CN116157522A - A1cf抑制剂用于治疗乙型肝炎病毒感染的用途 - Google Patents
A1cf抑制剂用于治疗乙型肝炎病毒感染的用途 Download PDFInfo
- Publication number
- CN116157522A CN116157522A CN202180051604.7A CN202180051604A CN116157522A CN 116157522 A CN116157522 A CN 116157522A CN 202180051604 A CN202180051604 A CN 202180051604A CN 116157522 A CN116157522 A CN 116157522A
- Authority
- CN
- China
- Prior art keywords
- nucleic acid
- a1cf
- acid molecule
- seq
- hbv
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 88
- 238000011282 treatment Methods 0.000 title claims abstract description 42
- 208000002672 hepatitis B Diseases 0.000 title description 6
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 324
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 324
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 324
- 230000000295 complement effect Effects 0.000 claims abstract description 89
- 208000015181 infectious disease Diseases 0.000 claims abstract description 69
- 108020004999 messenger RNA Proteins 0.000 claims abstract description 61
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 39
- 230000001684 chronic effect Effects 0.000 claims abstract description 20
- 101000799953 Homo sapiens APOBEC1 complementation factor Proteins 0.000 claims abstract description 18
- 108091034117 Oligonucleotide Proteins 0.000 claims description 206
- 125000003729 nucleotide group Chemical group 0.000 claims description 184
- 239000002773 nucleotide Substances 0.000 claims description 180
- 241000700721 Hepatitis B virus Species 0.000 claims description 157
- 125000003835 nucleoside group Chemical group 0.000 claims description 134
- 239000002777 nucleoside Substances 0.000 claims description 126
- 150000001875 compounds Chemical class 0.000 claims description 81
- 108020004459 Small interfering RNA Proteins 0.000 claims description 75
- 239000002924 silencing RNA Substances 0.000 claims description 70
- 108020004414 DNA Proteins 0.000 claims description 67
- 239000000074 antisense oligonucleotide Substances 0.000 claims description 54
- 238000012230 antisense oligonucleotides Methods 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 54
- 125000006850 spacer group Chemical group 0.000 claims description 45
- 108091027967 Small hairpin RNA Proteins 0.000 claims description 33
- 239000004055 small Interfering RNA Substances 0.000 claims description 31
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- 230000002829 reductive effect Effects 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 19
- 108020000948 Antisense Oligonucleotides Proteins 0.000 claims description 18
- 230000009368 gene silencing by RNA Effects 0.000 claims description 16
- 150000004713 phosphodiesters Chemical class 0.000 claims description 16
- 230000002401 inhibitory effect Effects 0.000 claims description 15
- 102000048197 human A1CF Human genes 0.000 claims description 14
- 238000001727 in vivo Methods 0.000 claims description 14
- 238000000338 in vitro Methods 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 5
- 108020004638 Circular DNA Proteins 0.000 claims description 4
- 208000037581 Persistent Infection Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- OVRNDRQMDRJTHS-KEWYIRBNSA-N N-acetyl-D-galactosamine Chemical group CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-KEWYIRBNSA-N 0.000 claims 4
- 108091030071 RNAI Proteins 0.000 claims 1
- 230000000368 destabilizing effect Effects 0.000 abstract description 4
- 102100033311 APOBEC1 complementation factor Human genes 0.000 abstract 4
- 210000004027 cell Anatomy 0.000 description 93
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 56
- 241000282414 Homo sapiens Species 0.000 description 53
- 150000003833 nucleoside derivatives Chemical class 0.000 description 47
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 41
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 39
- 125000005647 linker group Chemical group 0.000 description 31
- 102000005427 Asialoglycoprotein Receptor Human genes 0.000 description 27
- 108010006523 asialoglycoprotein receptor Proteins 0.000 description 27
- 239000000203 mixture Substances 0.000 description 27
- 108090000623 proteins and genes Proteins 0.000 description 27
- 230000000692 anti-sense effect Effects 0.000 description 23
- 102000004169 proteins and genes Human genes 0.000 description 23
- 230000005764 inhibitory process Effects 0.000 description 22
- -1 LNA (see Chemical class 0.000 description 21
- 230000000694 effects Effects 0.000 description 21
- 230000008685 targeting Effects 0.000 description 21
- 230000027455 binding Effects 0.000 description 18
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 15
- 108091027974 Mature messenger RNA Proteins 0.000 description 14
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical group CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 description 14
- 238000013461 design Methods 0.000 description 13
- 230000004048 modification Effects 0.000 description 13
- 238000012986 modification Methods 0.000 description 13
- 230000009467 reduction Effects 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 101710163270 Nuclease Proteins 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 11
- 210000003494 hepatocyte Anatomy 0.000 description 11
- 238000009396 hybridization Methods 0.000 description 11
- 210000004185 liver Anatomy 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- 102000000574 RNA-Induced Silencing Complex Human genes 0.000 description 10
