCAGTATAACC
CTGGCAGTATAACCC
TGGCAGTATAACCCC
GGCAGTATAACCCCA
GCAGTATAACCCCAA
CAGTATAACCCCAAG
AGTATAACCCCAAGA
GTATAACCCCAAGAT
TATAACCCCAAGATG
ATAACCCCAAGATGA
TAACCCCAAGATGAG
AACCCCAAGATGAGG
ACCCCAAGATGAGGC
CCCCAAGATGAGGCC
CCCAAGATGAGGCCT
CCAAGATGAGGCCTT
CAAGATGAGGCCTTC
AAGATGAGGCCTTCC
AGATGAGGCCTTCCT
GATGAGGCCTTCCTT
ATGAGGCCTTCCTTC
TGAGGCCTTCCTTCC
GAGGCCTTCCTTCCT
AGGCCTTCCTTCCTG
GGCCTTCCTTCCTGG
GCCTTCCTTCCTGGA
CCTTCCTTCCTGGAG
CTTCCTTCCTGGAGA
TTCCTTCCTGGAGAT
TCCTTCCTGGAGATC
CCTTCCTGGAGATCA
CTTCCTGGAGATCAT
TTCCTGGAGATCATC
TCCTGGAGATCATCA
CCTGGAGATCATCAG
CTGGAGATCATCAGC
TGGAGATCATCAGCA
GGAGATCATCAGCAG
GAGATCATCAGCAGC
AGATCATCAGCAGCA
GATCATCAGCAGCAT
ATCATCAGCAGCATC
TCATCAGCAGCATCA
CATCAGCAGCATCAA
ATCAGCAGCATCAAA
TCAGCAGCATCAAAG
CAGCAGCATCAAAGA
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AGCAGCATCAAAGAG
GCAGCATCAAAGAGG
GAG CATCAAAGAGGA
AGCATCAAAGAGGAG
GCATCAAAGAGGAGA
CATCAAAGAGGAGAT
ATCAAAGAGGAGATG
TCAAAGAGGAGATGG
CAAAGAGGAGATGGA
AAAGAGGAGATGGAG
AAGAGGAGATGGAGC
AGAGGAGATGGAGCC
GAGGAGATGGAGCCT
AGGAGATGGAGCCTG
GGAGATGGAGCCTGG
GAGATGGAGCCTGGC
AGATGGAGCCTGGCT
GATGGAGCCTGGCTT
ATGGAGCCTGGCTTC
TGGAGCCTGGCTTCC
GGAGCCTGGCTTCCG
GAGCCTGGCTTCCGG
AGCCTGGCTTCCGGG
GCCTGGCTTCCGGGA
CCTGGCTTCCGGGAG
CTGGCTTCCGGGAGG
TGGCTTCCGGGAGGT
GGCTTCCGGGAGGTC
GCTTCCGGGAGGTCT
CTTCCGGGAGGTCTC
TTCCGGGAGGTCTCC
TCCGGGAGGTCTCCT
CCGGGAGGTCTCCTT
CGGGAGGTCTCCTTC
GGGAGGTCTCCTTCT
GGAGGTCTCCTTCTA
GAGGTCTCCTTCTAC
AGGTCTCCTTCTACT
GGTCTCCTTCTACTA
GTCTCCTTCTACTAC
TCTCCTTCTACTACA
CTCCTTCTACTACAG
TCCTTCTACTACAGC
CCTTCTACTACAGCG
CTTCTACTACAGCGA
TTCTACTACAGCGAG
TCTACTACAGCGAGG
CTACTACAGCGAGGA
TACTACAGCGAGGAG
ACTACAGCGAGGAGA
CTACAGCGAGGAGAA
TACAGCGAGGAGAAC
ACAGCGAGGAGAACA
CAGCGAGGAGAACAA
AGCGAGGAGAACAAG
GCGAGGAGAACAAGC
CGAGGAGAACAAGCT
GAGGAGAACAAGCTG
AGGAGAACAAGCTGC
GGAGAACAAGCTGCC
GAGAACAAGCTGCCC
AGAACAAGCTGCCCG
GAACAAGCTGCCCGA
AACAAGCTGCCCGAG
ACAAGCTGCCCGAGC
CAAGCTGCCCGAGCC
AAGCTGCCCGAGCCG
AGCTGCCCGAGCCGG
GCTGCCCGAGCCGGA
CTGCCCGAGCCGGAG
TGCCCGAGCCGGAGG
GCCCGAGCCGGAGGA
CCCGAGCCGGAGGAG
CCGAGCCGGAGGAGC
CGAGCCGGAGGAGCT
GAGCCGGAGGAGCTG
AGCCGGAGGAGCTGG
GCCGGAGGAGCTGGA
CCGGAGGAGCTGGAC
CGGAGGAGCTGGACC
GGAGGAGCTGGACCT
GAGGAGCTGGACCTG
AGGAGCTGGACCTGG
GGAGCTGGACCTGGA
GAGCTGGACCTGGAG
AGCTGGACCTGGAGC
GCTGGACCTGGAGCC
CTGGACCTGGAGCCA
TGGACCTGGAGCCAG
GGACCTGGAGCCAGA
GACCTGGAGCCAGAG
ACCTGGAGCCAGAGA
CCTGGAGCCAGAGAA
CTGGAGCCAGAGAAC
TGGAGCCAGAGAACA
GGAGCCAGAGAACAT
GAGCCAGAGAACATG
AGCCAGAGAACATGG
GCCAGAGAACATGGA
CCAGAGAACATGGAG
CAGAGAACATGGAGA
AGAGAACATGGAGAG
GAGAACATGGAGAGC
AGAACATGGAGAGCG
GAACATGGAGAGCGT
AACATGGAGAGCGTC
ACATGGAGAGCGTCC
CATGGAGAGCGTCCC
ATGGAGAGCGTCCCC
TGGAGAGCGTCCCCC
GGAGAGCGTCCCCCT
GAGAGCGTCCCCCTG
AGAGCGTCCCCCTGG
GAGCGTCCCCCTGGA
AGCGTCCCCCTGGAC
GCGTCCCCCTGGACC
CGTCCCCCTGGACCC
GTCCCCCTGGACCCC
TCCCCCTGGACCCCT
CCCCCTGGACCCCTC
CCCCTGGACCCCTCG
CCCTGGACCCCTCGG
CCTGGACCCCTCGGC
CTGGACCCCTCGGCC
TGGACCCCTCGGCCT
GGACCCCTCGGCCTC
GACCCCTCGGCCTCC
ACCCCTCGGCCTCCT
CCCCTCGGCCTCCTC
CCCTCGGCCTCCTCG
CCTCGGCCTCCTCGT
CTCGGCCTCCTCGTC
TCGGCCTCCTCGTCC
CGGCCTCCTCGTCCT
GGCCTCCTCGTCCTC
GCCTCCTCGTCCTCC
CCTCCTCGTCCTCCC
CTCCTCGTCCTCCCT
TCCTCGTCCTCCCTG
CCTCGTCCTCCCTGC
CTCGTCCTCCCTGCC
TCGTCCTCCCTGCCA
CGTCCTCCCTGCCAC
GTCCTCCCTGCCACT
TCCTCCCTGCCACTG
CCTCCCTGCCACTGC
CTCCCTGCCACTGCC
TCCCTGCCACTGCCC
CCCTGCCACTGCCCG
CCTGCCACTGCCCGA
CTGCCACTGCCCGAC
TGCCACTGCCCGACA
GCCACTGCCCGACAG
WO 00178341 WO 0078341PCTAUOO/00693 87
CCACTGCCCGACAGA
CACTGCCCGACAGAC
ACTGCCCGACAGACA
CTGCCCGACAGACAC
TGCCCGACAGACACT
GCCCGACAGACACTC
CCCGACAGACACTCA
CCGACAGACACTCAG
CGACAGACACTCAGG
GACAGACACTCAGGA
ACAGACACTCAGGAC
CAGACACTCAGGACA
AGACACTCAGGACAC
GACACTCAGGACACA
ACACTCAGGACACAA
CACTCAGGACACAAG
ACTCAGGACACAAGG
CTCAGGACACAAGGC
TCAGGACACAAGGCC
CAGGACACAAGGCCG
AGGACACAAGGCCGA
GGACACAAGGCCGAG
GACACAAGGCCGAGA
ACACAAGGCCGAGAA
CACAAGGCCGAGAAC
ACAAGGCCGAGAACG
CAAGGCCGAGAACGG
AAGGCCGAGAACGGC
AGGCCGAGAACGGCC
GGCCGAGAACGGCCC
GCCGAGAACGGCCCC
CCGAGAACGGCCCCG
CGAGAACGGCCCCGG
GAGAACGGCCCCGGC
AGAACGGCCCCGGCC
GAACGGCCCCGGCCC
AACGGCCCCGGCCCT
ACGGCCCCGGCCCTG
CGGCCCCGGCCCTGG
GGCCCCGGCCCTGGG
GCCCCGGCCCTGGGG
CCCCGGCCCTGGGGT
CCCGGCCCTGGGGTG
CCGGCCCTGGGGTGC
CGGCCCTGGGGTGCT
GGCCCTGGGGTGCTG
GCCCTGGTGCTGG
CCCTGGGGTGCTGGT
CCTGGGGTGCTGGTC
CTGGGGTGCTGGTCC
TGGGGTGCTGGTCCT
GGGGTGCTGGTCCTC
GGGTGCTGGTCCTCC
GGTGCTGGTCCTCCG
GTGCTGGTCCTCCGC
TGCTGGTCCTCCGCG
GCTGGTCCTCCGCGC
CTGGTCCTCCGCGCC
TGGTCCTCCGCGCCA
GGTCCTCCGCGCCAG
GTCCTCCGCGCCAGC
TCCTCCGCGCCAGCT
CCTCCGCGCCAGCTT
CTCCGCGCCAGCTTC
TCCGCGCCAGCTTCG
CCGCGCCAGCTTCGA
CGCGCCAGCTTCGAC
GCGCCAGCTTCGACG
CGCCAGCTTCGACGA
GCCAGCTTCGACGAG
CCAGCTTCGACGAGA
CAGCTTCGACGAGAG
AGCTTCGACGAGAGA
GCTTCGACGAGAGAC
CTTCGACGAGAGACA
TTCGACGAGAGACAG
TCGACGAGAGACAGC
CGACGAGAGACAGCC
GACGAGAGACAGCCT
ACGAGAGACAGCCTT
CGAGAGACAGCCTTA
GAGAGACAGCCTTAC
AGAGACAGCCTTACG
GAGACAGCCTTACGC
AGACAGCCTTACGCC
GACAGCCTTACGCCC
ACAGCCTTACGCCCA
CAGCCTTACGCCCAC
AGCCTTACGCCCACA
GCCTTACGCCCACAT
CCTTACGCCCACATG
CTTACGCCCACATGA
TTACGCCCACATGAA
TACGCCCACATGAAC
ACGCCCACATGAACG
CGCCCACATGAACGG
GCCCACATGAACGGG
CCCACATGAACGGGG
CCACATGAACGGGGG
CACATGAACGGGGGC
ACATGAACGGGGGCC
CATGAACGGGGGCCG
ATGAACGGGGGCCGC
TGAACGGGGGCCGCA
GAACGGGGGCCGCAA
AACGGGGGCCGCAAG
ACGGGGGCCGCAAGA
CGGGGGCCGCAAGAA
GGGGGCCGCAAGAAC
GGGGCCGCAAGAACG
GGGCCGCAAGAACGA
GGCCGCAAGAACGAG
GCCGCAAGAACGAGC
CCGCAAGAACGAGCG
CGCAAGAACGAGCGG
GCAAGAACGAGCGGG
CAAGAACGAGCGGGC
AAGAACGAGCGGGCC
AGAACGAGCGGGCCT
GAACGAGCGGGCCTT
AACGAGCGGGCCTTG
ACGAGCGGGCCTTGC
CGAGCGGGCCTTGCC
GAGCGGGCCTTGCCG
AGCGGGCCTTGCCGC
GCGGGCCTTGCCGCT
CGGGCCTTGCCGCTG
GGGCCTTGCCGCTGC
GGCCTTGCCGCTGCC
GCCTTGCCGCTGCCC
CCTTGCCGCTGCCCC
CTTGCCGCTGCCCCA
TTGCCGCTGCCCCAG
TGCCGCTGCCCCAGT
GCCGCTGCCCCAGTC
CCGCTGCCCCAGTCT
CGCTGCCCCAGTCTT
GCTGCCCCAGTCTTC
CTGCCCCAGTCTTCG
TGCCCCAGTCTTCGA
GCCCCAGTCTTCGAC
CCCCAGTCTTCGACC
CCCAGTCTTCGACCT
CCAGTCTTCGACCTG
CAGTCTTCGACCTGC
AGTCTTCGACCTGCT
GTCTTCGACCTGCTG
TCTTCGACCTGCTGA
CTTCGACCTGCTGAT
TTCGACCTGCTGATC
TCGACCTGCTGATCC
CGACCTGCTGATCCT
GACCTGCTGATCCTT
WO 00178341 WO 00/834 1PCT/AUOO/00693 88
ACCTGCTGATCCTTG
CCTGCTGATCCTTGG
CTGCTGATCCTTGGA
TGCTGATCCTTGGAT
GCTGATCCTTGGATC
CTGATCCTTGGATCC
TGATCCTTGGATCCT
GATCCTTGGATCCTG
ATCCTTGGATCCTGA
TCCTTGGATCCTGAA
CCTTGGATCCTGAAT
CTTGGATCCTGAATC
TTGGATCCTGAATCT
TGGATCCTGAATCTG
GGATCCTGAATCTGT
GATCCTGAATCTGTG
ATCCTGAATCTGTGC
TCCTGAATCTGTGCA
CCTGAATCTGTGCAA
CTGAATCTGTGCAAA
TGAATCTGTGCAAAC
GAATCTGTGCAAACA
AATCTGTGCAAACAG
ATCTGTGCAAACAGT
TCTGTGCAAACAGTA
CTGTGCAAACAGTAA
TGTGCAAACAGTAAC
GTGCAAACAGTAACG
TGCAAACAGTAACGT
GCAAACAGTAACGTG
CAAACAGTAACGTGT
AAACAGTAACGTGTG
AACAGTAACGTGTGC
ACAGTAACGTGTGCG
CAGTAACGTGTGCGC
AGTAACGTGTGCGCA
GTAACGTGTGCGCAC
TAACGTGTGCGCACG
AACGTGTGCGCACGC
ACGTGTGCGCACGCG
CGTGTGCGCACGCGC
GTGTGCGCACGCGCA
TGTGCGCACGCGCAG
GTGCGCACGCGCAGC
TGCGCACGCGCAGCG
GCGCACGCGCAGCGG
CGCACGCGCAGCGGG
GCACGCGCAGCGGGG
CACGCGCAGCGGGGT
ACGCGCAGCGGGGTG
CGCGCAGCGGGGTGG
GCGCAGCGGGGTGGG
CGCAGCGGGGTGGGG
GCAGCGGGGTGGGGG
CAGCGGGGTGGGGGG
AGCGGGGTGGGGGGG
GCGGGGTGGGGGGGG
CGGGGTGGGGGGGGA
GGGGTGGGGGGGGAG
GGGTGGGGGGGGAGA
GGTGGGGGGGGAGAG
GTGGGGGGGGAGAGA
TGGGGGGGGAGAGAG
GGGGGGGGAGAGAGA
GGGGGGGAGAGAGAG
GGGGGGAGAGAGAGT
GGGGGAGAGAGAGTT
GGGGAGAGAGAGTTT
GGGAGAGAGAGTTTT
GGAGAGAGAGTTTTA
GAGAGAGAGTTTTAA
AGAGAGAGTTTTAAC
GAGAGAGTTTTAACA
AGAGAGTTTTAACAA
GAGAGTTTTAACAAT
AGAGTTTTAACAATC
GAGTTTTAACAATCC
AGTTTTAACAATCCA
GTTTTAACAAT CCAT
TTTTAACAATCCATT
TTTAACAATCCATTC
TTAACAATCCATTCA
TAACAATCCATTCAC
AACAATCCATTCACA
ACAATCCATTCACAA
CAATCCATTCACAAG
AATCCATTCACAAGC
ATCCATTCACAAGCC
TCCATTCACAAGCCT
CCATTCACAAGCCTC
CATTCACAAGCCTCC
ATTCACAAGCCTCCT
TTCACAAGCCTCCTG
TCACAAGCCTCCTGT
CACAAGCCTCCTGTA
ACAAGCCTCCTGTAC
CAAGCCTCCTGTACC
AAGCCTCCTGTACCT
AGCCTCCTGTACCTC
GCCTCCTGTACCTCA
CCTCCTGTACCTCAG
CTCCTGTACCTCAGT
TCCTGTACCTCAGTG
CCTGTACCTCAGTGG
CTGTACCTCAGTGGA
TGTACCTCAGTGGAT
GTACCTCAGTGGATC
TACCTCAGTGGATCT
ACCTCAGTGGATCTT
CCTCAGTGGATCTTC
CTCAGTGGATCTTCA
TCAGTGGATCTTCAG
CAGTGGATCTTCAGT
AGTGGATCTTCAGTT
GTGGATCTTCAGTTC
TGGATCTTCAGTTCT
GGATCTTCAGTTCTG
GATCTTCAGTTCTGC
ATCTTCAGTTCTGCC
TCTTCAGTTCTGCCC
CTTCAGTTCTGCCCT
TTCAGTTCTGCCCTT
TCAGTTCTGCCCTTG
CAGTTCTGCCCTTGC
AGTTCTGCCCTTGCT
GTTCTGCCCTTGCTG
TTCTGCCCTTGCTGC
TCTGCCCTTGCTGCC
CTGCCCTTGCTGCCC
TGCCCTTGCTGCCCG
GCCCTTGCTGCCCGC
CCCTTGCTGCCCGCG
CCTTGCTGCCCGCGG
CTTGCTGCCCGCGGG
TTGCTGCCCGCGGGA
TGCTGCCCGCGGGAG
GCTGCCCGCGGGAGA
CTGCCCGCGGGAGAC
TGCCCGCGGGAGACA
GCCCGCGGGAGACAG
CCCGCGGGAGACAGC
CCGCGGGAGACAGCT
CGCGGGAGACAGCTT
GCGGGAGACAGCTTC
CGGGAGACAGCTTCT
GGGAGACAGCTTCTC
GGAGACAGCTTCTCT
GAGACAGCTTCTCTG
AGACAGCTTCTCTGC
GACAGCTTCTCTGCA
ACAGCTTCTCTGCAG
CAGCTTCTCTGCAGT
AGCTTCTCTGCAGTA
WO 00/78341 WO 0078341PCT/AUDO/00693 89
GCTTCTCTGCAGTAA
CTTCTCTGCAGTAAA
TTCTCTGCAGTAAAA
TCTCTGCAGTAAAAC
CTCTGCAGTAAAACA
TCTGCAGTAAAACAC
CTGCAGTAAAACACA
TGCAGTAAAACACAT
GCAGTAAAACACATT
CAGTAAAACACATTT
AGTAAAACACATTTG
GTAAAACACATTTGG
TAAAACACATTTGGG
AAAACACATTTGGGA
AAACACATTTGGGAT
AACACATTTGGGATG
ACACATTTGGGATGT
CACATTTGGGATGTT
ACATTTGGGATGTTC
CATTTGGGATGTTCC
ATTTGGGATGTTCCT
TTTGGGATGTTCCTT
TTGGGATGTTCCTTT
TGGGATGTTCCTTTT
GGGATGTTCCTTTTT
GGATGTTCCTTTTTT
GATGTTCCTTTTTTC
ATGTTCCTTTTTTCA
TGTTCCTTTTTTCAA
GTTCCTTTTTTCAAT
TTCCTTTTTTCAATA
TCCTTTTTTCAATAT
CCTTTTTTCAATATG
CTTTTTTCAATATGC
TTTTTTCAATATGCA
TTTTTCAATATGCAA
TTTTCAATATGCAAG
TTTCAATATGCAAGC
TTCAATATGCAAGCA
TCAATATGCAAGCAG
CAATATGCAAGCAGC
AATATGCAAGCAGCT
ATATGCAAGCAGCTT
TATGCAAGCAGCTTT
ATGCAAGCAGCTTTT
TGCAAGCAGCTTTTT
GCAAGCAGCTTTTTA
CAAGCAGCTTTTTAT
AAGCAGCTTTTTATT
AGCAGCTTTTTATTC
GCAGCTTTTTATTCC
CAGCTTTTTATTCCC
AGCTTTTTATTCCCT
GCTTTTTATTCCCTG
CTTTTTATTCCCTGC
TTTTTATTCCCTGCC
TTTTATTCCCTGCCC
TTTATTCCCTGCCCA
TTATTCCCTGCCCAA
TATTCCCTGCCCAAA
ATTCCCTGCCCAAAC
TTCCCTGCCCAAACC
TCCCTGCCCAAACCC
CCCTGCCCAAACCCT
CCTGCCCAAACCCTT
CTGCCCAAACCCTTA
TGCCCAAACCCTTAA
GCCCAAACCCTTAAC
CCCAAACCCTTAACT
CCAAACCCTTAACTG
CAAACCCTTAACTGA
AAACCCTTAACTGAC
AACCCTTAACTGAC-A
ACCCTTAACTGACAT
CCCTTAACTGACATG
CCTTAACTGACATGG
CTTAACTGACATGGG
TTAACTGACATGGGC
TAACTGACATGGGCC
AACTGACATGGGCCT
ACTGACATGGGCCTT
CTGACATGGGCCTTT
TGACATGGGCCTTTA
GACATGGGCCTTTAA
ACATGGGCCTTTAAG
CATGGGCCTTTAAGA
ATGGGCCTTTAAGAA
TGGGCCTTTAAGAAC
GGGCCTTTAAGAACC
GGCCTTTAAGAACCT
GCCTTTAAGAACCTT
CCTTTAAGAACCTTA
CTTTAAGAACCTTAA
TTTAAGAACCTTAAT
TTAAGAACCTTAATG
TAAGAACCTTAATGA
AAGAACCTTAATGAC
AGAACCTTAATGACA
GAACCTTAATGACAA
AACCTTAATGACAAC
ACCTTAATGACAACA
CCTTAATGACAACAC
CTTAATGACAACACT
TTAATGACAACACTT
TAATGACAACACTTA
AATGACAACACTTAA
ATGACAACACTTAAT
TGACAACACTTAATA
GACAACACTTAATAG
ACAACACTTAATAGC
CAACACTTAATAGCA
AACACTTAATAGCAA
ACACTTAATAGCAAC
CACTTAATAGCAACA
ACTTAATAGCATACAG
CTTAATAGCAACAGA
TTAATAGCAACAGAG
TAATAGCAACAGAGC
AATAGCAACAGAGCA
ATAGCAACAGAGCAC
TAGCAACAGAGCACT
AGCAACAGAGCACTT
GCAACAGAGCACTTG
CAACAGAGCACTTGA
AACAGAGCACTTGAG
ACAGAGCACTTGAGA
CAGAGCACTTGAGAA
AGAGCACTTGAGAAC
GAGCACTTGAGAACC
AGCACTTGAGAACCA
GCACTTGAGAACCAG
CACTTGAGAACCAGT
ACTTGAGAACCAGTC
CTTGAGAACCAGTCT
TTGAGAACCAGTCTC
TGAGAACCAGTCTCC
GAGAACCAGTCTCCT
AGAACCAGTCTCCTC
GAACCAGTCTCCTCA
AACCAGTCTCCTCAC
ACCAGTCTCCTCACT
CCAGTCTCCTCACTC
CAGTCTCCTCACTCT
AGTCTCCTCACTCTG
GTCTCCTCACTCTGT
TCTCCTCACTCTGTC
CTCCTCACTCTGTCC
TCCTCACTCTGTCCC
CCTCACTCTGTCCCT'
CTCACTCTGTCCCTG
TCACTCTGTCCCTGT
CACTCTGTCCCTGTC
ACTCTGTCCCTGTCC
WO 00/78341 WO 0078341PCT/AUOO/00693 90
CTCTGTCCCTGTCCT
TCTGTCCCTGTCCTT
CTGTCCCTGTCCTTC
TGTCCCTGTCCTTCC
GTCCCTGTCCTTCCC
TCCCTGTCCTTCCCT
CCCTGTCCTTCCCTG
CCTGTCCTTCCCTGT
CTGTCCTTCCCTGTT
TGTCCTTCCCTGTTC
GTCCTTCCCTGTTCT
TCCTTCCCTGTTCTC
CCTTCCCTGTTCTCC
CTTCCCTGTTCTCCC
TTCCCTGTTCTCCCT
TCCCTGTTCTCCCTT
CCCTGTTCTCCCTTT
CCTGTTCTCCCTTTC
CTGTTCTCCCTTTCT
TGTTCTCCCTTTCTC
GTTCTCCCTTTCTCT
TTCTCCCTTTCTCTC
TCTCCCTTTCTCTCT
CTCCCTTTCTCTCTC
TCCCTTTCTCTCTCC
CCCTTTCTCTCTCCT
CCTTTCTCTCTCCTC
CTTTCTCTCTCCTCT
TTTCTCTCTCCTCTC
TTCTCTCTCCTCTCT
TCTCTCTCCTCTCTG
CTCTCTCCTCTCTGC
TCTCTCCTCTCTGCT
CTCTCCTCTCTGCTT
TCTCCTCTCTGCTTC
CTCCTCTCTGCTTCA
TCCTCTCTGCTTCAT
CCTCTCTGCTTCATA
CTCTCTGCTTCATAA
TCTCTGCTTCATAAC
CTCTGCTTCATAACG
TCTGCTTCATAACGG
CTGCTTCATAACGGA
TGCTTCATAACGGAA
GCTTCATAACGGAAA
CTTCATAACGGAAAA
TTCATAACGGAAAAA
TCATAACGGAAAAAT
CATAACGGAAAAATA
ATAACGGAAAAATAA
TAACGGAAAAATAAT
AACGGAAAAATAATT
ACGGAAAAATAATTG
CGGAAAAATAATTGC
GGAAAAATAATTGCC
GAAAAATAATTGCCA
AAAAATAATTGCCAC
AAAATAATTGCCACA
AAATAATTGCCACAA
AATAATTrGCCACAAG
ATAATTGCCACAAGT
TAATTGCCACAAGTC
AATTGCCACAAGTCC
ATTGCCACAAGTCCA
TTGCCACAAGTCCAG
TGCCACAAGTCCAGC
GCCACAAGTCCAGCT
CCACAAGTCCAGCTG
CACAAGTCCAGCTGG
ACAAGTCCAGCTGGG
CAAGTCCAGCTGGGA
AAGTCCAGCTGGGAA
AGTCCAGCTGGGAAG
GTCCAGCTGGGAAGC
TCCAGCTGGGAAGCC
CCAGCTGGGAAGCCC
CAGCTGGGAAGCCCT
AGCTGGGAAGCCCTT
GCTGGGAAGCCCTTT
CTGGGAAGCCCTTTT
TGGGAAGCCCTTTTT
GGGAAGCCCTTTTTA
GGAAGCCCTTTTTAT
GAAGCCCTTTTTATC
AAGCCCTTTTTATCA
AGCCCTTTTTATCAG
GCCCTTTTTATCAGT
CCCTTTTTATCAGTT
CCTTTTTATCAGTTT
CTTTTTATCAGTTTG
TTTTTATCAGTTTGA
TTTTATCAGTTTGAG
TTTATCAGTTTGAGG
TTATCAGTTTGAGGA
TATCAGTTTGAGGAA
ATCAGTTTGAGGAAG
TCAGTTTGAGGAAGT
CAGTTTGAGGAAGTG
AGTTTGAGGAAGTGG
GTTTGAGGAAGTGGC
TTTGAGGAAGTGGCT
TTGAGGAAGTGGCTG
TGAGGAAGTGGCTGT
GAGGAAGTGGCTGTC
AGGAAGTGGCTGTCC
GGAAGTGGCTGTCCC
GAAGTGGCTGTCCCT
AAGTGGCTGTCCCTG
AGTGGCTGTCCCTGT
GTGGCTGTCCCTGTG
TGGCTGTCCCTGTGG
GGCTGTCCCTGTGGC
GCTGTCCCTGTGGCC
CTGTCCCTGTGGCCC
TGTCCCTGTGGCCCC
GTCCCTGTGGCCCCA
TCCCTGTGGCCCCAT
CCCTGTGGCCCCATC
CCTGTGGCCCCATCC
CTGTGGCCCCATCCA
TGTGGCCCCATCCAA
GTGGCCCCATCCAAC
TGGCCCCATCCAACC
GGCCCCATCCAACCA
GCCCCATCCAACCAC
CCCCATCCAACCACT
CCCATCCAACCACTG
CCATCCAACCACTGT
CATCCAACCACTGTA
ATCCAACCACTGTAC
TCCAACCACTGTACA
CCAACCACTGTACAC
CAACCACTGTACACA
AACCACTGTACACAC
ACCACTGTACACACC
CCACTGTACACACCC
CACTGTACACACCCG
ACTGTACACACCCGC
CTGTACACACCCGCC
TGTACACACCCGCCT
GTACACACCCGCCTG
TACACACCCGCCTGA
ACACACCCGCCTGAC
CACACCCGCCTGACA
ACACCCGCCTGACAC
CACCCGCCTGACACC
ACCCGCCTGACACCG
CCCGCCTGACACCGT