- 108010016790 RNA-Induced Silencing Complex Proteins 0.000 description 10
- 230000003612 virological effect Effects 0.000 description 10
- 241000711549 Hepacivirus C Species 0.000 description 9
- 108091028043 Nucleic acid sequence Proteins 0.000 description 9
- 238000011529 RT qPCR Methods 0.000 description 9
- 108091081021 Sense strand Proteins 0.000 description 9
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 9
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 9
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 7
- 229940104302 cytosine Drugs 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000001890 transfection Methods 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 101710142246 External core antigen Proteins 0.000 description 6
- 102100034343 Integrase Human genes 0.000 description 6
- 102100040018 Interferon alpha-2 Human genes 0.000 description 6
- 241000282567 Macaca fascicularis Species 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 150000001720 carbohydrates Chemical group 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000003776 cleavage reaction Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 230000003834 intracellular effect Effects 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 238000004007 reversed phase HPLC Methods 0.000 description 6
- 230000007017 scission Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 description 5
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 101710203526 Integrase Proteins 0.000 description 5
- 108010047761 Interferon-alpha Proteins 0.000 description 5
- 102000006992 Interferon-alpha Human genes 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
- 239000013592 cell lysate Substances 0.000 description 5
- 230000003833 cell viability Effects 0.000 description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
- 229960000980 entecavir Drugs 0.000 description 5
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 5
- 229930182830 galactose Natural products 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 5
- 239000000178 monomer Substances 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 230000010076 replication Effects 0.000 description 5
- 230000028327 secretion Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 229940035893 uracil Drugs 0.000 description 5
- 102000012758 APOBEC-1 Deaminase Human genes 0.000 description 4
- 108010079649 APOBEC-1 Deaminase Proteins 0.000 description 4
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 4
- 229930024421 Adenine Natural products 0.000 description 4
- 101710095342 Apolipoprotein B Proteins 0.000 description 4
- 102100040202 Apolipoprotein B-100 Human genes 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 4
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 4
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 4
- 125000004103 aminoalkyl group Chemical group 0.000 description 4
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 239000002299 complementary DNA Substances 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 230000000593 degrading effect Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 210000005260 human cell Anatomy 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 4
- 208000019423 liver disease Diseases 0.000 description 4
- 210000004962 mammalian cell Anatomy 0.000 description 4
- 150000008300 phosphoramidites Chemical class 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 238000011321 prophylaxis Methods 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 description 4
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 229940021747 therapeutic vaccine Drugs 0.000 description 4
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 3
- 101150063318 A1CF gene Proteins 0.000 description 3
- 108091023037 Aptamer Proteins 0.000 description 3
- 108020004705 Codon Proteins 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 3
- 108010078049 Interferon alpha-2 Proteins 0.000 description 3
- 108010079944 Interferon-alpha2b Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 229960001997 adefovir Drugs 0.000 description 3
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 3
- 229960000643 adenine Drugs 0.000 description 3
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 3
- 238000009175 antibody therapy Methods 0.000 description 3
- 239000003443 antiviral agent Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 230000007882 cirrhosis Effects 0.000 description 3
- 208000019425 cirrhosis of liver Diseases 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- 239000013068 control sample Substances 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000009509 drug development Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229960001627 lamivudine Drugs 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 238000002515 oligonucleotide synthesis Methods 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 229960000329 ribavirin Drugs 0.000 description 3
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- XGDRLCRGKUCBQL-UHFFFAOYSA-N 1h-imidazole-4,5-dicarbonitrile Chemical compound N#CC=1N=CNC=1C#N XGDRLCRGKUCBQL-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 2
- KXTUJUVCAGXOBN-WQXQQRIOSA-N 2-methyl-N-[(3R,4R,5R,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]propanamide Chemical compound CC(C)C(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O KXTUJUVCAGXOBN-WQXQQRIOSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 2