CCGCCTGACACCGTG
CGCCTGACACCGTGG
GCCTGACACCGTGGG
CCTGACACCGTGGGT
CTGACACCGTGGGTC
WO 00/78341 WO 0078341PCT/AUOO/00693 -91-
TGACACCGTGGGTCA
GACACCGTGGGTCAT
ACACCGTGGGTCATT
CACCGTGGGTCATTA
ACCGTGGGTCATTAC
CCGTGGGTCATTACA
CGTGGGTCATTACAA
GTGGGTCATTACAAA
TGGGTCATTACAAAA
GGGTCATTACAAAAA
GGTCATTACAAAAAA
GTCATTACAAAAAAA
TCATTACAAAAAAAC
CATTACAAAAAAACA
ATTAcAAAAAAACAc
TTACAAAAAAACACG
TACAAAAAAACACGT
ACAAAAAAACACGTG
CAAAAAAACACGTGG
AAAAAAACACGTGGA
AAAAAACACGTGGAG
AAAAACACGTGGAGA
AAAACACGTGGAGAT
AAACACGTGGAGATG
AACACGTGGAGATGG
ACACGTGGAGATGGA
CACGTGGAGATGGAA
ACGTGGAGATGGAAA
CGTGGAGATGGAAAT
GTGGAGATGGAAATT
TGGAGATGGAAATTT
GGAGATGGAAATTTT
GAGATGGAAATTTTT
AGATGGAAATTTTTA
GATGGAAATTTTTAC
ATGGAAATTTTTACC
TGGAAATTTTTACCT
GGAAATTTTTACCTT
GAAATTTTTACCTTT
AAATTTTTACCTTTA
AATTTTTACCTTTAT
ATTTTTACCTTTATC
TTTTTACCTTTATCT
TTTTACCTTTATCTT
TTTACCTTTATCTTT
TTACCTTTATCTTTC
TACCTTTATCTTTCA
ACCTTTATCTTTCAC
CCTTTATCTTTCACC
CTTTATCTTTCACCT
TTTATCTTTCACCTT
TTATCTTTCACCTTT
TATCTTTCACCTTTC
ATCTTTCACCTTTCT
TCTTTCACCTTTCTA
CTTTCACCTTTCTAG
TTTCACCTTTCTAGG
TTCACCTTTCTAGG
TCACCTTTCTAGGGA
CACCTTTCTAGGGAC
ACCTTTCTAGGGACA
CCTTTCTAGGGACAT
CTTTCTAGGGACATG
TTTCTAGGGACATGA
TTCTAGGGACATGAA
TCTAGGGACATGAAA
CTAGGGACATGAAAT
TAGGGACATGAAATT
AGGGACATGAAATTT
GGGACATGAAATTTA
GGACATGAAATTTAC
GACATGAAATTTACA
ACATGAAATTTACAA
CATGAAATTTACAAA
ATGAAATTTACAAAG
TGAAATTTACAAAGG
GAAATTTACAAAGGG
AAATTTACAAAGGGC
AATTTACAAAGGGCC
ATTTACAAAGGGCCA
TTTACAAAGGGCCAT
TTACAAAGGGCCATC
TACAAAGGGCCATCG
ACAAAGGGCCATCGT
CAAAGGGCCATCGTT
AAAGGGCCATCGTTC
AAGGGCCATCGTTCA
AGGGCCATCGTTCAT
GGGCCATCGTTCATC
GGCCATCGTTCATCC
GCCATCGTTCATCCA
CCATCGTTCATCCAA
CATCGTTCATCCAAG
ATCGTTCATCCAAGG
TCGTTCATCCAAGGC
CGTTCATCCAAGGCT
GTTCATCCAAGGCTG
TTCATCCAAGGCTGT
TCATCCAAGGCTGTT
CATCCAAGGCTGTTA
ATCCAAGGCTGTTAC
TCCAAGGCTGTTACC
CCAAGGCTGTTACCA
CAAGGCTGTTACCAT
AAGGCTGTTACCATT
AGGCTGTTACCATTT
GGCTGTTACCATTTT
GCTGTTACCATTTTA
CTGTTACCATTTTAA
TGTTACCATTTTAAC
GTTACCATTTTAACG
TTACCATTTTAACGC
TACCATTTTAACGCT
ACCATTTTAACGCTG
CCATTTTAACGCTGC
CATTTTAACGCTGCC
ATTTTAACGCTGCCT
ITAACGCTGCCTA
TTTAACGCTGCCTAA
TTAACGCTGCCTAAT
TAACGCTGCCTAATT
AACGCTGCCTAATTT
ACGCTGCCTAATTTT
CGCTGCCTAATTTTG
GCTGCCTAATTTTGC
CTGCCTAATTTTGCC
TGCCTAATTTTGCCA
GCCTAATTTTGCCAA
CCTAATTTTGCCAAA
CTAATTTTGCCAAAA
TAATTTTGCCAAAAT
AATTTTGCCAAAATC
ATTTTGCCAAAATCC
'rrTTGCCAAAATCCT
TTTGCCAAAATCCTG
TTGCCAAAATCCTGA
TGCCAAAATCCTGAA
GCCAAAATCCTGAAC
CCAAAATCCTGAACT
CAAAATCCTGAACTT
AAAATCCTGAACTTT
AAATCCTGAACTTTC
AATCCTGAACTTTCT
ATCCTGAACTTTCTC
TCCTGAACTTTCTCC
CCTGAACTTTCTCCC
CTGAACTTTCTCCCT
TGAACTTTCTCCCTC
GAACTTTCTCCCTCA
AACTTTCTCCCTCAT
ACTTTCTCCCTCATC
CTTTCTCCCTCATCG
TTTCTCCCTCATCGG
WO 00/78341 WO 0078341PCT/AUOO/00693 92
TTCTCCCTCATCGGC
TCTCCCTCATCGGCC
CTCCCT CAT CGGCCC
TCCCTCATCGGCCCG
CCCTCATCGGCCCGG
CCTCATCGGCCCGGC
CTCATCGGCCCGGCG
TCATCGGCCCGGCGC
CATCGGCCCGGCGCT
ATCGGCCCGGCGCTG
TCGGCCCGGCGCTGA
CGGCCCGGCGCTGAT
GGCCCGGCGCTGATT
GCCCGGCGCTGATTC
CCCGGCGCTGATTCC
CCGGCGCTGATTCCT
CGGCGCTGATTCCTC
GGCGCTGATTCCTCG
GCGCTGATTCCTCGT
CGCTGATTCCTCGTG
GCTGATTCCTCGTGT
CTGATTCCTCGTGTC
TGATTCCTCGTGTCC
GATTCCTCGTGTCCG
ATTCCTCGTGTCCGG
TTCCTCGTGTCCGGA
TCCTCGTGTCCGGAG
CCTCGTGTCCGGAGG
CTCGTGTCCGGAGGC
TCGTGTCCGGAGGCA
CGTGTCCGGAGGCAT
GTGTCCGGAGGCATG
TGTCCGGAGGCATGG
GTCCGGAGGCATGGG
TCCGGAGGCATGGGT
CCGGAGGCATGGGTG
CGGAGGCATGGGTGA
GGAGGCATGGGTGAG
GAGGCATGGGTGAGC
AGGCATGGGTGAGCA
GGCATGGGTGAGCAT
GCATGGGTGAGCATG
CATGGGTGAGCATGG
ATGGGTGAGCATGGC
TGGGTGAGCATGGCA
GGGTGAGCATGGCAG
GGTGAGCATGGCAGC
GTGAGCATGGCAGCT
TGAGCATGGCAGCTG
GAGCATGGCAGCTGG
AGCATGGCAGCTGGT
GCATGGCAGCTGGTT
CATGGCAGCTGGTTG
ATGGCAGCTGGTTGC
TGGCAGCTGGTTGCT
GGCAGCTGGTTGCTC
GCAGCTGGTTGCTCC
CAGCTGGTTGCTCCA
AGCTGGTTGCTCCAT
GCTGGTTGCTCCATT
CTGGTTGCTCCATTT
TGGTTGCTCCATTTG
GGTTGCTCCATTTGA
GTTGCTCCATTTGAG
TTGCTCCATTTGAGA
TGCTCCATTTGAGAG
GCTCCATTTGAGAGA
CTCCATTTGAGAGAC
TCCATTTGAGAGACA
CCATTTGAGAGACAC
CATTTGAGAGACACG
ATTTGAGAGACACGC
TTTGAGAGACACGCT
TTGAGAGACACGCTG
TGAGAGACACGCTGG
GAGAGACACGCTGGC
AGAGACACGCTGGCG
GAGACACGCTGGCGA
AGACACGCTGGCGAC
GACACGCTGGCGACA
ACACGCTGGCGACAC
CACGCTGGCGACACA
ACGCTGGCGACACAC
CGCTGGCGACACACT
GCTGGCGACACACTC
CTGGCGACACACTCC
TGGCGACACACTCCG
GGCGACACACTCCGT
GCGACACACTCCGTC
CGACACACTCCGTCC
GACACACTCCGTCCA
ACACACTCCGTCCAT
CACACTCCGTCCATC
ACACTCCGTCCATCC
CACTCCGTCCATCCG
ACTCCGTCCATCCGA
CTCCGTCCATCCGAC
TCCGTCCATCCGACT
CCGTCCATCCGACTG
CGTCCATCCGACTGC
GTCCATCCGACTGCC
TCCATCCGACTGCCC
CCATCCGACTGCCCC
CATCCGACTGCCCCT
ATCCGACTGCCCCTG
TCCGACTGCCCCTGC
CCGACTGCCCCTGCT
CGACTGCCCCTGCTG
GACTGCCCCTGCTGT
ACTGCCCCTGCTGTG
CTGCCCCTGCTGTGC
TGCCCCTGCTGTGCT
GCCCCTGCTGTGCTG
CCCCTGCTGTGCTGC
CCCTGCTGTGCTGCT
CCTGCTGTGCTGCTC
CTGCTGTGCTGCTCA
TGCTGTGCTGCTCAA
GCTGTGCTGCTCAAG
CTGTGCTGCTCAAGG
TGTGCTGCTCAAGGC
GTGCTGCTCAAGGCC
TGCTGCTCAAGGCCA
GCTGCTCAAGGCCAC
CTGCTCAAGGCCACA
TGCTCAAGGCCACAG
GCTCAAGGCCACAGG
CTCAAGGCCACAGGC
TCAAGGCCACAGGCA
CAAGGCCACAGGCAC
AAGGCCACAGGCACA
AGGCCACAGGCACAC
GGCCACAGGCACACA
GCCACAGGCACACAG
CCACAGGCACACAGG
CACAGGCACACAGGT
ACAGGCACACAGGTC
CAGGCACACAGGTCT
AGGCACACAGGTCTC
GGCACACAGGTCTCA
GCACACAGGTCTCAT
CACACAGGTCTCATT
ACACAGGTCTCATTG
CACAGGTCTCATTGC,
ACAGGTCTCATTGCT
CAGGTCTCATTGCTT
AGGTCTCATTGCTTC
GGTCTCATTGCTTCT
GTCTCATTGCTTCTG
TCTCATTGCTTCTGA
CTCATTGCTTCTGAC
TCATTGCTTCTGACT
CATTGCTTCTGACTA
WO 00/78341 WO 0078341PCT/AUOO/00693 93
ATTGCTTCTGACTAG
TTGCTTCTGACTAGA
TGCTTCTGACTAGAT
GCTTCTGACTAGATT
CTTCTGACTAGATTA
TTCTGACTAGATTAT
TCTGACTAGATTATT
CTGACTAGATTATTA
TGACTAGATTATTAT
GACTAGATTATTATT
ACTAGATTATTATTT
CTAGATTATTATTTG
TAGATTATTATTTGG
AGATTATTATTTGGG
GATTATTATTTGGGG
ATTATTATTTGGGGG
TTATTATTTGGGGGA
TATTATTTGGGGGAA
ATTATTTGGGGGAAC
TTATTTGGGGGAACT
TATTTGGGGGAACTG
ATTTGGGGGAACTGG
TTTGGGGGAACTGGA
TTGGGGGAACTGGAC
TGGGGGAACTGGACA
GGGGGAACTGGACAC
GGGGAACTGGACACA
GGGAACTGGACACAA
GGAACTGGACACAAT
GAACTGGACACAATA
AACTGGACACAATAG
ACTGGACACAATAGG
CTGGACACAATAGGT
TGGACACAATAGGTC
GGACACAATAGGTCT
GACACAATAGGTCTT
ACACAATAGGTCTTT
CACAATAGGTCTTTC
ACAATAGGTCTTTCT
CAATAGGTCTTTCTC
AATAGGTCTTTCTCT
ATAGGTCTTTCTCTC
TAGGTCTTTCTCTCA
AGGTCTTTCTCTCAG
GGTCTTTCTCTCAGT
GTCTTTCTCTCAGTG
TCTTTCTCTCAGTGA
CTTTCTCTCAGTGAA
TTTCTCTCAGTGAAG
TTCTCTCAGTGAAGG
TCTCTCAGTGAAGGT
CTCTCAGTGAAGGTG
TCTCAGTGAAGGTGG
CTCAGTGAAGGTGGG
TCAGTGAAGGTGGGG
CAGTGAAGGTGGGGA
AGTGAAGGTGGGGAG
GTGAAGGTGGGGAGA
TGAAGGTGGGGAGAA
GAAGGTGGGGAGAAG
AAGGTGGGGAGAAGC
AGGTGGGGAGAAGCT
GGTGGGGAGAAGCTG
GTGGGGAGAAGCTGA
TGGGGAGAAGCTGAA
GGGGAGAAGCTGAAC
GGGAGAAGCTGAACC
GGAGAAGCTGAACCG
GAGAAGCTGAACCGG
AGAAGCTGAACCGGC
WO 00/78341 PCT/AU00/00693 -94- EXAMPLE 9 Sub-confluent HaCaT cells were treated as described above with phosphorothioate oligonucleotides IGFR.AS (antisense: 5'-ATCTCTCCGCTTCCTTTC-3'; (<400 10); ref 13) and IGFR.S (sense control: 5'-GAAAGGAAGCGGAGAGAT-3'; (<400> 11); ref 13) IGF-I binding to the cell monolayers was then measured as '"I-IGF-I.