- 102000000844 Cell Surface Receptors Human genes 0.000 description 2
- 108010001857 Cell Surface Receptors Proteins 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 108020004394 Complementary RNA Proteins 0.000 description 2
- 102000005381 Cytidine Deaminase Human genes 0.000 description 2
- 108010031325 Cytidine deaminase Proteins 0.000 description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 2
- 238000013382 DNA quantification Methods 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 238000008157 ELISA kit Methods 0.000 description 2
- 108010042407 Endonucleases Proteins 0.000 description 2
- 108700039887 Essential Genes Proteins 0.000 description 2
- 108700024394 Exon Proteins 0.000 description 2
- 101100489752 Homo sapiens A1CF gene Proteins 0.000 description 2
- 101001075561 Homo sapiens Rho GTPase-activating protein 32 Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108091092195 Intron Proteins 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- 229930182821 L-proline Natural products 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- FVMMQJUBNMOPPR-WLDMJGECSA-N N-[(3R,4R,5R,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]formamide Chemical compound OC[C@H]1OC(O)[C@H](NC=O)[C@@H](O)[C@H]1O FVMMQJUBNMOPPR-WLDMJGECSA-N 0.000 description 2
- RTEOJYOKWPEKKN-HXQZNRNWSA-N N-[(3R,4R,5R,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]propanamide Chemical compound CCC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O RTEOJYOKWPEKKN-HXQZNRNWSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 108091093037 Peptide nucleic acid Proteins 0.000 description 2
- 102100020900 Rho GTPase-activating protein 32 Human genes 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 108010067390 Viral Proteins Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000003184 complementary RNA Substances 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- NAGJZTKCGNOGPW-UHFFFAOYSA-K dioxido-sulfanylidene-sulfido-$l^{5}-phosphane Chemical compound [O-]P([O-])([S-])=S NAGJZTKCGNOGPW-UHFFFAOYSA-K 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000002222 downregulating effect Effects 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 150000002256 galaktoses Chemical class 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 230000030279 gene silencing Effects 0.000 description 2
- 238000003306 harvesting Methods 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 238000012606 in vitro cell culture Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000000111 isothermal titration calorimetry Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 238000007899 nucleic acid hybridization Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 102000054765 polymorphisms of proteins Human genes 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- 229960002429 proline Drugs 0.000 description 2
- 229940021993 prophylactic vaccine Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 238000000090 raster image correlation spectroscopy Methods 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 108010052833 ribonuclease HI Proteins 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 229960005311 telbivudine Drugs 0.000 description 2
- 229940104230 thymidine Drugs 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 229940113082 thymine Drugs 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 238000003026 viability measurement method Methods 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- XQCZBXHVTFVIFE-UHFFFAOYSA-N 2-amino-4-hydroxypyrimidine Chemical compound NC1=NC=CC(O)=N1 XQCZBXHVTFVIFE-UHFFFAOYSA-N 0.000 description 1
- HBJGQJWNMZDFKL-UHFFFAOYSA-N 2-chloro-7h-purin-6-amine Chemical compound NC1=NC(Cl)=NC2=C1NC=N2 HBJGQJWNMZDFKL-UHFFFAOYSA-N 0.000 description 1
- KMEMIMRPZGDOMG-UHFFFAOYSA-N 2-cyanoethoxyphosphonamidous acid Chemical compound NP(O)OCCC#N KMEMIMRPZGDOMG-UHFFFAOYSA-N 0.000 description 1
- 108020005065 3' Flanking Region Proteins 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 108020005029 5' Flanking Region Proteins 0.000 description 1
- LQLQRFGHAALLLE-UHFFFAOYSA-N 5-bromouracil Chemical compound BrC1=CNC(=O)NC1=O LQLQRFGHAALLLE-UHFFFAOYSA-N 0.000 description 1
- UJBCLAXPPIDQEE-UHFFFAOYSA-N 5-prop-1-ynyl-1h-pyrimidine-2,4-dione Chemical compound CC#CC1=CNC(=O)NC1=O UJBCLAXPPIDQEE-UHFFFAOYSA-N 0.000 description 1
- QSHQKIURKJITMZ-OBUPQJQESA-N 5β-cholane Chemical compound C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCC)[C@@]2(C)CC1 QSHQKIURKJITMZ-OBUPQJQESA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VKKXEIQIGGPMHT-UHFFFAOYSA-N 7h-purine-2,8-diamine Chemical compound NC1=NC=C2NC(N)=NC2=N1 VKKXEIQIGGPMHT-UHFFFAOYSA-N 0.000 description 1
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 102000008682 Argonaute Proteins Human genes 0.000 description 1
- 108010088141 Argonaute Proteins Proteins 0.000 description 1
- 231100000699 Bacterial toxin Toxicity 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102100040397 C->U-editing enzyme APOBEC-1 Human genes 0.000 description 1
- 101710189531 C->U-editing enzyme APOBEC-1 Proteins 0.000 description 1
- 108091079001 CRISPR RNA Proteins 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 206010057573 Chronic hepatic failure Diseases 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 101150018489 DNA-C gene Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 208000010334 End Stage Liver Disease Diseases 0.000 description 1
- 102100031780 Endonuclease Human genes 0.000 description 1
- 102000004533 Endonucleases Human genes 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108060002716 Exonuclease Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 241000285387 HBV genotype A Species 0.000 description 1
- 241000285452 HBV genotype B Species 0.000 description 1
- 241000285424 HBV genotype C Species 0.000 description 1
- 241000285366 HBV genotype D Species 0.000 description 1
- 241000285370 HBV genotype E Species 0.000 description 1
- 241000285563 HBV genotype F Species 0.000 description 1
- 241000285576 HBV genotype G Species 0.000 description 1
- 241000285579 HBV genotype H Species 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 102100023999 Heterogeneous nuclear ribonucleoprotein R Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000964330 Homo sapiens C->U-editing enzyme APOBEC-1 Proteins 0.000 description 1
- 101001047853 Homo sapiens Heterogeneous nuclear ribonucleoprotein R Proteins 0.000 description 1
- 101000693243 Homo sapiens Paternally-expressed gene 3 protein Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- MIJPAVRNWPDMOR-ZAFYKAAXSA-N L-ascorbic acid 2-phosphate Chemical compound OC[C@H](O)[C@H]1OC(=O)C(OP(O)(O)=O)=C1O MIJPAVRNWPDMOR-ZAFYKAAXSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 241000283923 Marmota monax Species 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- 101100377883 Mus musculus Apobec1 gene Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 102100025757 Paternally-expressed gene 3 protein Human genes 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102000044126 RNA-Binding Proteins Human genes 0.000 description 1
- 108700020471 RNA-Binding Proteins Proteins 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 108091027544 Subgenomic mRNA Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 108020005038 Terminator Codon Proteins 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 108020000411 Toll-like receptor Proteins 0.000 description 1
- 208000026487 Triploidy Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000005600 alkyl phosphonate group Chemical group 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940125714 antidiarrheal agent Drugs 0.000 description 1
- 239000003793 antidiarrheal agent Substances 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 229940125687 antiparasitic agent Drugs 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000000688 bacterial toxin Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 210000000234 capsid Anatomy 0.000 description 1
- 229940124765 capsid inhibitor Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 208000011444 chronic liver failure Diseases 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000001687 destabilization Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 102000013165 exonuclease Human genes 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000010230 functional analysis Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000001553 hepatotropic effect Effects 0.000 description 1
- 150000002402 hexoses Chemical group 0.000 description 1
- 102000046390 human APOBEC1 Human genes 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229940002988 pegasys Drugs 0.000 description 1
- 108010092853 peginterferon alfa-2a Proteins 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- 229960004946 tenofovir alafenamide Drugs 0.000 description 1
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 description 1
- 229960001355 tenofovir disoproxil Drugs 0.000 description 1
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000006177 thiolation reaction Methods 0.000 description 1
- ZEMGGZBWXRYJHK-UHFFFAOYSA-N thiouracil Chemical compound O=C1C=CNC(=S)N1 ZEMGGZBWXRYJHK-UHFFFAOYSA-N 0.000 description 1
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
- A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
- A61K48/0033—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being non-polymeric
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/11—Antisense
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- General Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Physics & Mathematics (AREA)
- Biophysics (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及一种A1CF抑制剂，其在HBV感染，特别是慢性HBV感染的治疗中使用。本发明特别地涉及A1CF抑制剂用于使cccDNA，诸如HBV cccDNA去稳定的用途。本发明还涉及与A1CF互补并且能够降低A1CF mRNA的水平的核酸分子。本发明还包括一种药物组合物及其在HBV感染的治疗中的用途。
Description
技术领域
本发明涉及A1CF抑制剂，其在乙型肝炎病毒(HBV)感染，特别是慢性HBV感染的治疗中使用。本发明特别地涉及A1CF抑制剂用于使cccDNA，诸如HBV cccDNA去稳定的用途。本发明还涉及核酸分子，诸如包括siRNA、shRNA和反义寡核苷酸的寡核苷酸，该寡核苷酸与A1CF互补并且能够降低A1CF的表达。本发明还包括一种药物组合物及其在HBV感染的治疗中的用途。
背景技术
乙型肝炎是一种由乙型肝炎病毒(HBV)引起的传染病，乙型肝炎病毒是一种小型的嗜肝病毒，其可通过反转录复制。慢性HBV感染是导致严重肝病(诸如肝硬化和肝细胞癌)的关键因素。目前对慢性HBV感染的治疗是基于施用聚乙二醇化的1型干扰素或核苷(核苷酸)类似物的，诸如拉米夫定、阿德福韦、恩替卡韦、替诺福韦二吡呋酯和替诺福韦艾拉酚胺，它们可靶向病毒聚合酶(一种多功能反转录酶)。治疗是否成功通常以乙型肝炎表面抗原(HBsAg)的损失量来衡量。然而，由于感染后乙型肝炎病毒DNA仍然存在于体内，因此很难完全清除HBsAg。HBV持续性是由附加体形式的HBV基因组介导的，该基因组稳定地存在于细胞核中。这种附加体形式被称为“共价闭合环状DNA”(cccDNA)。cccDNA可作为所有HBV转录本的模板，包括前基因组RNA(pgRNA，一种病毒复制中间体)。少量cccDNA拷贝的存在可能足以再次引发全面的HBV感染。目前对HBV的治疗并不针对cccDNA。然而，慢性HBV感染的治愈需要消除cccDNA(由Nassal,Gut.2015年12月；64(12):1972-84.doi:10.1136/Gutjnl-2015-309809综述)。
A1CF(APOBEC1complementation factor(互补因子))是载脂蛋白B mRNA编辑酶复合物(负责将Gln的CAA密码子转录后编辑为UAA密码子以终止载脂蛋白B mRNA)的组分。将终止密码子引入载脂蛋白B mRNA会改变胃肠道中的脂质代谢。编辑酶复合物包含由胞苷脱氨酶APOBEC-1(载脂蛋白B mRNA编辑酶1)组成的最小核心和由A1CF基因编码的互补因子。A1CF蛋白具有三个不相同的RNA识别基序并且属于RNA结合蛋白的hnRNP R家族。它与载脂蛋白B mRNA结合并且可能负责将催化亚基APOBEC1与mRNA对接，以使其脱氨其靶标胞嘧啶(参见Chester等人,EMBO J.2003Aug1；22(15):3971-82)。
关于载脂蛋白B mRNA编辑酶复合物的许多报道都集中在胞苷脱氨酶APOBEC1上，而不是在APOBEC1互补因子上。已经表明，APOBEC1不仅编辑载脂蛋白B mRNA，还编辑包括HBV的病毒基因组。