EXAMPLE The results of this experiment are shown in Figures 7 and 8.
HaCaT cells were initially plated in DMEM with 10% v/v serum, then AS oligo experiments were performed in complete "Keratinocyte-SFM" (Gibco) to exclude the influence of exogenous IGFBPs. Oligos were synthesised as phosphorothioate (nuclease-resistant) derivatives (Bresatec, South Australia) and were as follows: antisense: AS2, GCGCCCGCTGCATGACGCCTGCAAC-3' (IGFBP-3 start codon); controls: AS2NS, CGGAGATGCCGCATGCCAGCGCAGG-3'; AS4, 5'-AGGCGGCTGACGGCACTA-3'; AS4NS, 5'-GACAGCGTCGGAGCGATC-3'; IGFRAS, 5'-ATCTCTCCGCTTCCTTTC-3'; IGFRS, -5'-GAAAGGAAGCGGAGAGAT-3'. Oligos to IGFBP-3 were based on the published sequence of Spratt et al AS oligos were added to HaCaT monolayers in medium in 24-well plates at the concentrations and addition frequencies indicated. IGFBP-3 measured in cell-conditioned medium using a dot-blot assay, adapted from the Western ligand blot method of Hossenlopp et al in which 1001l of conditioned medium was applied to nitrocellulose filters with a vacuum dot-blot apparatus. After drying the membranes at 37 C, relative amounts of IGFBP are determined by '"I-IGF-I-binding, autoradiography and computerised imaging densitometry. Triplicate wells (except in Figure 7, where duplicate wells were measured as shown) were analysed and corrected for changes in cell number per well. Relative cell number per well was determined using an amido black dye method, developed specifically for cultured monolayers of HaCaT cells Cell numbers differed by less than 10% after treatment. For oligos to the IGF receptor, receptor quantitation in WO 00/78341 PCT/AU00/00693 intact HaCaT monolayers was by overnight incubation with 'SI-IGF-I (30,000cpm/well) at 4°C.
EXAMPLE 11 Experiments involving ribozymes are generally conducted as described in Internaitonal Patent Application No. WO 89/05852 and in Haselhoff and Gerlach Ribozymes are constructed with a hybridising region which is complementary in nucleotide sequence to at least part of a target RNA which, in this case, encodes IGFBP-2. Activity of ribozymes is measurable on, for example, Northern blots or using animal models such as in the nude mouse model (15; 16) or the "flaky skin" mouse model (17; 18).
EXAMPLE 12 The methods described in Example 11 are used for the screening of ribozymes which inhibit IGFBP-3 production. The activity of the ribozymes is determined as in Example 11.
EXAMPLE 13 The methods described in Example 11 are used for the screening of ribozymes which inhibit IGF-1 production. The activity of the ribozymes is determined as in Example 11.
EXAMPLE 14 The methods described in Example 11 are used for the screening of ribozymes which inhibit IGF-1 production. The activity of the ribozymes is determined as in Example 11.
EXAMPLE Twenty-one antisense oligonucleotides targeted to mRNA sequences enducing the IGF-1 receptor, and four random oligonucleotides were synthesized. The antisense oligonucleotides are C5-propynyl-dU, dC 15mer phosphorothioate oligodeoxyribonucleotides. In these oligonucleotides, a phosphorothioate backbone replaces the phosphodiester backbone of naturally occurring DNA. The positions of the 21 sequence specific antisense oligonucleotides relative to the IGF-1 receptor mRNA structure are shown in Figure 9.
WO 00/78341 PCT/AU00/00693 -96- EXAMPLE 16 Experiments were performed to determine the uptake of the antisense oligonucleotides of Example 15 into keratinocytes. Cells of the differentiated human keratinocyte cell line, HaCaT, were incubated for 24 hours in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal calf serum (FCS) containing fluorescently labelled oligonucleotide (R451, a randomized sequence oligonucleotide, 30nM) and cytofectin GSV (2p/g/ml, Glen Research, 44901 Falcon Place, Sterling, VA 20166, Cat. No. 70-3815-78).
Cells were then transferred to oligonucleotide-free medium and fluorescence microcopy and phase contrast images of the cells were obtained. Figure 10 shows fluorescence microscopy (Panel A) and phase contrast (Panel B) images of uptake of fluorescently labelled oligonucleotide in the majority of cells in a HaCaT monolayer. The degree of uptake obtained with the cationic lipid cytofectin was far greater than the uptake obtained with the next best lipid tried, A further experiment was performed to assess the uptake and toxicity associated with the use of cytofectin GSV over five days. Confluent HaCaT keratinocytes were incubated in DMEM containing fluorescently labelled oligonucleotide R451 (30nM or 100 nM) plus cytofectin GSV 2 /g/ml or 5/g/ml) over 120 hours, viewed by fluorescence microscopy, tryptan blue stained, and counted. The graphs in Figure 11 depict uptake (Panel A) and toxicity (Panel The proportion of cells containing oligonucleotide remained high over the 120 hour period. The combination of 30 nM oligonucleotide and 2J/g/ml GSV provided optimal uptake and minimal toxicity.
EXAMPLE 17 The twenty-one oligonucleotides of Example 15 were then screened for their ability to inhibit IGF-I receptor mRNA levels in HaCaT cells, in accordance with the teachings herein. HaCaT cells were grown to 90% confluence in DMEM supplemented with 10% FCS.
Antisense oligonucleotides (30nM) were completed with cytofectin GSV (2k/g/ml) and added tot he cells in the presence of serum. HaCaT keratinocytes were treated with the oligonucleotide/GSV complexes or randomized sequence oligonucleotides (R451, R766), WO 00/78341 PCT/AU00/00693 -97liposome alone (GSV), or were left untreated Duplicate treatments were performed.
Repeat additions of the oligonucleotides/GSV complex were performed at 24, 48 and 76 hours following the first addition. Total RNA was isolated as per the RNAzolB protocol (Biotecx Laboratories, Inc. 6023 South Loop East, Houston, TX 77033) 96 hours following the first addition.
IGF-I receptor mRNA and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA levels were simultaneously determined by a ribonuclease (RNase) protection assay. The RNase Protection Assay kit, in vitro transcription kit, and IGF-I receptor and GAPDH DNA templates were obtained from Ambion, Inc. (2130 Woodward St., Houston, TX 78744). The amount of IGF-I receptor mRNA in any given sample was expressed as the amount of IGF-I receptor mRNA relative to the amount of GAPDH mRNA. Each oligonucleotide was tested in at least two separate experiments.
Figure 12 depicts representative results of the screening process. Panel A shows an electrophoretic analysis of IGF-I receptor and GAPDH mRNA fragments after RNase protection. Molecular weight markers are shown on the right hand side. The full-length probe is shown on the left hand side; G-probe indicates the IGF-I receptor probe. GAPDH protected fragments are seen at 316 bases and IGF-I protected fragments are seen at 276 bases. Exhibit E, Panel B provides a graph indicating the relative level of IGF-I receptor mRNA following each treatment.
The results obtaining from the above screening assays are summarized in Figure 13. The graph depicts the relative level of IGF-I receptor mRNA after treatment with oligonucleotides complementary to the human IGF-I receptor mRNA (26-86), four randomized sequence oligonucleotides (R1, R4, R7, R9), liposome alone (GSV), or no treatment Asterisks indicate a significant different in relative IGF-I receptor mRNA as compared to GSV treated cells (n=4-10, p<0.05).
WO 00/78341 PCT/AU00/00693 -98- As demonstrated in Figure 13, treatment with eighteen of the twenty-one oligonucleotides resulted in a significant different in levels of IGF-I receptor mRNA relative to GSV treated cells. Three of the antisense oligonucleotides tested in the screening assay reduce IGF-I receptor mRNA to less than 35% of GSV-treated cells. These antisense oligonucleotides have the following sequences, presented in the 5' to 3' direction: #27 UCCGGAGCCAGACUU #64 CACAGUUGCUGCAAG #78 UCUCCGCUUCCUUUC As further demonstrated in Figure 13, six of the antisense oligonucleotides tested in the screening assay reduce IGF-I receptor mRNA to between 35 and 50% of GSV-treated cells.
These antisense oligonucleotides have the following sequences, presented in the 5' to 3' direction: #28 AGCCCCCACAGCGAG #32 GCCUUGGAGAUGAGC
UAACAGAGGUCAGCA
#42 GGAUCAGGGACCAGU #46 CGGCAAGCUACACAG
GGCAGGCAGGCACAC
EXAMPLE 19 Another experiment was performed demonstrating that antisense oligonucleotides targeted to genetic sequences encoding the IGFOI receptor and that reduce IGF-I receptor mRNA levels also inhibit the IGF-I receptor level on the surface of the treated cultured keratinocytes.
HaCaT cells were grown to confluence in 24-well plates in DMEM containing 10% (v/v) FCS. Oligodeoxynucleotide and cytofectin GSV were mixed together in serum-free DMEM, and incubated at room temperature for 10 minutes before being diluted ten-fold in medium and placed on the cells. Cells were incubated for 72 hours with 30nM random sequence or WO 00/78341 PCT/AU00/00693 -99antisense oligonucleotide and 2ym/ml GSV, or with GSV alone in DMEM containing FCS with solutions replaced every 24 hours. This was followed by incubation with oligonucleotide/GSV in serum-free DMEM for 48 hours. All incubations were performed at 37 0 C. Cells were washed twice with Iml cold PBS. Serum-free DMEM containing '"M12I-IGF-I was added with or without the IGF-I analogue, des IGF-I, at 10-"M to 7 M. Cells were incubated at 4 0 C for 17 hours with gentle shaking, then washed three times with Iml cold PBS and lysed in 250lA 0.5M NaOH/0.1% Triton X-100 at room temperature for 4 hours. Specific binding of the solubilised cell extract was measured using a gamma counter. As shown in Figure 14, treatment of HaCaT keratinocytes with oligonucleotide reduced cell surface IGF-I receptor levels to 30% of levels in untreated keratinocytes or in keratinocytes treated with liposome alone or a random oligonucleotide, R766. As shown in Figure 15, treatment with oligonucleotide #27 also significantly reduced cell surface IGF-I receptor levels relative to untreated keratinocytes or treatment with liposome alone or random nucleotide R451. As demonstrated in Example 17, oligonucleotides #64 and #27 reduce IGF-I receptor mRNA levels in cultured keratinocytes to less than 35% of GSV-treated cells. Accordingly, the ability of an oligonucleotide to reduce IGF-I receptor mRNA levels in correlated with its ability to reduce cell surface IGF-I receptor levels.
The forgoing Examples demonstrate that antisense oligonucleotides targeted to the IGF-I receptor can be delivered to human keratinocytes in vitro, can inhibit IGF-I receptor mRNA levels in human keratinocytes in vitro, and that inhibition of mRNA levels is correlated with reduction of cell surface IGF-I receptor levels.
EXAMPLE 19 Further experiments demonstrated the efficacy of antisense oligonucleotides targeted tot he IGF-I receptor in an in vivo model of psoriasis. An animal model of psoriasis is the human psoriatic skin xenograft model. The skin used in this model contains the true disease state.
In this model, reduction in epidermal thickness of psoriatic grafts in response to treatment is positively correlated with efficacy of treatment. Both normal and psoriatic human skin were WO 00/78341 PCT/AU00/00693 -100grated into a thymic (nude) mice in accordance with a thymic (nude) mice in accordance with the methods of Baker et al (1992) Brit. J. Dermatol. 126:105 and Nanney et al (1992) J.
Invest. Dermatol, 92:296. Successful grafting was achieved, as demonstrated in Figure 16, which shows hemotoxylin and eosin stained sections of a 49-day old psoriatic human skin graft (Panel B) compared to the histology of the skin graft prior to grafting (Panel A).
The histological features of psoriasis present in the pregraft section parakeratosis, acanthosis and pronounced rete ridges) are present in the grafts more than seven weeks post grafting.
Using the model, oligonucleotide uptake was measured in epidermal keratinocytes in vivo after intradermal injection. Fluorescently labelled oligonucleotide (R451, 50/l, injection) was intradermally injected into psoriatic and normal skin grafts on a thymic mice.
Live confocal microscopy and fluorescence microscopy of fixed sections was then employed.
Using both techniques, oligonucleotide was found to localize in the nucleus of over 90% of basal keratinocytes. Figure 17 shows the nuclear localization of oligonucleotide in psoriatic skin cells using conventional fluorescence microscopy of a graft that was removed and sectioned after 24 hours.
After establishing oligonucleotide uptake in the in vivo model, a small number of pilots experiments were performed to determine a schedule for treatment of grated mice with antisense oligonucleotides targeted to genetic sequences encoding the IGF-I receptor. The treatment schedule was finalized as follows: WO 00/78341 PCT/AU00/00693 -101- Graft Number Treatment Volume ODN Duration of of Concentration Treatment Injection 1-3 Vehicle (PBS) 50l 20 days 4-6 RandomODN#R451 50 1 10gM 20 days 7-9 ODN#27 5041 10'zM 20 days 10-12 ODN#74 50l 10gM 20 days 13-15 ODN#50 50Al 10AZM 20 days As determined above, oligonucleotide #27 (ODN #27) reduced IGF-I receptor mRNA in vitro to less than 35% of GSV-treated cells. Oligonucleotide #50 (ODN#50) reduced IGF- I receptor mRNA in vitro to between 35 and 50% of GSV-treated cells. Oligonucleotide #74 (ODN #74) was not inhibitory to IGF-I receptor mRNA in vitro. In the in vivo model, each mouse received two grafts. Random oligonucleotide or vehicle was injected intradermally in one graft and acted as a control. The second graft was injected with the targeted oligonucleotide. Each graft received an injection every second day for the duration of the treatment.
Histology of representative grafts from each treatment type are shown in Figures 18(a)-(d) and 19(a) Each sheet shows three images of H&E stained sections: the pregraft histology, the control treated graft, and the targeted oligonucleotide treated graft. Figures are shown at 100x magnification; figures are shown at 400x magnification. The total cross sectional area of epidermis of each graft was assessed using MCID analysis software. The pooled results from all of the treated grafts are shown in Figure As shown in Figures and the vehicle-treated (control) grafts were marginally thinner than thepregraft sections. The degree of regression in these experiments less than 10%) is not significant. A similar amount of marginal thinning WO 00/78341 PCT/AU00/00693 102of epidermis compared to pregraft also occurred in pilot experiments in which psoriatic grafts were not injected, and thsu it is unlikely that the vehicle itself has any effect.
Histological features of psoriasis present in skin samples prior to grafting (clubbing of rete ridges, parakeratosis, acanthosis) were present in these grafts.
The random oliognucleotide treated grafts varied in epidermal thickness after 20 days of treatment. Grafts were either a similar thickness to the pregraft histology, or marginally thinner. Random oligonucleotide treated grafts were in each case significantly thicker than their targeted oligonucleotide treated pairs.
As shown in Figure 20, the targeted oligonucleotide treated grafts were significantly thinner than the pregraft sections and showed less parakeratosis and clubbing of rete ridges. Antisense oligonucleotides which were effective at reducing IGF-I receptor mRNA levels in vitro (#27 and #50) produced greatere epidermal thinning than an oligonucleotide which was not inhibitory to IGF-I receptor mRNA in vitro Accordingly, there is a direct correlation between the ability of an oligonucleotide targeted to the IGF-I receptor to inhibit IGF-I receptor mRNA levels in vitro and the efficacy of the oligonucleotide as an anti-psoriasis agent in an in vivo model.
EXAMPLE Another experiment demonstrated that treatment of psoriatic grafts with an oligonucleotide targeted to a genetic sequence encoding the IGF-I receptor results in inhibition of proliferation. Pregrafts from psoriatic patients, control grafts treated with R4541, and grafts treated with oligonucleotide #27 were obtained as described in Example 19. An antibody to the cell cycle-specific nuclear antigen Ki67 was used to immunohistochemically detect actively dividing cells and tereby assess proliferation. The aKi67 antibody (DAKO, Glostrup, Denmark) recognizes the Ki67 antigen transiently expressed in nuclei of proliferating cells during late S, M and G 2 phases of the cycle and thsu provides a marker for proliferation. Pregraft and graft sections were immunohistochemically processed by standard methods using aKi67 (according to the WO 00/78341 PCT/AU00/00693 -103manufacturer's instructions), peroxidase-conjugated anti-rabbit second stage antibody, and a chromogenic peroxidase substrate.
The results of this experiment are presented in Figure 21 as immunohistochemical sections at 100x magnification. The top panel of Figure 21 depicts a pregraft section obtained from a psoriatic patient. The epidermis is thicker than normal and nucleic are evident in the stratum corneum. Ki67 positive cells, appearing as brown dots, are evidence in the basal and suprabasal layers, and indicate actively proliferating cells. The control (R450-treated) graft in the bottom panel of Figure 21 also exhibits evidence of proliferation, including parakeratosis and Ki67-positive cells appearing as brown-staining nuclei. The center panel of Figure 21 exhibits the oligonucleotide #27-treated graft. This graft exhibits significantly reduced proliferation as evidenced by normal (thin) epidermis, lack of imaginations, and substantial loss of Ki67-positive cells.
These results indicate that treatment of human psoriatic grafts with an oligonucleotide targeted to mRNA encoding the IGF-I receptor results in inhibition of epidermal proliferation.
EXAMPLE 21 Topical formulations of complexes of oligonucleotides with cytofectin GSV in aqueous or methylcellulose gel formulations were prepared and assessed foruptake of the oligonucleotide by keratinocytes in vivo. The topical formulations contained oligonucleotides complexed with cytofectin GSV in an aqueous solution or methylcellulose carrier, as taught herein. With both aqueous and methylcellulose gel formulations, locatlization of oligonucleotide R451 to nuclei and cytoplasm of keratinocytes in normal human skin grafts on nuce mice was observed. Figure 22 shows an image from confocal microscopy demonstrating oligonucleotide locatlization in the nuclei and cytoplasm of keratinocytes in normal human skin grafts after topical application of fluroescently labeled oligonucleotide (10/M R451) complexed with cytofectin GSV (10g/ml). Figure 23 shows an image from confocal microscopy demonstrating that topical application of the WO 00/78341 PCT/AU00/00693 -104same oligonucleotide/GSV concentrations in a 3% methylcellulose gel produced similar uptake in the target keratinocyte population. Using an aqueous formulation of oligonucleotide/GSV complexes, penetration of oligonucleotide into the viable epidermis was observed, whereas application of formulations of oliognucleotide complexed with other cationic lipids resulted in localization of oligonucleotide in the stratum corneum.
EXAMPLE 22 Thirteen antisense oligonucleotides targeted to IGFBP-3 were synthesized. The antisense oligonucleotides are C5-propynyl-dU, Dcl5 mer phosphorothioate oligodeoxyribonucleotides. Figure 24 attached hereto is a schematic diagram indicating the position of the thirteen oligonucleotides relative to the IGFBP-3 mRNA structure.
These oligonucleotides were screened for their ability to inhibit IGFBP-3 mRNA levels of HaCaT cells in accordance with the teachings herein. HaCaT cells were grown to confluence in DMEM supplemented with 10% FCS, then placed in complete keratinocyte serum free medium (KSFM, Gibco), which has a defined amount of EGF, for 24 hours. Oligonucleotides (30nM or 100nM) were complexed with GSV cytofectin (2ug/ml) and added to cells in complete KSFM to allow oligonucleotides to enter the nucleus before removal of EGF. Repeat additions were performed at three hours (in serum free DMEM, which releases the EGF inhibition of IGFBP-3 mRNA) and again after another 24 hours. HaCaT cells were also treated with randomized sequence oligonucleotides (R121, R451, R766 and R961), liposome alone (GSV) or were left untreated Total RNA was isolated as described in Example 17, 24 hours after the last treatment. Total RNA (15Mg) was analyzed by Northern analysis and phosphoroimager quantitation for IGFBP-3 and GADPH mRNA. IGFBP-3 mRNA is expressed as the amount of IGFBP-3 mRNA relative to the amount of GAPDH mRNA.
Figures provide graphs which depict results in this screening process. In these graphs, R1 and R12 refer to R121; R4, R4(0) and R45 rfer to R451; R7, R7(0) and R76 refer to R766; and R9 and R96 refer to R961. The values were standardized to GSV- WO 00/78341 PCT/AU00/00693 -105treated cells, and data was pooled and statistically analyzed by ANOVA followed by Domet's test to compare each treatment to GSV-treated cells. The pooled data are presented as a bar graph in Figure 26. As demonstrated, at a concentration of treatment of HaCaT cells with 8 of the 12 targeted oligonucleotides tested resulted in a statistically significant reduction in levels of IGFBP-3 mRNA relative to GSV-treated cells. At a concentration of 100nM, treatment with 9 fo the 13 targeted oligonucleotides tested resulted in a statistically significant reduction in levels of IGFBP-3 mRNA relative to GSV-treated cells.
These experiments demonstrate that antisense oligonucleotides targeted to genetic sequences encoding IGFBP-3 can inhibit IGFBP-3 mRNA levels in human keratinocytes in vitro.
EXAMPLE 23 IGF-I receptor is a potent mitotic signalling molecule for keratinocytes and the human receptor elicits separate intracellular signals that prevent apoptosis It is proposed in accordance with the present invention that inactivation of IGF-I receptors in epidermal keratinocytes will achieve three important outcomes in subsequent UV treatment of lesions: Acute epidermal hyperplasia following UV has been suggested to increase the risk of keratinocyte carcinogenic transformation By reducing IGF-I receptor expression in the epidermis, the incidence of epidermal hyperplasia following UV exposure is likely to be reduced leading to an overall acceleration in normalization of the lesion and reduced carcinogenic risk.
(ii) Inhibition of anti-apoptotic action of IGF-I receptor will enhance the reversal of epidermal thickening and accelerate normalization of differentiation. Topical or injected IGF-I receptor antisense as adjunctive treatment will increase apoptosis in WO 00/78341 PCT/AU00/00693 -106the epidermal layer thereby enhancing the reduction in acanthosis observed in UV treatments.
(iii) Survival of keratinocytes, ie. those which evade apoptosis is likely to occur when cells have damaged DNA. Such mutations may be in the tumor suppressor region.
Consequently, the use of antisense therapy will result in less frequent selection of mutated keratinocytes and therefore reduced incidence of basal cell carcinomas and squamous.
Accordingly, antisense therapy, especially against IGF-I-receptor is useful in combination with UV therapy in the treatment of epidermal hyperplasia.
EXAMPLE 24 HaCaT cells were treated with antisense oligonucleotides directed to IGF-I receptor mRNA. Levels of IGF-I receptor mRNA were then monitored. In essence, confluent HaCaT cells were treated every 24 hours for four days with 2 jg/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I receptor specific oligonucleotides (#26 to #86) or random sequence oligonucleotides (R121, R451 and R766). Figure 27(a) is a photographic representation showing representative RNase protection assay gel showing IGF-I receptor (IGFR) and GAPDH mRNA in untreated or treated HaCaT cells. Figure 27(b) is a densitometric quantification of IGF-I receptor mRNA in a HaCaT cells following treatment with IGF-I receptor specific oligonucleotides (solid black) random sequence oligonucleotides (horizontal striped bar) or GSV alone (shaded bar) compared to untreated cells (UT, vertical striped bar).
EXAMPLE In this example, reduction in total cellular IGF-I receptor protein was monitored following antisense oligonucleotide treatment. Confluence HaCaT cells were treated with 24 hours for 4 days with 2 gg/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I receptor specific AONS #50 and #64) or the random sequence oligonucleotide, R451. Total WO 00/78341 PCT/AU00/00693 -107cellular protein was isolated and analysed for IGF-I receptor by SDS PAGE followed by western blotting with antibody specific for the human IGF-I receptor. Figure 28(a) shows duplicate treated cellular extracts following the IGF-I receptor at the predicted size of 110 kD. Figure 28(b) is a densitometric quantification of IGF-I receptor protein.
EXAMPLE 26 The reduction in IGF-I receptor numbers was determined on the keratinocyte cell surface after antisense oligonucleotide treatment. HaCaT cells were tranfected with IGF-I receptor specific AONs #27, #50, #64, a random sequence oligonucleotides (R451) or following treatment with GSV a lipid alone every 24 hours for 4 days. Competition binding assays using 25 I-IGF-I and the receptor-specific analogue, des(1-3)IGF-I were performed.
Results are shown in Figure 29.
EXAMPLE 27 In this example, the apoptotic protecting effects of IGF-I receptor on keratinocyte cells was tested by following the reduction in keratino cell numbers following antisense oligonucleotide treatment. HaCaT cells, initially at 40% confluence, were transfected with the IGF-I receptor specific AON #64, control sequences R451 and 6414 or treated with GSV a lipid alone every 24 hours for 2 days. The cell number was measured in culture wells using a dye binding assay. The results are presented in Figure 30. The results clearly confirm that the IGF-I receptor exhibits an anti-apoptotic effect. By reducing IGF-I receptor levels using antisense oligonucleotide treatment, the anti-apoptotic effect is interrupted and apoptosis results in the reduction in keratinocyte cell number. Results are shown in Figure EXAMPLE 28 This example shows a reversal of epidermal hyperplasia in psoriatic human skin grafts on nude mice following intradermal injection with antisense oligonucleotides. Grafted psoriasis lesions were injected with IGF-I receptor specific AONs, a random sequence oligonucleotide in PBS, or with PBS alone, every 2 days for 20 days, then analysed WO 00/78341 PCT/AU00/00693 108histologically. The results are shown in Figure 31. In Figure 31(a), donor A graft treated with AON #50 showing epidermal thinning compared with the pregraft and control (PBS) treated graft and donor graft treated with AON #27 showing epidermal thinning compared with pregraft and control (R451) treated graft. In Figure 31(b), the mean epidermal crosssectional area over the full width of grafts is shown as determined by digital image analysis. The results show that epidermal hyperplasia is reversed following the intradermal injection of antisense oligonucleotides.
EXAMPLE 29 Figure 32 shows the reversal of epidermal hyperplasia correlating with reduced IGF-I receptor mRNA in grafted psoriasis lesions treated with antisense oligonucleotides. Figure 32(a) shows a psoriasis lesion prior to grafting and after grafting and treatment with IGF-I receptor specific oligonucleotide #27 (AON #27) or random sequence (R451) immunostained with antibodies to Ki67 to identify proliferating cells. Proliferating cells are indicated by a dark brown nucleus (arrows). Figure 32(b) shows the same lesion prior to grafting and after oligonucleotide treatment as in Figure 32(a) but subjected to in situ hybridisation with "S-labelled cRNA probe complementary to the human IGF-I receptor mRNA. The presence of IGF-I receptor mRNA is indicated by silver grains which are almost eliminated in the epidermis of the lesion treated with IGF-I receptor specific oligonucleotide 27 (AON This experiment shows that reversal of epidermal hyperplasia correlates with reduced IGF-I receptor mRNA in grafted psoriasis lesions treated with antisense oligonucleotides.
EXAMPLE Figure 33 treatment with oligonucleotides. HaCaT cell monolayers were grown to confluence in DMEM containing 10% fetal calf serum treated every 24 hours for two days with 2 ug/ml GSV lipid alone (GSV) or complexed with 30 nM oligonucleotide. Total RNA was isolated and analysed for IGF-I receptor and GAPDH mRNA using a commercially available ribonuclease protection assay kit. The results show a reduction in IGF-I receptor mRNA in the HaCaT keratinocyte cells.
WO 00/78341 PCT/AU00/00693 -109- EXAMPLE 31 Figure 34 treatment with oligonucleotides. HaCaT cell monolayers were grown to confluence in DMEM containing 10% fetal calf serum treated every 24 hours for 4 days with 2 gg/ml GSV lipid alone (GSV) or complexed with 30 nM oligonucleotide. Cells were lysed in a buffer containing 50 mM HEPES, 150 mM NaCI, 10% v/v glycerol, 1 v/v Trison X-100 and 100 gg/ml aprotinin on ice for 30 minutes, then 30 /g of lysate was loaded onto a denaturing 7% w/v polyacrylamide gel followed by transfer onto an Immobilon-P membrane. Membranes were then incubated with anti-IGF-I receptor antibodies C20 (available from Santa Cruz Biotechnology Inc., Santa Cruz, California) for 1 hour at room temperature and developed using the Vistra ECF western blotting kit (Amersham). The results shown in Figure 34 confirm that IGF-I receptor protein is reduced in HaCaT keratinocytes following treatment with oligonucleotides.