在HBV复制的小鼠模型中，Renard等人表明小鼠APOBEC1在体内编辑HBV(Renard等人,J Mol Biol.2010Jul 16；400(3):323-34.doi:10.1016/j.jmb.2010.05.029)。相反，大鼠APOBEC1不抑制HBV DNA产生(
等人,Hepatology.2005Aug；42(2):301-9)。
Gonzalez等人表明人APOBEC1编辑HBV DNA。在用HBV和人APOBEC1共转染的细胞中，在HBV基因组中识别到几个G到A超突变。此外，人APOBEC1的存在影响了HBV DNA的复制。具体而言，已表明APOBEC1的表达增加导致HBV DNA量减少(Gonzalez等人,Retrovirology.2009Oct 21；6:96.doi:10.1186/1742-4690-6-96)。
据我们所知，在cccDNA的稳定性和维持性方面，从未将A1CF识别为cccDNA依赖性因子，也没有有人提出将抑制A1CF的分子用作cccDNA去稳定剂用于治疗HBV感染。
此外，据我们所知，WO 2016/142948中提出了可能与A1CF表达的调节相关的寡核苷酸的唯一公开。然而，WO 2016/142948涉及改变包括A1CF的许多列出的目标的剪接，以产生可变剪接变体。然而，寡核苷酸是编码剪接因子结合位点的诱饵寡核苷酸，并且因此不与这样的目标结合。WO 2016/142948还提到了一系列治疗，其包括：癌症、炎症、免疫紊乱、神经退行性变、阿尔茨海默病、帕金森病、病毒感染(HIV、HSV、HBV)。然而，没有靶向A1CF的寡核苷酸及其在HBV中的用途的具体实例。
发明目的
本发明表明，在HBV感染细胞中A1CF的抑制与cccDNA的量的减少之间存在关联，其与HBV感染者的治疗有关。本发明的目的是识别减少HBV感染细胞中cccDNA的量的A1CF抑制剂。此类A1CF抑制剂可用于治疗HBV感染。
本发明进一步识别了新型核酸分子，其能够在体外和体内抑制A1CF的表达。
发明内容
本发明涉及靶向核酸的寡核苷酸，所述寡核苷酸能够调节A1CF的表达并治疗或预防与A1CF功能有关的疾病。
因此，一方面，本发明提供了一种A1CF抑制剂，其在治疗乙型肝炎病毒(HBV)感染的治疗和/或预防中使用。特别地，一种能够减少HBV cccDNA和/或HBV前基因组RNA(pgRNA)的量的A1CF抑制剂是有用的。此类抑制剂有利为长度是12个至60个核苷酸的核酸分子，该核酸分子能够减少A1CF mRNA。
在另一方面，本发明涉及12个至60个核苷酸(诸如12个至30个核苷酸)的核酸分子，其包含与哺乳动物A1CF(例如人A1CF、小鼠A1CF或食蟹猴A1CF)至少90％互补(诸如完全互补)的至少10个核苷酸(特别是16个至20个核苷酸)的连续核苷酸序列。此类核酸分子能够在表达A1CF的细胞中抑制A1CF的表达。抑制A1CF允许细胞中存在的cccDNA的量减少。核酸分子可以选自单链反义寡核苷酸、双链siRNA分子或shRNA核酸分子(特别是过化学方法产生的shRNA分子)。
本发明的另一方面涉及抑制A1CF的表达和/或活性的单链反义寡核苷酸或siRNA’s。特别地，包含一个或多个2'糖修饰的核苷和一个或多个硫代磷酸酯键合的经修饰的反义寡核苷酸或经修饰的siRNA(其减少A1CF mRNA)是有利的。
在另一方面，本发明提供药物组合物，该药物组合物包含本发明的A1CF抑制剂，诸如本发明的反义寡核苷酸或siRNA以及药用赋形剂。
在另一方面，本发明提供了用于调节表达A1CF的靶细胞中的A1CF表达的体内或体外方法，该方法通过以有效量向所述细胞施用本发明的A1CF抑制剂(诸如本发明的反义寡核苷酸或组合物)来实施。在一些实施例中，与未经任何处理或经对照物处理的水平相比，靶细胞中的A1CF表达降低了至少50％、或至少60％、或至少70％、或至少80％。在一些实施例中，靶细胞被HBV感染，并且在HBV感染靶细胞中，与未经任何处理或经对照物处理的水平相比，HBV感染细胞中的cccDNA减少了至少50％、或至少60％、或至少70％。在一些实施例中，靶细胞被HBV感染，并且与未经任何处理或经对照物处理的水平相比，在HBV感染靶细胞中，HBV感染细胞中的pgRNA减少了至少50％、或至少60％。
在另一方面，本发明提供了用于治疗或预防与A1CF的体内活性相关联的疾病、疾患或功能障碍的方法，该方法包括向患有或易患该疾病、疾患或功能障碍的受试者施用治疗或预防有效量的本发明的A1CF抑制剂(诸如本发明的反义寡核苷酸或siRNA)。
本发明的其他方面是本发明的核酸分子与药物组合物的缀合物，该缀合物包含本发明的分子。特别关注靶向肝脏的缀合物，诸如GalNAc簇。
附图说明
图1A-L：说明了示例性反义寡核苷酸缀合物，其中寡核苷酸由术语“寡核苷酸”表示，并且脱唾液酸糖蛋白受体靶向缀合物部分为三价N-乙酰半乳糖胺部分。图1A-D中的化合物包含二赖氨酸支链分子，PEG3间隔物和三个末端GalNAc碳水化合物部分。在图1A(图1A-1和图1A-2示出了同一化合物的两种不同非对映异构体)和图1B(图1B-1和图1B-2示出了同一化合物的两种不同非对映异构体)的化合物中，寡核苷酸在无接头的情况下直接连接至脱唾液酸糖蛋白受体靶向缀合物部分。在图1C(图1C-1和图1C-2示出了同一化合物的两种不同非对映异构体)和图1D(图1D-1和图1D-2示出了同一化合物的两种不同非对映异构体)的化合物中，寡核苷酸经由C6接头连接至脱唾液酸糖蛋白受体靶向缀合物部分。图1E-K中的化合物包含可商业获得的三倍体支链分子和不同长度和结构的间隔物以及三个末端GalNAc碳水化合物部分。图1L中的化合物由单体GalNAc亚磷酰胺组成，该亚磷酰胺作为合成的一部分添加至寡核苷酸，同时仍在固体支持物上，其中X＝S或O且独立地Y＝S或O并且n＝1至3(参见WO 2017/178656)。图1B和图1D在本文中也被称为GalNAc2或GN2，其分别不带有和带有C6接头。
图1A-D中示出的两种不同非对映异构体为缀合反应的结果。因此，特异性反义寡核苷酸缀合物池可以仅包含两种不同非对映异构体中的一种非对映异构体，或者特异性反义寡核苷酸缀合物池可以包含两种不同非对映异构体的混合物。
定义
HBV感染
术语“乙型肝炎病毒感染”或“HBV感染”在本领域中是公知的，是指由乙型肝炎病毒(HBV)引起并影响肝脏的传染病。HBV感染可以是急性或慢性感染。慢性乙型肝炎病毒(CHB)感染是一种全球性疾病难题，影响着全球2.48亿人。每年约有686,000例死亡归因于HBV相关的晚期肝病和肝细胞癌(HCC)(GBD 2013；Schweitzer等人,Lancet.2015Oct 17；386(10003):1546-55)。WHO预测，如果不加大干预措施，未来40至50年内，CHB感染者的人数将保持在目前的高水平，2015年至2030年之间累计死亡人数将达到2000万(WHO 2016)。CHB感染不是具有单一临床表现的同质性疾病。感染者在其一生中经历了与CHB相关的肝病的几个阶段，这些疾病阶段也是采用标准护理(SOC)治疗的基础。目前的指南建议基于三个标准(血清ALT水平、HBV DNA水平和肝病严重程度)，仅对选定的CHB感染者进行治疗(EASL，2017)。该建议归因于SOC(即核苷(核苷酸)类似物(NAs)和聚乙二醇化干扰素-α(PEG-IFN))无法治愈，必须长期施用从而增加其安全风险的事实。NAs可以有效抑制HBV DNA复制；然而，它们对其他病毒标记物的作用非常有限/没有影响。HBV感染的两个标志，即乙型肝炎表面抗原(HBsAg)和共价闭合环状DNA(cccDNA)，是针对治愈HBV的新药的主要目标。在CHB个体的血浆中，HBsAg亚病毒(空)颗粒数超过HBV病毒粒子103至105倍(Ganem&Prince，N EnglJ Med.2004Mar 11；350(11):1118-29)；据信，其过量可能导致该疾病的免疫发病机制，包括个体无法产生中和性抗HBs抗体，这是在急性HBV感染消退后观察到的血清学标记物。
在一些实施例中，术语“HBV感染”是指“慢性HBV感染”。
此外，该术语涵盖任何HBV基因型感染。
在一些实施例中，待治疗的患者被HBV基因型A感染。
在一些实施例中，待治疗的患者被HBV基因型B感染。
在一些实施例中，待治疗的患者被HBV基因型C感染。
在一些实施例中，待治疗的患者被HBV基因型D感染。
在一些实施例中，待治疗的患者被HBV基因型E感染。
在一些实施例中，待治疗的患者被HBV基因型F感染。
在一些实施例中，待治疗的患者被HBV基因型G感染。
在一些实施例中，待治疗的患者被HBV基因型H感染。
在一些实施例中，待治疗的患者被HBV基因型I感染。
在一些实施例中，待治疗的患者被HBV基因型J感染。
cccDNA(共价闭合环状DNA)
cccDNA是位于感染的肝细胞细胞核中的HBV的病毒遗传模板，其中它会产生增值性感染所需的所有HBV RNA转录本，并且在慢性HBV感染的自然过程中负责病毒的持续性(Locarnini&Zoulim，Antivir Ther.2010；15Suppl3:3-14.doi:10.3851/IMP1619)。cccDNA用作病毒库，是停止治疗后病毒反弹的来源，因此需要长期(通常是终生)治疗。由于各种副作用，因此PEG-IFN仅可施用于一小部分CHB。
因此，大多数CHB患者迫切需要新的治疗方法，即通过降解或清除HBV cccDNA来实现完全治愈。
化合物
在本文中，术语“化合物”是指能够抑制A1CF表达或活性的任何分子。本发明的特别化合物是核酸分子，诸如根据本发明的RNAi分子或反义寡核苷酸或包含这种核酸分子的任何缀合物。例如，本文中化合物可以是靶向A1CF的核酸分子，特别是反义寡核苷酸或siRNA。
寡核苷酸
如本文所用，术语“寡核苷酸”如本领域技术人员通常理解的那样被定义为包含两个或更多个共价连接的核苷的分子。此类共价结合的核苷也可被称为核酸分子或寡聚物。
说明书和权利要求书中提及的寡核苷酸通常是长度小于70个核苷酸的治疗性寡核苷酸。寡核苷酸可以是或者可以包含单链反义寡核苷酸，或者可以是另一种核酸分子，诸如CRISPR RNA、siRNA、shRNA、适体或核酶。治疗性寡核苷酸分子通常在实验室中通过固相化学合成然后纯化和分离来制备。然而，shRNA通常使用慢病毒载体传递至细胞中，然后从慢病毒载体中转录以产生单链RNA，该单链RNA将形成茎环(发夹)RNA结构，该结构能够与RNA干扰机制(包括RNA诱导沉默复合物(RISC))交互作用。在本发明的实施例中，shRNA是通过化学方法产生的shRNA分子(不依赖于来自质粒或病毒的基于细胞的表达)。当提及寡核苷酸的序列时，提及的是共价联接的核苷酸或核苷的核碱基部分或其修饰的序列或顺序。通常，本发明的寡核苷酸是人造的，并且是化学合成的，并且通常是纯化或分离的。尽管在一些实施例中，本发明的寡核苷酸是在进入靶细胞时从载体转录的shRNA。本发明的寡核苷酸可包含一个或多个经修饰的核苷或核苷酸。
在一些实施例中，本发明的寡核苷酸包含或由长度为10个至70个核苷酸组成，诸如长度为12个至60个、诸如13个至50个、诸如14个至40个、诸如15个至30个、诸如16个至25个、诸如16个至22个、诸如16个至20个连续核苷酸。因此，在一些实施例中，本发明的寡核苷酸长度可为12个至25个核苷酸。替代地，在一些实施例中，本发明的寡核苷酸长度可为15个至22个核苷酸。
在一些实施例中，寡核苷酸或其连续核苷酸序列包含或由24个或更少的核苷酸组成，诸如22个、诸如20个或更少、诸如18个或更少、诸如14个、15个、16个或17个核苷酸。应当理解的是，本文中给出的任何范围均包括范围的端点。因此，如果说核酸分子包含12至25个核苷酸，则12和25个核苷酸均包含在内。
在一些实施例中，连续核苷酸序列包含或由长度为12个、13个、14个、15个、16个、17个、18个、19个、20个、21个或22个连续核苷酸组成
寡核苷酸用于调节哺乳动物中靶核酸的表达。在一些实施例中，核酸分子，例如siRNA、shRNA和反义寡核苷酸的核酸分子通常用于抑制靶核酸的表达。
在本发明的一个实施例中，寡核苷酸选自RNAi剂，诸如siRNA或shRNA。在另一个实施例中，寡核苷酸是单链反义寡核苷酸，诸如与RNA酶H交互作用的高亲和力修饰的反义寡核苷酸。
在一些实施例中，本发明的寡核苷酸可包含一个或多个修饰的核苷或核苷酸，例如2'糖修饰的核苷。
在一些实施例中，寡核苷酸包含硫代磷酸酯核苷间键。
在一些实施例中，寡核苷酸可以缀合至非核苷部分(缀合物部分)。