EXAMPLE 32 This example shows a reduction in HaCaT keratinocyte cell number following treatment with oligonucleotides. The results are shown in Figure 35. HaCaT cell monolayers were grown at 40% confluence in DMEM containing 10% fetal calf serum treated every 24 hours for 3 days with 2 g/ml GSV lipid alone (GSV) or complexed with 15 nM oligonucleotide. Cell numbers were then measured every 24 hours using the amido black dye binding assay Results show that HaCaT keratino cells decrease in number following treatment with oligonucleotides due to a reduction in the anti-apoptotic effect of the IGF-I receptor.
Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.
WO 00/78341 WO 0078341PCT/AUOO/00693 -110-
REFERENCES:
1. Sara V Physiological Reviews 70.591-614, 1990.
2. Rechler MM and Brown AL Growth Regulation 2:55-68, 1992.
3. Clemnmons DR Growth Regn 2:80, 1992.
4. Oakes SR, KM Haynes, MJ Waters, AC Herington. and GA Werther J. Clin Endocrinol Metab 73:1368-1373,1992.
Camnacho-Hubner Cet al. JBiol Chem 267:-11949-11956, 1992.
6. NeelyKEetal. JlnvDerm 96:104, 1991.
7. Ts'O POP, Aurelian L, Chang E and Miller PS. Nonionic oligonucleotide analogs (Matagen. TM) as anticodic agents in duplex and triplex formation. in "Antisense Strategies", Annals of the New York Academy of Sciences 660.159-177 (Baserga R and Denhardt DT, eds.), 1993.
8. Haseloff J and Gerlach L Nature 334.586-591, 1988.
9. Boukamnp P, Petrussevska RT, Breitkreuz D, Hornung J, Markham A, Fusenig NE. J Cell Biol 106:761-771, 1988.
Rheinwald and Green Cell 6:331-344, 1975.
11. Hossenlopp P, Seurin D, Segovia-Quinson B, Hardouin S, Binoux M. Anal Biochem 154:138-143, 1986.
WO 00/78341 WO 0078341PCT/AUOO/00693 -111l 12. Spratt SK, Tatsuno GP, Yamanaka MK, Ark BC, Detmer J, Mascarenhas D, Flynn J, Talkington-Verser C, Spencer EM. Growth Factors 3:63 -72, 1990.
13. Pietrzkowski, Z, Sell C, Lammers R, Ulirich A and Baserga R. Mo!. Cell. Bio. 12: 3883-3889, 1992.
14. Schulz J, Dettlaff S, Fritzsche U, Harms U, Schiebel H, Derer W, Fusenig NE, Hulsen A and Bohm M. J. Immunol. Meth. 167.1-13, 1994.
Baker BS, Brent L, Valdimarsson H, Powles AV, AI-Imara L, Walker M and Fry L.
Brit. J Berm atol 126:105-110, 1992.
16. Nanney LB et a! J In vest. Berm atol 9 8:296-301, 1992.
17. Sundberg Jr et al Immunol. Investigations 22:389-401, 1993.
18. Sundberg JP et al J. Invest. Dermatol 102:781-788, 1994.
19. O'Connor et a! Mo! Cell Biol 17:427-435, 1997.
Kuhn et a! Int JCancer 80.431-438, 1999.
21. Resnicoff et a! Cancer Res 55:3739-3 741, 1995.
22. Ouhtit et al Am J Pathol 156:201-207, 2000.
23. Froehler et a! Tetrahednin Lett 34:1003 -1006, 1992.
24. Gennaro (Ed) Remington 's Pharmaceutical Sciences 18th Edition Mack Publishing Co., Easton PA USA, 1990.
WO 00/78341 WO 0078341PCT/AUOO/00693 112 Flanagan et alNat Biotechnol 14.1139-1145, 1996.
26. Flanagan et al/Nucleic Acids Res 24:2936-2941, 1996.
27. Flanagan et alMo! Cell/Biochemn 172:213-225, 1997.
28. Gutierrez et al Biochemistry 36:743-748, 1997.
29. Moulds el a/ Biochemistry 34:5044-5053, 1995.
Wagner et a! Science 260:1510-1513, 1993.
31. Wagner et a/ Nature 372:333-335, 1994.
32. Schultz et al J immunol Meth 167.1-13, 1994.
EDITORIAL NOTE APPLICATION NUMBER 52020/00 The following Sequence Listing pages 1 to 14 are part of the description. The claims pages follow on pages "113" to "118".
WO 00/78341 WO 00/834 1PCTAUOO/00693 -1I- SEQUENCE LISTING <110> MURDOCH CHILDREN'S RESEARCH INSTITUTE <120> A METHOD FOR THE PROPHYLAXIS AND/OR TREATMENT OF MEDICAL DISORDERS <130> 2288267/EJH <140> INTERNATIONAL <141> 2000-06-21 <150> 60/140345 <151> 1999-06-21 <160> 24 <170> Patentln Ver. 2.1 <210> 1 <211> 1433 <212> DNA <213> synthetic construct <400> 1 attcggggcg cctgcccgcc ctgccgagag ccgctgctgc ctgttccgct gcgccgcccg gtccgggagc ggcgtctaca ctgcccctgc tatggcgcca gtggagaacc aagcccctca caccggcaga cgaccacccc tccaccatgc agggaggagg cgcccgctcg tgggctgccc tgctgctact gcccgcCctg ccgcggtggc cgggctgcgg ccccgcgctg aggcgctggt gcccggagca acgtggacag agt cgggtat tgggcaaggg ctgccaggac gcc ttccgga aagaagcgga ctcgctcgcc cgcgctgccg gggcgcgagt cacacccgag cgcagtggcc ctgctgctcg cggccagggg catgggcgag ggttgcagac caccatgaac gaaggagctg tggcaagcat tccctgccaa tgagcggggc ggaggcggct cgccgcgccg ctgcCgccgc ggcggcggcg cgcctggccg ggaggcgccc gtgtgcgccc ctgcgctgct ggcacttgtg aatggcgatg atgttgggcg gccgtgt tcc caccttggcc cccgctcgca cgctgccgac cgccgctgct gcggggcgcg cctgcgggcc gcatgccatg ggc tggaggg atccccaccc agaagcgccg acc act caga ggggaggcag gggagaaggt tggaggagcc gggccgtgca cgccagcatg gccgctgctg cgcggaggtg cccgccggtt cgcggagctc cgaggcgtgc gggctCCgag ggacgccgag aggaggcctg tgctggccgg cactgagcag caagaagctg ggagcggatc cctgcacatc caggaactgg accaggtcct cctctggagc acctctactc WO 00/78341 WO 00/834 1PCT/AUOO/00693 cccaactgtg cagcgtgggg accatccggg gtgcacaccc gcc cct ct CC ttccagttct cccggcctct gaggaagggg tttatttttg acaagcatgg agtgctggtg gggaccccga agcggatgca aaacaccggc gacacacgta ctcttcccag gttgtggtcg aacccctgtg cctgtacaac tgtgaacccc gtgtcatctc gtagaccgca agaaaacgga tttatatttg ctgcagatgc gggagctggg tccct tttgc ctcaaacagt aacaccggga ttctacaatg gccagccggt gagtgcttgg gaaagagacc cacacctgct gtacaggttt ataagattaa gcaagatgtc agctgatcca agcagcagga gcctggcgcc gtggtgggtg agcaccgagc ccttcttgct ggggaggggg aggaaggaaa tctgaacggg gggagccccc ggcttgcggg cctgcccccc ctggaggatt tcggcacctc ttccccgggg aagagaaatt agt 960 1020 1080 1140 1200 1260 1320 1380 1433 <210> 2 <211> 2474 <212> DNA <213> synthetic construct <400> 2 ctcagcgccc at ccc tgcgc gcgacccacg ggcgcgggct cgcgcgtgca gccgggctgc caccgagcgc gcaggcgctg cgcc tac ctg cagcgccggc gttccacccc gcgctacaaa caagcgggag gaagttcctc attttataag tgtggataag ctgctacagc ccttattttg atatttctgt aatgcctatg aaagagcagt cacccagact tgact ttgtg ccgtacagtg agccgcttcc gcccagcctg ctctgggccg ggcgcgagct ctggcccagt ggctgctgcc tgtggctccg ctggacggcc ctgccagcgc agtgtggaga ctccattcaa gttgactacg acagaatatg aatgtgctga aaaaagcagt tatgggcagc atgcagagca cacaaaagac ttgtggtgaa gtttctttga ttgaattttc tcatgcgccc acttaggcgg cgcacaggct tgcctggatt ccaagcagcg ctgcgctgac cggggggctt gcgcgcctcc tgacgtgcgc gccttcgctg gcgggctctg cgccagctcc gcccgtccgt agataatcat agtctcagag gtccctgccg gtcccagggg gtcgcccttc c tc tcc cagg agtagacgcc tgccaaggac ctgatttttt atggtaaact ttgtcgcttc gtggaatgct ctgtgttgcc ttatcgagaa ccacagcttc tgccccggtt tctgctggtg gggtcccgtg gcccgccgtg actgagcgag ccagccgtcg cgtcaacgct aggaaatgct ctccagcacg gcgccgtgta gcagjgcgtca ctgctccgcg gtgcgctgcg tgcgcggagc ggc cagccgt cccgacgagg agtgccgtca agtgagtcgg caccgggtgt catcaagaaa gggcatgcta cacagatacc cagaacttct tagagaaatg gaagacacac tgtacacatt cccaactgtg caaaggcagg aagcggggct ctgtcgcccc tgcagcgggc ggccgccggt agccgtgcga tggtgcgcga gcggcatcta cgcgaccgct gccgcctgcg aggaagaccg c tga tcc caa aagacagcca cctccgagtc tgaatcacct acaagaaggg tctgctggtg aggacgtgca ctcaaatatg gcctcgattt aggtttttga agtagtcagc tcgagcacag ggccgaccac cccccactcc ggtcatccgg 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 ctacaccacc tgccgcaagt atgaccagca ttaaaccaaa tgagcatctt ctatcaaaat caccacatgt tatgtagaga taggaaaacc aaggggaagg taatgtggag gctggctaca gtttagaaag ttcactttcc attcagagac tggtcgaagc acacgcttca tt taaacccc WO 00/78341 WO 00/834 1PCT/AUOO/00693 acatcccaac gcgtggatcc actattggag ctagggcact cctgaagaca gagggacaga aattcttcgg atttctgagg ccttagcaca gggagcccat gtcattctca aacattgtat aatgttagag agagactggg ggagactctg aaacagaggg gcatgctcct ctcaaccaag aaaataaggt ctgggaacct tggcccagtc gagacgggag atgactgcag ataagctctt atgtaaaaaa ccaggacact tgcttttctt acaacatagc atgctatatg ctgCtctccc ccctgctgca gt ctcaagac ggagctcaca aagaatgttt ggagtcctac ataaaggcag gaaggcccag agtcdgcctc aaaatagtgt taaaggcaaa gaatagtaat gggagcacat ta taat t cac cc caaata ta atacaactgt ggaggccaaa gacctcggtg attctgccta gccttctgtg atgtcttcaa ttgtttaaaa gtatttcggg gatggcttt t cacattcaga tttgtagttc gctttatttt at cagaacag agagattcac acatatatgc gtaagatcta ggccatgac t cccaagaagg tggacacacg cctattagct gtgtcatttc gtgacctgta aa tatgt ate ccctcctctt gctgcggccc ggcatcacaa aacaactcaa catctctcat gaaggaggaa ccatgtttgt agagaagata tactagataa gaggaaagga tct ggcaaag ctgcatagag tttctttatt tgaaacaagg ctgcttgggg taagaatgtt caggaatctt .cgtggggtag gtaatggcac gacgaagctt cttttgtCct tggcttgctg tgaacttaga tgttcttgtt tcctagatga gct ca cgc cc tcaggctcag ctctccttga tttttaactt 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 tttgggggga aaagtatttt aagtttttac catt tgagaagttt gtcttgcaat gtatttataa atagtaaata 2460 2474 <210> 3 <211> 4989 <212> DNA <213> synthetic construct <400> 3 tttttttttt ggaggagggt tggccgacga ctgaagcgcc aaggccgagg ctgctgttcc atccgcggct aaggatattg aatgctgacc aataactaca atggaggaga tggaccacaa gagaacaatg acggcctgtg cccaacacct ttttgagaaa ccccgacctc gtggagaaat tggagaactg actaccgcag gagtggctgg ggaaactctt ggctttacaa tctgttacct t tgtggggaa agccgatgtg accgctgcca agtgc tgcca tagcttgccg acaggtttga gggaatttca gctgtggggg ctgcgggcca cacggtgatc ctaccgcttc cctcgagagc ctacaactac cctgaggaac ctccactgtg taagccccca tgagaagacc gaaaatgtgc ccccgagtgc ccactactac gggctggcgc tcccaaataa ctcctgtttc ggcatcgaca gagggctacc cccaagctca ctcggagacc gccctggt ca attactcggg gactggtccc aaggaatgtg accatcaaca ccaagcacgt ctgggcagct tatgccggtg tgtgtggacc aaggaatgaa tctccgccgc tccgcaacga tccacatcct cggtcattac tcttccccaa tcttcgagat gggccatcag tgatcctgga gggacctgtg atgagtacaa gtgggaagcg gcagcgcgcc tctgtgtgcc gtgacttctg gtctggctcc gctctcgctc ctatcagcag gctcatctcc cgagtacttg cctcacggtc gaccaatctc gattgagaaa tgcggtgtcc tccagggacc ctaccgctgc ggcgtgcacc tgacaacgac tgcctgcccg cgccaacatc WO 00/78341 WO 0078341PCT/AUOO/00693 ctcagcgccg gagtgcccct ggtccttgcc tctgctcaga cgggggaata ggctacgtga cgcc tcat cc cagaacttgc atgtactttg acggggacta gcctcctgtg atcataacct tactacaagg t ccaa cagct atcttactac ctcaccatgg accaatgctt cagttaatcg gtgcgctggc gacaaaatcc aaccccaaga gaagccgaga ctgcacaact gccaacacca accgacccgg gagagaactg tgcaaccacg atgcccgcag aactccatct gaaataaaat aggaagtatg caggccacat gccaaaacag ttgatcgtgg aggc tgggga gtgtacgttc gggcaggggt cctgaaacca gagtttctca ctgggtgtgg gatctcaaaa agagcagcga cgggcttcat cgaaggtctg tgctccaagg acat tgcttc agatccgcca taggagagga agcaactgtg ct ttcaatcc aagggcgcca aaagtgacgt ggcaccggta aagcaccctt ggaacatggt atgggctgaa tggagaacga cagttccttc tgaagtggaa agcggcagcc ccatcaggaa ctgaggtgtg agcaggccga ccatcttcgt ccatgtccag aagagctgga tcatttctaa aggctgagaa aaggagcaga ttttaaagtg acgga tcaca gaggggccaa ctctc tc tgg gatatgaaaa gagggttggt atggagtgct ctgatgagtg cgt ttgggat gagtggccat acgaagcttc tgtcccaagg gttatctccg ctccgagggg ccgcaacggc tgaggaagaa atgcaccatc agagctggag ttctcatgcc gcagctagaa ggactgggac caaattatgt aagcaaaggg cctgcatttc ccggccccct taagaatgtc ggacgtggac gccctggact ccatatccgt cattcccttg ccctccctct tcaggacggc gtatgccgac tggtggggag gaaggaggag gcccagacct ccgaagcagg gacagagtac ccttcggcct gctgggctgc tgacattcct gccggaacct agttgaggat gctaaaccgg gaatgggtcg cttcatccat gattatgctg gtatgcctct ggaggtggct ggtctatgaa taaaacagtg tgtgatgaag ccagccaaca gtctctgagg tttgtgatcc agccagagca aagaaaacaa ttcaagggca aacttcatgg t tggtctcc t gggaattact caccgcaacc gtttccgaaa gacataaaca acctccacca gactacaggg acagagtatg ctcccgccca cagt acgccg ggggccaaga gacgttcttt ctgcccaacg tacctttacc ggcaccatcg aaagggcct t gctgaatacc gaaaggaagc aacaccacgg cctttctttg ttcacattgt agcgc ctcc a gggccagtga gagaatccca cagcgagaa t ctaaacccgg tggacagatc ctgatcatcg tacgtcttcc gtgaacccgg cgggagaaga ggagt tgcca aacgaggccg gagttcaatt C tggt ca tca ccagaaatgg acgacggcga tgtactgcat agaccattga atttgctcat ggctcatcga tgtCCttcct ccttctacgt tgaccatcaa tttaccgcat ccaggaacaa ccacgtcgaa atctcatCag atgggcagga acaaggacgt tttacgtcaa gtgagatctt cagcatcgaa gcaacctgag ggcacaatta acattgagga gctgcgcctg gcaaagtctt ggagagatgt ccgcagacac agagcagagt accgcatcga acttcgtctt cctgggagcc atggattgat gtgtgtccag ggaactacac ctgtgttctt ctCtgcccgt atagaaagag agtacttcag tcaccatgag agggtgtggt caagcatgcg gtcaccatgt tggaactgat agaataatcc gtgcatgcag cccttgtgaa ttctgttact taacatccga ggtggtgacg aaaaaacctt cctcgacaac agcagggaaa ggaggaagtg cggggagaga gaatcgcatc cttcaccgtt tgcctgcggC ggagcccggc qgctgtgaCC gtacattcgc ctcctcttct ttactacatt ctgctccaaa ggtcacagag ccccaaaact tgagaatttc catgcaagtg ctacaacatc ggataacaag tatccaCagc tgcaaggact aaggcctgaa tctaatgtat acaggaatac agcccggatt ctatgtccag cgctgtcctg aaataacagc cgctgctgat ccgggaact t gaaagatgaa tgagaggat t ggtgcgattg gacacggggc agtcctagca 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 WO 00/78341 WO 0078341PCT/AUOO/00693 cctccaagcc ctcaacgcca gat ttcacag taccggaaag gatggagtct gccacactgg atggagggcg cgcatgtgct atcaaagagg aagctgcccg gacccctcgg gagaacggcc tacgcccaca acctgctgat ggtggggggg cttcagttct atgttccttt tgggccttta tcctcactct ggaaaaataa tgtccctgtg aaaaacacgt ttacaaaggg aaatcctgaa tgagcatggc gactgcccct attattattt tgaaccggc tgagcaagat ataagttcgt tcaaaatcgg gaggcaaagg tcaccactta ccgagcagcc gccttctgga ggcagtataa agatggagcc agccggagga cctcctcgtc ccggccctgg tgaacggggg ccttggatcc gagagagagt gcccttgctg tttcaatatg agaaccttaa gtccctgtcc ttgccacaag gccccat cca ggagatggaa ccatcgttca ctttctccct agctggttgc gctgtgctgc gggggaactg gattcagatg ccacagagac agatt ttggt gctgctgccc ctcggacgtc ctac cagggc caagccagac ccccaagatg tggcttccgg gctggacctg ctccctgcca ggtgctggtc ccgcaagaac tgaatctgtg tttaacaatc cccgcgggag caagcagctt tgacaacac t ttccctgttc tccagctggg accactgtac a tt t ttacct tccaaggctg catcggcccg tccatttgag tcaaggccac gacacaatag gccggagaga ttgcagacgg cttgctgccc ggaattgcat atgacgcgag gtgcgctgga tggtccttcg ttgtccaacg aactgtcctg aggccttcct.
gaggtctcct.
gagccagaga ctgcccgaca ctccgcgcca gagcgggcc t caaacagtaa cattcacaag acagct tct c tttattccct taatagcaac tccctttctc aagccctttt acacccgcct ttaictttca ttaccatttt gcgctgattc agacacgctg aggcacacag gtctttctct atatctatga tgtctcctga gggtcgtcct agcaagtcct acatgctgtt tcc tggagat tct ac tacag acatggagag gacactcagg gcttcgacga tgc cgctgcc cgtgtgcgca cctcctgtac tgcagtaaaa gcccaaaccc agagcacttg tctcctctct tatcagtttg gacaccgtgg cctttctagg aacgctgcct Ctcgtgtccg gcgacacact gtctcattgc cagtgaaggt catggcatac ggtagccgaa gacagactat gtccctcaag ctgggagatc tcgcttcgtc tgaactgatg catcagcagc cgaggagaac cgtccccctg acacaaggcc gagacagcct ccagtcttcg cgcgcagcgg ctcagtggat cacatttggg ttaactgaca agaaccagtc gcttcataac aggaagtggc gtcattacaa gacatgaaat aattttgcca gaggcatggg ccgtccatcc tt ctgactag ggggagaagc 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 4989 <210>. 4 <211> <212> DNA <213> synthetic construct <400> 4 gcgcccgctg catgacgcct gcaac <210> <211> 24 WO 00/78341 WO 0078341PCT/AUOO/00693 <212> DNA <213> synthetic construct <400> cgggcggctc acctggagct ggcg 24 <210> 6 <211> 18 <212> DNA <213> synthetic construct <400> 6 aggcggctga cggcacta 18 <210> 7 <211> 19 <212> DNA <213> synthetic construct <400> 7 caggcgtcat gcagcgggc 19 <210> 8 <211> <212> DNA <213> synthetic construct <400> 8 cggagatgcc gcatgccagc gcagg <210> 9 <211> 18 <212> DNA <213> synthetic construct <400> 9 gacagcgtcg gagcgatC 1 WO 00/78341 WO 0078341PCT/AUOO/00693 <210> <211> 18 <212> DNA <213> synthetic construct <400> atctctccgc ttcctttc <210> 11 <211> 18 <212> DNA <213> synthetic construct <400> 11 gaaaggaagc ggagagat <210> 12 <211> 12 <212> DNA <213> synthetic construct <400> 12 ccggagccag ac <210> 13 <211> 12 <212> DNA <213> synthetic construct <400> 13 cacaggcgca ag <210> 14 <211> 8 <212> DNA <213> synthetic construct WO 00/78341 WO 00/834 1PCT/AUOO/00693 <400> 14 cccgcccc 8 <210> <211> <212> DNA <213> synthetic construct <400> agcccccaca gcgag <210> 16 <211> 12 <212> DNA <213> synthetic construct <400> 16 gccggagaga gc 12 <210> 17 <211> 13 <212> DNA <213> synthetic construct <400> 17 aacagaggca gca 13 <210> 18 <211> 13 <212> DNA <213> synthetic construct <400> 18 ggacagggac cag 13 <210> 19 WO 00/78341 WO 0078341PCT/AUOO/00693 <211> 14 <212> DNA <213> synthetic construct 4400> 19 cggcaagcac acag <210> <211> <212> DNA <213> synthetic construct <400> ggcaggcagg cacac <210> 21 <211> 328 <212> PRT <213> human <400> 21 Met Leu Pro Arg Val Gly Cys Pro Ala Leu Pro Leu Pro Pro 1 5 10 Pro Pro Leu Leu Pro Gly Gly Gly Leu Pro Leu Leu Leu Leu Leu Leu Gly Ala Ser Gly Pro Pro Cys Gly Ala Arg Ala Glu Val Leu Phe Arg Thr Pro s0 Glu Arg Leu Ala Cys Gly Pro Pro Pro Val Ala Pro Pro Ala Ala Val Ala Ala Val Ala Gly Gly Ala Met Pro Cys Ala Leu Val Arg Glu Pro Gly Cys Gly Cys Cys Ser Val Cys Ala Arg Leu WO 00/78341 WO 0078341PCT/AUOO/00693 10 Glu Gly Giu Arg Cys Tyr 115 Cys Gly Val Tyr Pro Arg Cys Gly Gin Gly Leu 110 Ala Leu Val Pro His Pro Gly Giu Leu Pro Leu Met Gly 130 Giu Gly Thr Cys Glu Lys Arg Arg Asp 135 Glu Tyr Gly Ala Pro Glu Gin Val Ala Asp Asn Gly Asp 150 His Ser Glu Gly Leu Val Giu Asn Val Asp Ser Thr Asn Met Leu Gly Gly Gly 175 Gly Ser Ala Val Phe Arg 195 Arg Lys Pro Leu Ser Giy Met Lys Giu Leu Ala 190 Gly Lys Gly Glu Lys Val Thr Gin His Arg Gin Gly Lys His His Leu Gly 210 Giu Glu Pro Lys Lys 220 Leu Arg Pro Pro Ala Arg Thr Pro Gin Gin Glu Leu Gin Val Leu Glu Ile Ser Thr Met Arg Leu Pro Asp Glu 245 Gly Pro Leu Giu His Leu 255 Tyr Ser Leu Lys Gin Cys 275 Ile Pro Asn Cys Lys His Gly Leu Tyr Asn Leu 270 Cys Trp Cys Lys Met Ser Leu Gly Gin Arg Gly Vai Asn 290 Pro Asn Thr Gly Leu Ile Gin Gly Al a 300 Pro Thr Ile Arg Asp Pro Glu Cys Asp Po Gi Cys Leu Phe Tyr Asn Giu Gin Gin Glu Ala WO 00/78341 WO 0078341PCT/AUOO/00693 -1I1I- Gly Val His Thr Gin Arg Met Gin 325 ':210> 22 <211> 39 <212> PRT <213> human <400> 22 Met Leu Pro Arg 1 Gly Cys Pro Ala Leu Pro Leu Pro 10 Pro Pro Pro Ala Ser Gly Leu Leu Pro Leu Leu Pro Leu Leu Leu. Leu Leu Leu Gly Gly Gly Gly Gly Ala Arg Ala '210> 23 '211> 289 <212> PRT ':213> human <400> 23 Giu Val Leu Phe Arg 1 5 Cys Pro Pro Cys Pro Glu Arg Leu Ala Ala Cys Gly Pro Gly Gly Ala Pro Pro Val Ala Pro Pro Ala Ala Val Ala 25 Arg Met Pro Cys Ala Glu Leu Val Arg Glu 40 Ala Val Ala Pro Gly Cys Gly Cys Cys Ser Val Cys Ala Arg Leu Glu Gly Ala Cys Gly Val Tyr Thr Pro Arg Cys Gly Gin Gly Leu Arg Cys Tyr Pro His Pro 70 WO 00/78341 WO 0078341PCT/AUOO/00693 12- Ser Glu Leu Pro Gin Ala Leu Val Gly Glu Gly Thr Cys Glu Lys Arg Arg Asp Ala Giu Tyr Gly 100 Ser Pro Glu Gin Asn Gly Asp 115 Asp His Ser Glu Gly Gly Leu Val 120 Glu Asn 125 Ala Gly 140 Val Ala Asp 110 His Val Asp Arg Lys Pro Ser Thr Met Asn Met Leu Gly Gly Gly Gly Ser Lys Ser Gly Met Glu Leu Ala Val Arg Glu Lys Val Giu Gin His Arg Met Gly Lys Gly Lys His His Leu Gly Leu 175 Glu Glu Pro Gin Giu Leu 195 Lys Leu Arg Pro Pro Ala Arg Thr Pro Cys Gin 190 Asp Gin Val Leu Arg Ilie Ser Thr Arg Leu Pro Asp Glu 210 Arg Gly Pro Leu Giu His Leu Tyr Ser 215 Leu 220 His Ile Pro Asn Asp Lys His Giy Leu Tyr Asn Leu Lys 230 Cys Lys Met Ser Asn Gly Gin Arg Glu Cys Trp Cys Asn Pro Asn Thr Gly Lys 255 Leu Ile Gin Phe Tyr Asn 275 Ala Pro Thr Ile Gly Asp Pro Glu Cys His Leu 270 Gin Arg Met Glu Gin Gin Giu Cys Gly Val His WO 00/78341 WO 0078341PCT/AUOO/00693 13 <210> 24 <211> 291 <212> PRT <213> human <400> 24 Met Gin Arg Ala 1 Val Leu Leu Arg Gly Leu Gly Pro Arg Pro Thr Leu Trp 5 Gly Pro Pro Val Ala Ala Ala Leu Thr Leu Leu Ala Gly Ala Val Val Arg Glu Pro Cys Asp Ser Ser Gly Arg Ala Leu Val Arg Glu Ala Gin Cys Ala Pro Pro Val Cys Ala Pro Gly Cys Gly Cys Thr Cys Ala Glu Gly Gin Gly Ile Tyr Arg Cys Gly Gly Leu. Arg Cys Gin Pro Ser Pro Asp Leu Cys Val 115 Pro Ala Pro Arg Pro Leu Leu Leu Asp Gly Arg Gly 110 Tyr Leu Leu Ala Ser Ala Arg Leu Arg Ala Pro Ala Pro Ala Ser Glu 130 Ser Ala Glu Glu Asp Arg Thr His Arg Val Gly Ser Val Pro Ser Val Asp Pro Lys Pro Leu His Ile Ilie Ile Lys Gly His Ala Lys Asp Ser Gin Arg Tyr Lys Val Asp Tyr Glu Ser WO 00/78341 WO 0078341PCT/AUOO/00693 14 Gin 5cr Thr 195 Asp Thr Gin Asn Phe Ser Ser Glu Ser 200 Arg Giu Thr Glu Tyr 210 Gly Pro Cys Arg Giu Met Glu Asp Leu Asn His Leu Phe Leu Asn Val 5cr Pro Arg Gly His Ile Pro Asn Asp Lys Lys Gly Tyr Lys Lys Lys Cys Arg Pro Ser Lys Gly 255 Arg Lys Arg Pro Gly Tyr 275 Gin Ser Lys 290 Phe Cys Trp Cys Asp Lys Tyr Giy Gin Pro Leu 270 Thr Thr Lys Giy Lys 280 Giu Asp Val His Cys Tyr Ser Met 285

Claims (1)