寡核苷酸文库应理解为变异寡核苷酸的集合。寡核苷酸文库的目的可以变化。在一些实施例中，寡核苷酸文库由具有重叠核碱基序列的寡核苷酸组成，该序列靶向一个或多个哺乳动物A1CF靶核酸，目的是识别寡核苷酸文库中最有效的序列。在一些实施例中，寡核苷酸文库是亲代或祖代寡核苷酸的寡核苷酸设计变体(子核酸分子)文库，其中寡核苷酸设计变体保留了亲代核酸分子的核心核碱基序列。
反义寡核苷酸
如本文所用，术语“反义寡核苷酸”或“ASO”定义为能够通过与靶核酸，特别是与靶核酸上的连续序列杂交来调节靶基因的表达的寡核苷酸。反义寡核苷酸基本上不为双链的，因此不为siRNA或shRNA。优选地，本发明的反义寡核苷酸为单链的。应当理解的是，本发明的单链寡核苷酸可以形成发夹或分子间双链体结构(同一寡核苷酸的两个分子之间的双链体)，只要其内部或相互间的自身互补程度小于寡核苷酸全长的50％。
优选地，本发明的单链反义寡核苷酸不包含RNA核苷，因为这将降低核酸酶抗性。
优选地，本发明的寡核苷酸包含一个或多个修饰的核苷或核苷酸，诸如2'糖修饰的核苷。此外，优选的是未修饰的核苷是DNA核苷。
RNAi分子
在本文中，术语“RNA干扰(RNA interference,RNAi)分子”是指含有RNA核苷的短双链寡核苷酸，该短双链寡核苷酸经由RNA诱导的沉默复合物(RNA-induced silencingcomplex,RISC)介导RNA转录物的靶向切割，其中它们与催化性RISC组分argonaute相互作用。RNAi分子调节，例如，抑制靶核酸在细胞(例如受试者，诸如哺乳动物受试者体内的细胞)中的表达。RNAi分子包括单链RNAi分子(Lima等人2012Cell 150:883)和双链siRNA，以及短发夹RNA(shRNA)。在本发明的一些实施例中，本发明的寡核苷酸或其连续核苷酸序列是RNAi剂，诸如siRNA。
siRNA
术语“小干扰核糖核酸”或“siRNA”是指小干扰核糖核酸RNAi分子。它是一类双链RNA分子，在本领域中也称为短干扰RNA或沉默RNA。siRNA通常包含有义链(也称为过客链)和反义链(也称为引导链)，其中每条链的长度为17至30个核苷酸，通常为19至25个核苷，其中反义链与靶核酸(合适地是成熟的mRNA序列)互补，诸如至少95％互补，诸如完全互补，并且有义链与反义链互补，使得有义链和反义链形成双链体或双链体区域。siRNA链可形成平末端双链体，或者优选地，正义和反义链的3'端可形成3'突出端，例如1个、2个或3个核苷，类似于Dicer生产的产物，可在体内形成RISC底物。Dicer底物的有效扩展形式已在US 8,349,809和US 8,513,207中进行了描述，在此通过引用并入。在一些实施例中，正义链和反义链均具有2nt 3'突出端。因此，双链体区域的长度可以是例如17至25个核苷酸，诸如长度是21至23个核苷酸。
一旦进入细胞内，反义链就被掺入到RISC复合物中，该RISC复合物介导靶核酸的靶降解或靶抑制。siRNA除了RNA核苷外，通常还包含修饰的核苷。在一个实施例中，siRNA分子可以使用修饰的核苷酸间键和2'糖修饰的核苷进行化学修饰，诸如2′-4'双环核糖修饰的核苷(包括LNA和cET)或2'取代的修饰，如2'-O-烷基-RNA、2'-O-甲基-RNA，2'-烷氧基-RNA、2'-O-甲氧基乙基-RNA(MOE)、2′-氨基-DNA、2′-氟-DNA、阿糖核酸(ANA)、2′-氟-ANA。特别地，可以将2′氟、2′-O-甲基或2′-O-甲氧基乙基掺入siRNA。
在一些实施例中，可以用2′糖修饰的核苷(诸如LNA)修饰siRNA正义(过客)链的所有核苷酸(例如，参见WO2004/083430、WO2007/085485)。在一些实施例中，siRNA的过客链可以是不连续的(例如，参见WO2007/107162)。已经报道了在siRNA的反义链的种子区域中出现的热去稳定核苷酸的掺入可用于减少siRNA的脱靶活性(例如，参见WO2018/098328)。合适地，siRNA在反义链的5'端包含5'磷酸酯基团或5'-磷酸模拟物。在一些实施例中，反义链的5'端是RNA核苷。
在一个实施例中，siRNA分子进一步包含至少一个硫代磷酸酯或甲基膦酸酯核苷间键。硫代磷酸酯或甲基膦酸酯的核苷间键可以在一条或两条链(例如，反义链；或正义链)的3'-末端上；或者硫代磷酸酯或甲基膦酸酯的核苷间键可以在一条或两条链(例如，反义链；或正义链)的5'末端上；或者硫代磷酸酯或甲基膦酸酯的核苷间键可以在一条或两条链(例如反义链；或正义链)的5'-和3'-末端上。在一些实施例中，剩余的核苷间键是磷酸二酯键。在一些实施例中，siRNA分子包含一个或多个硫代磷酸酯核苷间键。在siRNA分子中，硫代磷酸酯核苷间键可能会减少或在RICS中进行核酸酶切割，因此优选的是，并非反义链中的所有核苷间键都被修饰。
siRNA分子可以进一步包含配体。在一些实施例中，配体缀合至正义链的3'端。
对于生物学分布，可将siRNA缀合至靶向配体和/或配制成脂质纳米颗粒。
本发明的其他方面涉及包含这些dsRNA的药物组合物，例如适合用于治疗用途的siRNA分子，以及通过施用dsRNA分子(例如本发明的siRNA)来抑制靶基因表达的方法，例如用于治疗如本文所公开的各种疾病。
shRNA
术语“短发夹RNA”或“shRNA”是指这样的分子，所述分子的长度通常介于40个与70个核苷酸之间，诸如长度介于45个与65个核苷酸之间，诸如长度介于50个与60个核苷酸之间，并形成茎环(发夹)RNA结构，该结构与称为Dicer的核酸内切酶相互作用，据信，Dicer将dsRNA加工成具有特征性的两个碱基3'突出端的19-23个碱基对的短干扰RNA，然后将其掺入RNA诱导的沉默复合物(RISC)中。与适当的靶mRNA结合后，RISC内的一个或多个核酸内切酶切割靶以诱导沉默，shRNA寡核苷酸可以使用修饰的核苷酸间键和2'糖修饰的核苷进行化学修饰，诸如2'-4′双环核糖修饰的核苷(包括LNA和cET)或2'取代的修饰，如2'-O-烷基-RNA、2'-O-甲基-RNA，2′-烷氧基-RNA、2′-O-甲氧基乙基-RNA(MOE)、2′-氨基-DNA、2'-氟-DNA、阿糖核酸(ANA)、2'-氟-ANA。
在一些实施例中，shRNA分子包含一个或多个硫代磷酸酯核苷间键。在RNAi分子中，硫代磷酸酯核苷间键可减少或在RICS中进行核酸酶切割，因此优选的是，并非shRNA分子茎环中的所有核苷间键都被修饰。硫代磷酸酯核苷间键可以有利地位于shRNA分子茎环的3'和/或5'端，特别是在与靶核酸不互补的分子的一部分。然而，shRNA分子的与靶核酸互补的区域也可以在预计通过Dicer切割后会成为3'和/或5′末端部分的前2个至3个核苷间键中被修饰。
连续核苷酸序列
术语“连续核苷酸序列”是指核酸分子的与靶核酸互补的区域。该术语在本文中与术语“连续核碱基序列”和术语“寡核苷酸基序序列”可互换使用。在一些实施例中，寡核苷酸的所有核苷酸构成连续核苷酸序列。在一些实施例中，连续核苷酸序列包括在siRNA分子的前导链中。在一些实施例中，连续核苷酸序列是shRNA分子的部分，其与靶核酸100％互补。在一些实施例中，寡核苷酸包含连续核苷酸序列，诸如F-G-F'间隔聚体区域，并且可以任选地包含其他核苷酸，例如可以用于将官能团(例如用于靶向的缀合物基团)连接至连续核苷酸序列的核苷酸接头区域。核苷酸接头区域可与靶核酸互补或不互补。在一些实施例中，反义寡核苷酸的核碱基序列是连续核苷酸序列。在一些实施例中，连续核苷酸序列与靶核酸100％互补。
核苷酸和核苷
核苷酸和核苷是寡核苷酸和多核苷酸的组成部分，并且出于本发明的目的，包括天然存在的和非天然存在的核苷酸和核苷。在自然界中，核苷酸，诸如DNA和RNA核苷酸包含核糖糖部分、核碱基部分和一个或多个磷酸酯基团(其不存在于核苷中)。核苷和核苷酸也可以可互换地称为“单元”或“单体”。
修饰的核苷
如本文所用，术语“修饰的核苷”或“核苷修饰”是指与等同的DNA或RNA核苷相比，通过引入糖部分或(核)碱基部分的一种或多种修饰而被修饰的核苷。有利地，修饰的核苷中的一个或多个修饰的核苷包含修饰的糖部分。术语修饰的核苷在本文中还可与术语“核苷类似物”或修饰的“单元”或修饰的“单体”互换使用。具有未修饰的DNA或RNA糖部分的核苷在本文中被称为DNA或RNA核苷。在DNA或RNA核苷的碱基区域中具有修饰的核苷如果允许沃森克里克(Watson Crick)碱基配对，则通常仍称为DNA或RNA。
修饰的核苷间键合
如技术人员通常所理解的，术语“修饰的核苷间键合”定义为除磷酸二酯(PO)键合以外的键合，其将两个核苷共价偶联在一起。因此，本发明的寡核苷酸可包含一个或多个修饰的核苷间键，诸如一个或多个硫代磷酸酯核苷间键，或一个或多个二硫代磷酸酯核苷间键。
对于本发明的寡核苷酸，使用硫代磷酸酯核苷间键是优选的。
硫代磷酸酯核苷间键合由于核酸酶抗性、有益的药代动力学和易于制造而特别有用。在一些实施例中，寡核苷酸或其连续核苷酸序列中至少50％的核苷间键是硫代磷酸酯，寡核苷酸或其连续核苷酸序列中的诸如至少60％、诸如至少70％、诸如至少75％、诸如至少80％或诸如至少90％的核苷间键是硫代磷酸酯。在一些实施例中，寡核苷酸或其连续核苷酸序列的全部核苷间键均为硫代磷酸酯。
在一些有利实施例中，寡核苷酸的连续核苷酸序列的所有核苷间键均为硫代磷酸酯，或寡核苷酸的所有核苷间键均为硫代磷酸酯键。
应当认识到，如EP 2 742 135中所公开的，反义寡核苷酸可包含其他核苷间键(除磷酸二酯和硫代磷酸酯以外)，例如烷基膦酸酯/甲基膦酸酯核苷间键，其根据EP 2 742135可以例如以其他方式在DNA硫代磷酸酯的缺口区域中被耐受。
核碱基
术语“核碱基”包括存在于核苷和核苷酸中的嘌呤(例如腺嘌呤和鸟嘌呤)和嘧啶(例如尿嘧啶、胸腺嘧啶和胞嘧啶)部分，它们在核酸杂交中形成氢键。在本发明的上下文中，术语核碱基还包括修饰的核碱基，其可不同于天然存在的核碱基，但在核酸杂交过程中为功能性的。在此上下文中，“核碱基”是指天然存在的核碱基，诸如腺嘌呤、鸟嘌呤、胞嘧啶、胸苷、尿嘧啶、黄嘌呤和次黄嘌呤，以及非天然存在的变体。此类变体例如描述于Hirao等人(2012)，Accounts of Chemical Research，第45卷第2055页和Bergstrom(2009)Current Protocols in Nucleic Acid Chemistry，增刊37 1.4.1中。
在一些实施例中，通过以下方式修饰核碱基部分：将嘌呤或嘧啶改变为修饰的嘌呤或嘧啶，诸如取代的嘌呤或取代的嘧啶，诸如选自异胞嘧啶、假异胞嘧啶、5-甲基胞嘧啶、5-噻唑并-胞嘧啶、5-丙炔基-胞嘧啶、5-丙炔基-尿嘧啶、5-溴尿嘧啶、5-噻唑并-尿嘧啶、2-硫代-尿嘧啶、2’-硫代-胸腺嘧啶、肌苷、二氨基嘌呤、6-氨基嘌呤、2-氨基嘌呤、2,6-二氨基嘌呤和2-氯-6-氨基嘌呤的核碱基。
核碱基部分可由每个相应核碱基的字母代码来表示，例如A、T、G、C或U，其中每个字母可任选地包括具有同等功能的修饰的核碱基。例如，在示例性的寡核苷酸中，核碱基部分选自A、T、G、C和5-甲基胞嘧啶。任选地，对于LNA间隔聚体，可使用5-甲基胞嘧啶LNA核苷。
修饰的寡核苷酸
术语“修饰的寡核苷酸”描述了一种寡核苷酸，其包含一个或多个糖修饰的核苷和/或修饰的核苷间键。术语“嵌合”寡核苷酸是已经在文献中用于描述包含经修饰的核苷和DNA核苷的寡核苷酸的术语。本发明的反义寡核苷酸优选地是嵌合寡核苷酸。
互补性
术语“互补性”或“互补”描述了核苷/核苷酸的Watson-Crick碱基配对的能力。沃森克里克碱基对为鸟嘌呤(G)-胞嘧啶(C)和腺嘌呤(A)-胸腺嘧啶(T)/尿嘧啶(U)。应当理解，寡核苷酸可包含具有修饰的核碱基的核苷，例如经常使用5-甲基胞嘧啶代替胞嘧啶，因此，术语互补性涵盖未修饰的核碱基和修饰的核碱基之间的沃森克里克碱基配对(参见例如Hirao等人(2012)Accounts of Chemical Research，第45卷第2055页和Bergstrom(2009)Current Protocols in Nucleic Acid Chemistry，增刊37 1.4.1)。
如本文所用，术语“互补性百分比”是指核酸分子(例如寡核苷酸)中连续核苷酸序列的与参考序列(例如靶序列或序列基序)互补的核苷酸比例(以百分比表示)，该核酸分子跨连续核苷酸序列。因此，通过计数两个序列之间(当与靶序列5'-3’和3'-5’的寡核苷酸序列比对时)互补(形成Watson Crick碱基对)的对准的核碱基数，将其除以寡核苷酸中核苷酸的总数，然后乘以100，来计算互补性的百分比。在这种比较中，未对齐(形成碱基对)的核碱基/核苷酸被称为错配。在计算连续核苷酸序列的互补性百分比时，不允许***和删除。应当理解的是，在确定互补性时，只要保留了形成Watson Crick碱基配对的核碱基的功能能力，就不考虑核碱基的化学修饰(例如，在计算互补性百分比时，认为5'-甲基胞嘧啶与胞嘧啶相同)。
术语“完全互补”是指100％互补性。