113- CLAIMS: 1. A method for ameliorating the effects of a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation with an effective amount of a nucleic acid molecule selected from the group consisting of UCCGGAGCCAGACUU-3' (SEQ ID NO:12); 5'-CACAGUUGCUGCAAG-3' (SEQ ID NO:13); 5'-UCUCCGCUUCCUUUC-3' (SEQ ID NO:14); 3' (SEQ ID NO:15); 5'-GCCUUGGAGAUGAGC-3' (SEQ ID NO:16); UAACAGAGGUCAGCA-3' (SEQ ID NO:17); 5'-GGAUCAGGGACCAGU-3' (SEQ ID NO:18); 5'-CGGCAAGCUACACAG-5' (SEQ ID NO:19); 3' (SEQ ID NO:20) or chemical analogue of any one of said nucleic acid molecules wherein said nucleic acid molecule or its chemical analogue is capable of inhibiting or otherwise reducing growth factor mediated cell proliferation and/or inflammation and/or other medical disorders. 2. A method according to Claim 1 wherein the mammal is a human. 3. A method according to Claim 1 or 2 wherein cell proliferation and/or inflammation is mediated by at least one of insulin-like growth factor I (IGF-I), keratinocyte growth factor (KGF), transforming growth factor-a (TGFa), tumour necrosis factor-a (TNFa), interleukin (IL) -1 IL-4, IL-6, IL-8 and/or basic fibroblast growth factor (bFGF). 4. A method according to Claim 3 wherein cell proliferation and/or inflammation is mediated by IGF-I. A method according to Claim 1 or 2 wherein the proliferative or inflammatory skin disorder is psoriasis, eczema, ichthyosis, pityriasis, rubra, pilaris, serborrhoea, keloids, keratosis, neoplasias, scleroderma, warts, benign growths or cancers of the skin. AMENDED SHEE- IPEAAU PCT/AU00/00693 Re> red 27 September 2001 P:\Opcr~j'.pmM$8270.mumdch.Pcl i doc27/09 -114- A method according to Claim 5 wherein the skin condition is psoriasis. 7. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-UCCGGAGCCAGACUU-3' (SEQ ID NO:12) or chemical analogue thereof. 8. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-CACAGUUGCUGCAAG-3' (SEQ ID NO:13) or chemical analogue thereof. 9. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-UCUCCGCUUCCUUUC-3' (SEQ ID NO:14) or chemical analogue thereof. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-AGCCCCCACAGCGAG-3' (SEQ ID NO:15) or chemical analogue thereof. 11. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-GCCUUGGAGAUGAGC-3' (SEQ ID NO:16) or chemical analogue thereof. 12. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-UAACAGAGGUCAGCA-3' (SEQ ID NO:17) or chemical analogue thereof. 13. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-GGAUCAGGGACCAGU-3' (SEQ ID NO:18) or chemical analogue thereof. 14. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-CGGCAAGCUACACAG-5' (SEQ ID NO:19) or chemical analogue thereof. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-GGCAGGCAGGCACAC-3' (SEQ ID NO:20) or chemical analogue thereof. AMENDED SHEET IPEAAU PCT/AU00/00693 Re ved 27 September 2001 P:\OpsEj.pts\2288270.mmrdoch.pcLmmxdcdd im.doc-27/001 -115- 16. A nucleic acid molecule comprising at least about 15 nucleotides capable of hybridizing to or forming a heteroduplex or otherwise interacting with a complementary form of SEQID ID NO:12 to SEQ ID NO:20 inclusive. 17. A nucleic acid molecule comprising at least about 15 nucleotides capable of hybridizing to or forming a heteroduplex or otherwise interacting with a complementary form of SEQ ID NO:12 to SEQ ID NO:20 inclusive. 18. A nucleic acid molecule comprising at least about 15 nucleotides capable of hybridizing to or forming a heteroduplex or otherwise interacting with a complementary form of SEQ ID NO:12 to SEQ ID NO:14 or SEQ ID NO:20 inclusive. 19. A method of ameliorating the effects of psoriasis in a mammal, said method comprising contacting proliferating skin or skin capable of proliferation with an effective amount of one or more nucleic acid molecules or chemical analogues thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation wherein said one or more molecules comprises a polynucleotide selected from the group consisting of UCCGGAGCCAGACUU-3' (SEQ ID NO:12); 5'-CACAGUUGCUGCAAG-3' (SEQ ID NO:13); 5'-UCUCCGCUUCCUUUC-3' (SEQ ID NO:14); 3' (SEQ ID NO:15); 5'-GCCUUGGAGAUGAGC-3' (SEQ ID NO:16); UAACAGAGGUCAGCA-3' (SEQ ID NO:17); 5'-GGAUCAGGGACCAGU-3' (SEQ ID NO:18); 5'-CGGCAAGCUACACAG-5' (SEQ ID NO:19); 3' (SEQ ID NO:20) or chemical analogue of any one of said nucleic acid molecules which is capable of interacting with mRNA directed from an IGF-I gene, an IGF-I receptor gene or a gene encoding an IGFBP. A method according to Claim 19 wherein the mammal is a human. 21. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-UCCGGAGCCAGACUU-3' (SEQ ID NO:12) or chemical analogue thereof. AMENDED SHEET IPEA/AU PCT/AU00/00693 Re. led 27 September 2001 P:'OparEjpcu\2288270.murdochb.ptmm dedclaims.do-27/OWO -116- 22. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-CACAGUUGCUGCAAG-3' (SEQ ID NO: 13) or chemical analogue thereof. 23. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-UCUCCGCUUCCUUUC-3' (SEQ ID NO: 14) or chemical analogue thereof. 24. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-AGCCCCCACAGCGAG-3' (SEQ ID NO:15) or chemical analogue thereof. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-GCCUUGGAGAUGAGC-3' (SEQ ID NO: 16) or chemical analogue thereof. 26. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-UAACAGAGGUCAGCA-3' (SEQ ID NO: 17) or chemical analogue thereof. 27. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-GGAUCAGGGACCAGU-3' (SEQ ID NO:18) or chemical analogue thereof. 28. A method according to Claim 19 or 20 wherein the nucleic acid molecule is (SEQ ID NO: 19) or chemical analogue thereof. 29. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-GGCAGGCAGGCACAC-3' (SEQ ID NO:20) or chemical analogue thereof. A composition comprising a nucleic acid molecule capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation, said composition comprising a nucleic acid molecule selected from the group consisting of 3' (SEQ ID NO:12); 5'-CACAGUUGCUGCAAG-3' (SEQ ID NO:13); UCUCCGCUUCCUUUC-3' (SEQ ID NO:14); 5'-AGCCCCCACAGCGAG-3' (SEQ ID NO: 15); 5'-GCCUUGGAGAUGAGC-3' (SEQ ID NO:16); 3' (SEQ ID NO:17); 5'-GGAUCAGGGACCAGU-3' (SEQ ID NO:18); AMENDED SHEET IPENAU PCT/AU00/00693 Re ved 27 September 2001 P:OpA\Ejipct\2288270mwdioch.pclmm lr lim.doc-27/091O -117- (SEQ ID NO:19); 5'-GGCAGGCAGGCACAC-3' (SEQ ID or chemical analogue of any one of said nucleic acid molecules, said composition further comprising one or more pharmaceutically acceptable carriers and/or diluents. 31. A method according to Claim 30 wherein the mammal is a human. 32. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-UCCGGAGCCAGACUU-3' (SEQ ID NO: 12) or chemical analogue thereof. 33. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-CACAGUUGCUGCAAG-3' (SEQ ID NO:13) or chemical analogue thereof. 34. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-UCUCCGCUUCCUUUC-3' (SEQ ID NO: 14) or chemical analogue thereof. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-AGCCCCCACAGCGAG-3' (SEQ ID NO: 15) or chemical analogue thereof. 36. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-GCCUUGGAGAUGAGC-3' (SEQ ID NO:16) or chemical analogue thereof. 37. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-UAACAGAGGUCAGCA-3' (SEQ ID NO: 17) or chemical analogue thereof. 38. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-GGAUCAGGGACCAGU-3' (SEQ ID NO: 18) or chemical analogue thereof. 39. A method according to Claim 30 or 31 wherein the nucleic acid molecule is (SEQ ID NO: 19) or chemical analogue thereof. AMENDED SHEET IPEAAU PCT/AUOO/00693 R, .ived 27 September 2001 P:\OpeMjbLpeWI288270.mwdmh.pcL=emd labmd 27/WOI -118- A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-GGCAGGCAGGCACAC-3' (SEQ ID NO:20) or chemical analogue thereof. AMENDED SHEEI MEAAU
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Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020165196A1 (en) * 2001-05-07 2002-11-07 Eric Wickstrom Oligonucleotide inhibitors of cancer cell proliferation
AU2002365374A1 (en) * 2001-11-28 2003-06-10 Angiogenetics Sweden Ab Regulation of hypoxia-inducible gene expression with antisense inhibitory pas domain protein
DK1465995T3 (en) 2002-01-17 2008-10-20 Univ British Columbia Bispecific antisense oligonucleotides inhibiting IGFBP-2 and IGFBP and methods for their use
EP1432724A4 (en) * 2002-02-20 2006-02-01 Sirna Therapeutics Inc Rna interference mediated inhibition of map kinase genes
JP4338527B2 (en) 2002-04-05 2009-10-07 サンタリス ファーマ アー／エス Oligomer compounds that regulate HIF-1α expression
EP1641910B1 (en) * 2003-07-02 2013-02-20 Verenium Corporation Glucanases, nucleic acids encoding them and methods for making and using them
CN1829794B (en) 2003-08-05 2011-06-08 Avi生物制药公司 Oligonucleotide analog and method for treating flavivirus infections
CA2539727C (en) 2003-10-01 2016-11-01 The University Of British Columbia Bispecific oligonucleotide for the treatment of cns malignancies
US8618054B2 (en) 2004-05-05 2013-12-31 Valorisation-Rechereche Société en Commandite Interleukin-1 receptor antagonists, compositions, and methods of treatment
EP4272748A3 (en) 2004-06-28 2024-03-27 The University Of Western Australia Antisense oligonucleotides for inducing exon skipping and methods of use thereof
WO2006050734A2 (en) 2004-11-09 2006-05-18 Santaris Pharma A/S Potent lna oligonucleotides for the inhibition of hif-1a expression
US9447138B2 (en) 2004-11-09 2016-09-20 Roche Innovation Center Copenhagen A/S Potent LNA oligonucleotides for the inhibition of HIF-1a expression
WO2007004060A2 (en) 2005-05-05 2007-01-11 Valorisation Hsj, Societe En Commandite Cytokine receptor modulators and uses thereof
AU2006330435C1 (en) * 2005-12-29 2014-03-06 Arrowhead Research Corporation RNAi-mediated inhibition of IGFIR for treatment of ocular angiogenesis
CA2655997A1 (en) * 2006-06-30 2008-01-10 Schering Corporation Igfbp2 biomarker
EP2152873A2 (en) * 2007-03-16 2010-02-17 Biorigen S.r.l Gene expression regulation technology and noncoding rnas for diagnosis and therapy
ES2714787T3 (en) 2008-10-24 2019-05-30 Sarepta Therapeutics Inc Exon skipping compositions for DMD
CN102387817B (en) * 2009-02-12 2018-01-30 库尔纳公司 By suppressing to treat the related diseases of BDNF for the natural antisense transcript of neurotrophic factor derived from brain (BDNF)
JP2013500017A (en) * 2009-07-24 2013-01-07 カッパーアールエヌエー，インコーポレイテッド Treatment of sirtuin (SIRT) related diseases by blocking natural antisense transcripts to sirtuin (SIRT)
JP5943836B2 (en) * 2009-08-21 2016-07-05 カッパーアールエヌエー，インコーポレイテッド Treatment of CHIP-related diseases by inhibition of natural antisense transcripts on 'HSP70 interacting protein C-terminus' (CHIP)
IL297299A (en) 2009-11-12 2022-12-01 Univ Western Australia Antisense oligonucleotides for inducing exon skipping in the dystrophin gene
EP2802674B1 (en) * 2012-01-11 2020-12-16 Ionis Pharmaceuticals, Inc. Compositions and methods for modulation of ikbkap splicing
KR102521608B1 (en) 2013-03-14 2023-04-14 사렙타 쎄러퓨틱스 인코퍼레이티드 Exon skipping compositions for treating muscular dystrophy
KR20200139271A (en) 2013-03-15 2020-12-11 사렙타 쎄러퓨틱스 인코퍼레이티드 Improved compositions for treating muscular dystrophy
NO344051B1 (en) * 2017-05-04 2019-08-26 Patogen As Novel virus in Fish and Method for detection

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69431631T2 (en) * 1993-09-20 2003-07-31 Celtrix Pharma TREATMENT OF HEMATOLOGICAL DISORDERS WITH AN IGF-1 / IGFBP-3 COMPLEX
AUPM672594A0 (en) * 1994-07-08 1994-08-04 Royal Children's Hospital Research Foundation A method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders
AU692278B2 (en) * 1994-07-08 1998-06-04 Murdoch Childrens Research Institute, The A method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders
SE9501472D0 (en) * 1995-04-21 1995-04-21 Pharmacia Ab Truncated IGF-I

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