同一性
如本文所用，术语“同一性”是指核酸分子(例如寡核苷酸)中连续核苷酸序列的与参考序列(例如序列基序)相同的核苷酸比例(以百分比表示)，该核酸分子跨连续核苷酸序列。因此，通过计数两个序列(在本发明的化合物的连续核苷酸序列中和在参考序列中)相同(匹配)的对准核碱基数，将该数除以寡核苷酸的核苷酸总数再乘以100，来计算同一性百分比。因此，同一性百分比＝(匹配数x 100)/比对区域的长度(例如，连续核苷酸序列)。在计算连续核苷酸序列的同一性百分比时，不允许***和删除。应当理解的是，在确定同一性时，只要保留了形成Watson Crick碱基配对的核碱基的功能能力，就不考虑核碱基的化学修饰(例如，在计算同一性百分比时，认为5-甲基胞嘧啶与胞嘧啶相同)。
杂交
如本文所用，术语“杂交”(hybridizing/hybridizes)应当理解为两条核酸链(例如寡核苷酸和靶核酸)在相反链上的碱基对之间形成氢键，从而形成双链体。两条核酸链之间结合的亲和力为杂交的强度。它通常根据解链温度(Tm)来描述，该解链温度被定义为一半寡核苷酸与靶核酸形成双链体的温度。在生理条件下，Tm与亲和力并不严格成比例(Mergny and Lacroix,2003,Oligonucleotides 13:515–537)。标准状态的吉布斯自由能ΔG°更精确地表示结合亲和力，并且通过ΔG°＝-RTln(Kd)与反应的解离常数(Kd)相关，其中R为气体常数，T为绝对温度。因此，寡核苷酸与靶核酸之间的反应的非常低的ΔG°反映了寡核苷酸与靶核酸之间的强杂交。ΔG°是与水浓度为1M、pH为7、温度为37℃的反应相关的能量。寡核苷酸与靶核酸的杂交是自发反应，而自发反应的ΔG°小于零。ΔG°可以通过实验来测量，例如，通过使用如Hansen等人,1965,Chem.Comm.36–38和Holdgate等人,2005,DrugDiscov Today中所述的等温滴定量热法(ITC)方法测量。技术人员将知道商用设备可用于ΔG°测量。ΔG°还可以使用SantaLucia,1998,Proc Natl Acad Sci USA.95:1460–1465描述的最近邻居模型，使用由Sugimoto等人,1995,Biochemistry 34:11211–11216和McTigue等人,2004,Biochemistry43:5388–5405描述的适当推导的热力学参数进行数值评估。为了具有通过杂交调节其预期的核酸靶标的可能性，对于长度为10至30个核苷酸的寡核苷酸，本发明的寡核苷酸与靶核酸以低于-10kcal的估计ΔG°杂交。在一些实施例中，杂交的程度或强度通过标准状态吉布斯自由能ΔG°测量。对于长度为8个至30个核苷酸的寡核苷酸，寡核苷酸可以与靶核酸以低于-10kcal，诸如低于-15kcal、诸如低于-20kcal以及诸如低于-25kcal的估计ΔG°值杂交。在一些实施例中，寡核苷酸以-10至-60kcal，诸如-12至-40kcal、诸如-15至-30kcal或-16至-27kcal、诸如-18至-25kcal的范围的ΔG°估值与靶核酸杂交。
靶核酸
根据本发明，靶核酸是编码哺乳动物A1CF的核酸，并且可以例如是基因、RNA、mRNA和前体mRNA、成熟的mRNA或cDNA序列。该靶标因此可以称为A1CF靶核酸。
合适地，靶核酸编码A1CF蛋白，特别是哺乳动物A1CF，诸如本文提供的人A1CF基因编码的前体mRNA或mRNA序列为SEQ ID NO:1、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10或SEQ ID NO:11。
本发明的治疗性寡核苷酸可以例如靶向哺乳动物A1CF的外显子区域(特别是siRNA和shRNA，但也可以是反义寡核苷酸)，或者可以例如靶向A1CF前体mRNA中的任何内含子区域(特别是反义寡核苷酸)。人A1CF基因编码10个转录本，该转录本中的8个转录本是蛋白质编码的，并且因此是潜在的核酸靶标。
表1列出了SEQ ID NO:1(即，人A1CF前体mRNA序列)的预测外显子区域和内含子区域。
表1.人A1CF前体mRNA中的外显子区域和内含子区域。
合适地，靶核酸编码A1CF蛋白，特别是哺乳动物A1CF，诸如人A1CF(参见例如表2和表3)，该表提供了关于人、食蟹猴和小鼠A1CF的基因组序列(表2)以及关于人、食蟹猴和小鼠A1CF的前体mRNA序列和人A1CF的成熟的mRNA(表3)的概述。
在一些实施例中，靶核酸选自由SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ IDNO:4、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:10和SEQ ID NO:11或其天然存在的变体(例如，编码哺乳动物A1CF的序列)组成的组。
表2.多个物种的A1CF的基因组和组装体信息。
Fwd＝正向链。Rv＝反相链。基因组坐标提供了前体mRNA序列(基因组序列)。
如果在研究或诊断中采用本发明的核酸分子，则靶核酸可以是cDNA或衍生自DNA或RNA的合成核酸。
对于体内或体外应用，本发明的治疗性核酸分子通常能够在表达A1CF靶核酸的细胞中抑制A1CF靶核酸的表达。在一些实施例中，所述细胞包含HBV cccDNA。本发明的核酸分子的核碱基的连续序列通常与A1CF靶核酸的保守区域互补，如在整个核酸分子的长度上测量的，任选地，除了一个或两个错配以外，并且任选地排除可以将寡核苷酸与任选的官能团(诸如缀合物)或其他非互补性末端核苷酸连接的基于核苷酸的接头区域。靶核酸为信使RNA，例如编码哺乳动物A1CF蛋白的前体mRNA，诸如人A1CF，诸如人A1CF前体mRNA序列，诸如作为SEQ ID NO:1，猴A1CF前体mRNA序列而公开的序列，诸如作为SEQ ID NO:2或小鼠A1CF前体mRNA序列而公开的序列，诸如作为SEQ ID NO:3或成熟的A1CF mRNA而公开的序列，诸如作为SEQ ID NO:4、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:10或SEQ IDNO:11而公开的人成熟的mRNA。SEQ ID NO:1至SEQ ID NO:13是DNA序列-应当理解，靶RNA序列具有代替胸苷碱基(T)的尿嘧啶(U)碱基。
表2和表3提供了有关示例性靶核酸的更多信息。
表3.关于靶核酸的概述。
| 靶核酸、物种、参考 | 序列ID |
| A1CF智人前体mRNA | SEQ ID NO:1 |
| A1CF食蟹猴前体mRNA | SEQ ID NO:2 |
| A1CF小家鼠前体mRNA | SEQ ID NO:3 |
| A1CF智人成熟的mRNA，变体1(ENST00000374001) | SEQ ID NO:4 |
| A1CF智人成熟的mRNA，变体2(ENST00000395489) | SEQ ID NO:5 |
| A1CF智人成熟的mRNA，变体3(ENST00000282641) | SEQ ID NO:6 |
| A1CF智人成熟的mRNA，变体4(ENST00000395495) | SEQ ID NO:7 |
| A1CF智人成熟的mRNA，变体5(ENST00000373997) | SEQ ID NO:8 |
| A1CF智人成熟的mRNA，变体6(ENST00000373995) | SEQ ID NO:9 |
| A1CF智人成熟的mRNA，变体8(ENST00000373993) | SEQ ID NO:10 |
| A1CF智人成熟的mRNA，变体9(ENST00000414883) | SEQ ID NO:11 |
在一些实施例中，靶核酸是SEQ ID NO:1。
在一些实施例中，靶核酸是SEQ ID NO:2。
在一些实施例中，靶核酸是SEQ ID NO:3。
在一些实施例中，靶核酸是SEQ ID NO:4。
在一些实施例中，靶核酸是SEQ ID NO:5。
在一些实施例中，靶核酸是SEQ ID NO:6。
在一些实施例中，靶核酸是SEQ ID NO:7。
在一些实施例中，靶核酸是SEQ ID NO:8。
在一些实施例中，靶核酸是SEQ ID NO:9。
在一些实施例中，靶核酸是SEQ ID NO:10。
在一些实施例中，靶核酸是SEQ ID NO:11。
靶序列
本文所用的术语“靶序列”是指存在于靶核酸中的核苷酸的序列，其包含与本发明的寡核苷酸或核酸分子互补的核碱基序列。在一些实施例中，靶序列由靶核酸上具有与本发明寡核苷酸的连续核苷酸序列互补的核碱基序列的区域组成。靶核酸的这一区域可以互换地称为靶标核苷酸序列、靶序列或靶标区域。在一些实施例中，靶序列比本发明的核酸分子的互补序列更长，并且可以例如代表靶核酸的可以被本发明的若干核酸分子所靶向的优选区域。
在一些实施例中，靶序列是选自由人A1CF mRNA外显子组成的组的序列，诸如选自由e1、e2、e3、e4、e5、e6、e7、e8、e9、e10、e11、e12、e13、e14和e15(参见例如上表1)组成的组的A1CF人mRNA外显子。
因此，本发明提供了寡核苷酸，其中所述寡核苷酸包含与SEQ ID NO:1的外显子区域至少90％互补(诸如完全互补)的连续序列，该外显子区域选自由e1至e15组成的组(参见表1)。
在一些实施例中，靶序列是选自由人A1CFmRNA内含子组成的组的序列，诸如选自由i1、i2、i3、i4、i5、i6、i7、i8、i9、i10、i11、i12、i13和i14(参见例如上表1)组成的组的A1CF人mRNA内含子。
因此，本发明提供了寡核苷酸，其中所述寡核苷酸包含与SEQ ID NO:1的外显子区域至少90％互补(诸如完全互补)的连续序列，该内含子区域选自由i1至i14组成的组(参见表1)。
在一些实施例中，该靶序列选自由SEQ ID NO:12,13,14和15组成的组。在一些实施例中，如本文所指的连续核苷酸序列与选自由SEQ ID NO:12,13,14和15组成的组的靶序列至少90％互补，诸如至少95％互补。在一些实施例中，该连续核苷酸序列与选自由SEQ IDNO:12,13,14和15组成的组的靶序列完全互补。
本发明的寡核苷酸包含与靶核酸(诸如本文所述的靶序列)上的区域互补或杂交的连续核苷酸序列。
与治疗性寡核苷酸互补或杂交的靶核酸序列通常包含一段至少10个核苷酸的连续核碱基。该连续核苷酸序列的长度介于12至70个核苷酸，诸如12至50个、诸如13至30个、诸如14至25个、诸如15至20个、诸如16至18个邻接核苷酸。
在一些实施例中，本发明的寡核苷酸靶向表4或5中所示的区域。
表4：示例性靶标区域
在一些实施例中，靶序列选自由以下项组成的组：如上表4所示的靶标区域1A至2001A。
表5：示例性靶标区域
在一些实施例中，靶序列选自由以下项组成的组：如上表5所示的靶标区域1C至178C。
靶细胞
如本文所用，术语“靶细胞”是指表达靶核酸的细胞。对于本发明的治疗用途，如果靶细胞被HBV感染则是优选的。在一些实施例中，靶细胞可以是体内或体外的。在一些实施例中，靶细胞是哺乳动物细胞诸如啮齿动物细胞，诸如小鼠细胞或大鼠细胞或土拨鼠细胞，或者灵长类细胞，诸如猴细胞(例如食蟹猴细胞)或人类细胞。
在优选的实施例中，靶细胞表达A1CF mRNA，诸如A1CF前体mRNA或A1CF成熟的mRNA。对于反义寡核苷酸靶向作用，通常不考虑A1CF mRNA的聚腺苷(poly A)尾部。
此外，靶细胞可以是肝细胞。在一个实施例中，靶细胞是HBV感染的原代人肝细胞，其衍生自HBV感染者或具有人源化肝脏的HBV感染的小鼠(PhoenixBio，PXB-小鼠)。
根据本发明，靶细胞可以被HBV感染。此外，靶细胞可包含HBV cccDNA。因此，靶细胞优选地包含A1CF mRNA，诸如A1CF前体mRNA或A1CF成熟的mRNA，以及HBV cccDNA。在一个实施例中，靶细胞是人细胞。在一个实施例中，人细胞是肝细胞。
天然存在的变体
术语“天然存在的变体”是指A1CF基因或转录本的变体，其源自与靶核酸相同的遗传基因座，但是可能例如由于遗传密码的简并性导致编码相同氨基酸的密码子的多样性而不同，或由于前体mRNA的可变剪接、或存在多态性诸如单核苷酸多态性(SNP)和等位基因变体而不同。基于与寡核苷酸足够互补序列的存在，本发明的寡核苷酸因此可以靶向靶核酸及其天然存在的变体。
在一些实施例中，天然存在的变体与哺乳动物A1CF靶核酸具有至少95％，诸如至少98％或至少99％的同源性，该靶核酸为诸如SEQ ID NO:1和/或SEQ ID NO:2的靶核酸。在一些实施例中，天然存在的变体与SEQ ID NO:1的人A1CF靶核酸具有至少99％的同源性。在一些实施例中，天然存在的变体是已知的多态性。
表达的抑制
如本文所用，术语“表达的抑制”理解为A1CF(APOBEC1互补因子)抑制剂在靶细胞中抑制A1CF的量或活性的能力的总称。表达或活性的抑制可以通过测量A1CF前体mRNA或A1CF mRNA的水平，或通过测量细胞中A1CF蛋白的水平或活性来进行确定。表达的抑制可以在体外或体内确定。通过参考对照来确定抑制。通常理解，对照是用盐水组合物处理的个体或靶细胞。
术语“抑制(名词)”或“抑制(动词)”也可以是指下调、减少、压制、减轻、降低、减弱A1CF的表达或活性。
A1CF的表达的抑制可以例如通过例如使用募集RNA酶H的寡核苷酸(诸如间隔聚体)或经由RNA干扰途径发挥作用的核酸分子(诸如siRNA或shRNA)来降解前体mRNA或mRNA而发生。替代地，本发明的抑制剂可以与A1CF多肽结合并且抑制A1CF的活性或防止其与其他分子结合。
在一些实施例中，A1CF靶核酸的表达或A1CF蛋白的活性的抑制导致靶细胞中HBVcccDNA的量下降。优选地，与对照相比，HBV cccDNA的量下降。在一些实施例中，与对照相比，HBV cccDNA的量下降至少20％，至少30％。在一些实施例中，当与对照相比时，HBV感染细胞中的cccDNA的量减少了至少50％，诸如60％，诸如70％。
在一些实施例中，A1CF靶核酸的表达或A1CF蛋白的活性的抑制导致靶细胞中HBVpgRNA的量下降。优选地，与对照相比，HBV pgRNA的量下降。在一些实施例中，与对照相比，HBV pgRNA的量的下降为至少20％，至少30％。在一些实施例中，当与对照相比时，HBV感染细胞中的pgRNA的量减少了至少50％，诸如60％。
糖修饰
本发明的寡核苷酸可以包含一种或多种具有修饰的糖部分的核苷，所述修饰的糖部分即与DNA和RNA中发现的核糖糖部分相比时糖部分的修饰。
已经制备了许多具有核糖糖部分的修饰的核苷，主要目的为改善寡核苷酸的某些特性，诸如亲和力和/或核酸酶抗性。
此类修饰包括以下修饰，其中例如通过用以下替换而修饰核糖环结构：己糖环(HNA)或一般在核糖环(LNA)上C2碳与C4碳之间具有双基桥的双环状环或一般在C2碳与C3碳之间缺少键的非连接核糖环(例如UNA)。其他糖修饰的核苷包括，例如，双环己糖核酸(WO2011/017521)或三环核酸(WO2013/154798)。修饰的核苷还包括其中糖部分被非糖部分替换的核苷，例如在肽核酸(PNA)或吗啉代核酸的情况下。
糖修饰还包括通过将核糖环上的取代基改变为除氢以外的基团或DNA和RNA核苷中天然存在的2'-OH基团而进行的修饰。例如，可以在2'、3'、4'或5'位置引入取代基。
高亲和力修饰的核苷
高亲和力修饰的核苷是修饰的核苷酸，其在掺入到寡核苷酸中时，增强了寡核苷酸对其互补靶标的亲和力，例如通过解链温度(Tm)测量。本发明的高亲和力修饰的核苷优选地使每一个修饰的核苷的解链温度增加+0.5℃至+12℃的范围，更优选地+1.5℃至+10℃的范围并且最优选地+3℃至+8℃的范围。许多高亲和力修饰的核苷是本领域已知的，并且包括例如许多2'取代的核苷以及锁定的核酸(LNA)(参见例如Freier&Altmann；Nucl.AcidRes.,1997,25,4429-4443和Uhlmann；Curr.Opinion in Drug Development,2000,3(2),293-213)。
2'糖修饰的核苷
2'糖修饰的核苷是一种核苷，其在2'位置具有除H或-OH以外的取代基(2'取代的核苷)或包含能够在2'碳与核糖环中的第二个碳之间形成桥的2'连接双基，诸如LNA(2'-4'双基桥连)核苷。
事实上，人们已花费很多精力开发2'糖取代的核苷，并且发现许多2'取代的核苷掺入寡核苷酸后具有有益的特性。例如，2'修饰的糖可提供对寡核苷酸的增强的结合亲和力和/或增加的核酸酶抗性。2'取代的修饰的核苷的实例是2'-O-烷基-RNA、2'-O-甲基-RNA、2'-烷氧基-RNA、2'-O-甲氧基乙基-RNA(MOE)、2'-氨基-DNA、2'-氟-RNA和2'-F-ANA核苷。有关进一步的实例，请参见例如Freier&Altmann；Nucl.Acid Res.,1997,25,4429-4443和Uhlmann；Curr.Opinion in Drug Development,2000,3(2),293-213以及Deleavey和Damha，Chemistry and Biology 2012,19,937。下面为一些2'取代的修饰的核苷的示意图。
关于本发明，2'取代的糖修饰的核苷不包括像LNA那样的2′桥连的核苷。
锁定的核酸核苷(LNA核苷)
“LNA核苷”是一种2'-糖修饰的核苷，其包含连接所述核苷的核糖环的C2'和C4'的双基(也称为“2'-4'桥”)，其限制或锁定核糖环的构象。这些核苷在文献中也被称为桥连核酸或双环核酸(BNA)。当将LNA掺入互补RNA或DNA分子的寡核苷酸中时，核糖构象的锁定与杂交亲和力的增强(双链体稳定化)相关。这可通过测量寡核苷酸/互补双链体的解链温度来常规确定。
非限制性的示例性LNA核苷公开于WO 99/014226、WO 00/66604、WO 98/039352、WO2004/046160、WO 00/047599、WO 2007/134181、WO 2010/077578、WO 2010/036698、WO2007/090071、WO 2009/006478、WO 2011/156202、WO 2008/154401、WO 2009/067647,WO2008/150729、Morita等人,Bioorganic&Med.Chem.Lett.12,73-76,Seth etal.J.Org.Chem.2010,Vol 75(5)pp.1569-81,Mitsuoka等人,Nucleic Acids Research2009,37(4),1225-1238以及Wan和Seth,J.Medical Chemistry 2016,59,9645-9667。
本发明的LNA核苷的特定实例在方案1中给出(其中B如上所定义)。
方案1
特定的LNA核苷是β-D-氧基-LNA、6'-甲基-β-D-氧基LNA诸如(S)-6'-甲基-β-D-氧基-LNA(ScET)和ENA。
RNA酶H活性和募集
反义寡核苷酸的RNA酶H活性是指其与互补RNA分子形成双链体时募集RNA酶H的能力。WO01/23613提供了用于确定RNA酶H活性的体外方法，该方法可用于确定募集RNA酶H的能力。如果在向寡核苷酸提供互补靶核酸序列时具有以下初始速率(以pmol/l/min计)，则一般认为其能够募集RNA酶H，该初始速率是使用WO 01/23613(通过引用在此并入)的实例91至95提供的方法学，使用具有与所测试的经修饰的寡核苷酸相同的碱基序列但在寡核苷酸中的所有单体之间仅包含具有硫代磷酸酯键的DNA单体的寡核苷酸确定的初始速率的至少5％，诸如至少10％或超过20％。为了用于确定RNA酶H活性，可从Creative 
(与大肠杆菌中表达的His标签融合的重组人RNA酶H1)获得重组人RNA酶H1。
间隔聚体
本发明的反义寡核苷酸或其连续核苷酸序列可以是间隔聚体，也称为间隔聚体寡核苷酸或间隔聚体设计。反义间隔聚体一般用于通过RNA酶H介导的降解来抑制靶核酸。间隔聚体寡核苷酸包含至少三个不同的结构区域，分别为“5->3”方向的5'侧翼、缺口和3'侧翼F-G-F'。“缺口”区域(G)包含一段使寡核苷酸能够募集RNA酶H的连续DNA核苷酸。该缺口区域的侧翼是包含一个或多个糖修饰的核苷(优选地是高亲和力糖修饰的核苷)的5'侧翼区域(F)，以及包含一个或多个糖修饰的核苷(优选地是高亲和力糖修饰的核苷)的3’侧翼区域(F’)。区域F和F’中的一个或多个糖修饰的核苷增强寡核苷酸对靶核酸的亲和力(即，亲和力增强的糖修饰的核苷)。在一些实施例中，区域F和F'中的一个或多个糖修饰的核苷是2'糖修饰的核苷，诸如高亲和力的2'糖修饰、诸如独立地选自LNA和2'-MOE。
在间隔聚体设计中，缺口区域的5’和3’最末端核苷是DNA核苷，分别位于5'(F)或3'(F')区域的糖修饰核苷附近。侧翼可进一步定义为在距缺口区域最远的端，即在5’侧翼的5’端和3’侧翼的3’端，具有至少一个糖修饰的核苷。
区域F-G-F’形成连续核苷酸序列。本发明的反义寡核苷酸或其连续核苷酸序列可包含式F-G-F’的间隔聚体区域。
间隔聚体设计F-G-F'的总长度可以是例如12至32个核苷，诸如13至24个核苷，诸如14至22个核苷，诸如15至20个核苷，诸如16至18个核苷。
举例而言，本发明的间隔聚体寡核苷酸可由下式代表：
F1-8-G5-18-F'1-8，诸如
F1-8-G7-18-F'2-8
前提条件是间隔聚体区域F-G-F'的总长度至少为12，诸如至少14个核苷酸。
在本发明的一个方面，反义寡核苷酸或其连续核苷酸序列包含式5'-F-G-F'-3′的间隔聚体或由其组成，其中区域F和F'独立地包含1个至8个核苷或由其组成，其中1个至4个核苷经2'糖修饰且限定F和F'区域的5′和3'端，并且G为介于6个与18个核苷之间的能够募集RNA酶H的区域。在一些实施例中，G区域由DNA核苷组成。
在一些实施例中，区域F和F’独立地由糖修饰的核苷的连续序列组成或包含糖修饰的核苷的连续序列。在一些实施例中，区域F的糖修饰的核苷可独立地选自2′-O-烷基-RNA单元、2'-O-甲基-RNA、2′-氨基-DNA单元、2′-氟-DNA单元、2′-烷氧基-RNA、MOE单元、LNA单元、阿糖核酸(ANA)单元和2′-氟-ANA单元。
在一些实施例中，区域F和F′独立地包含LNA和2′-取代的糖修饰的核苷酸两者(混合型翼设计)。在一些实施例中，2′-取代的糖修饰的核苷酸独立地选自由以下项组成的组：2′-O-烷基-RNA单元、2′-O-甲基-RNA、2′-氨基-DNA单元、2′-氟-DNA单元、2′-烷氧基-RNA、MOE单元、阿糖核酸(ANA)单元和2′-氟-ANA单元。
在一些实施例中，区域F和F′的所有修饰的核苷均为LNA核苷，诸如独立地选自β-D-氧基LNA、ENA或ScET核苷，其中区域F或F′或者F和F′可以任选地包含DNA核苷。在一些实施例中，区域F和F′的所有修饰的核苷均为β-D-氧基LNA核苷，其中区域F或F′或者F和F'可以任选地包含DNA核苷。在这样的实施例中，侧翼区域F或F′，或F和F′两者都包含至少三个核苷，其中F和/或F′区域的5'和3'最末端核苷是LNA核苷。
LNA间隔聚体
LNA间隔聚体是其中区域F和F’中的一者或两者包含LNA核苷或由LNA核苷组成的间隔聚体。β-D-氧基间隔聚体是其中区域F和F'中的一者或两者包含β-D-氧基LNA核苷或由其组成的间隔聚体。
在一些实施例中，LNA间隔聚体具有下式：[LNA]1–5-[区域G]6-18-[LNA]1-5，其中区域G具有如在间隔聚体区域G定义中的定义。
MOE间隔聚体
MOE间隔聚体是其中区域F和F’由MOE核苷所构成的间隔聚体。在一些实施例中，MOE间隔聚体的设计为[MOE]1-8-[区域G]5-16-[MOE]1-8，诸如[MOE]2-7-[区域G]6-14-[MOE]2-7，诸如[MOE]3-6-[区域G]8-12-[MOE]3-6，诸如[MOE]5-[区域G]10-[MOE]5，其中区域G具有如间隔聚体定义中的定义。具有5-10-5设计的MOE间隔聚体(MOE-DNA-MOE)已在本领域中广泛使用。
寡核苷酸中的区域D'或D″
在一些实施例中，本发明的寡核苷酸可以包含以下项或由其组成：与靶核酸互补的寡核苷酸的连续核苷酸序列，诸如间隔聚体区域F-G-F'，以及另外的5'和/或3'核苷。所述其他的5’和/或3’核苷可与或不与所述靶核酸为完全互补。此类其他的5’和/或3’核苷本文中可称为区域D’和D″。
出于将连续核苷酸序列(诸如间隔聚体)与缀合物部分或另一个官能团接合的目的，可以使用添加区域D'或D″。当用于将连续核苷酸序列与缀合物部分接合时，其可用作可生物裂解的接头。另选地，其可用于提供核酸外切酶保护或促进合成或制造。
可以将区域D’和D”分别附接于区域F的5’端或区域F’的3’端，以生成下式D'-F-G-F'、F-G-F'-D”或D'-F-G-F'-D″的设计。在这种情况下，F-G-F’是寡核苷酸的间隔聚体部分，而区域D’或D”构成寡核苷酸的单独部分。
区域D’或D”可以独立地包含1个、2个、3个、4个或5个另外的核苷酸或由其组成，它们可以与靶核酸互补或不互补。与F或F'区域相邻的核苷酸不是糖修饰的核苷酸，诸如DNA或RNA或这些的碱基修饰形式。D’或D”区域可用作核酸酶敏感的可生物裂解的接头(参见接头的定义)。在一些实施例中，另外的5'和/或3'端核苷酸与磷酸二酯键联接，并且是DNA或RNA。WO2014/076195中公开了适合用作区域D'或D″的基于核苷酸的可生物裂解的接头，其包括例如磷酸二酯连接的DNA二核苷酸。WO2015/113922中公开了在聚寡核苷酸构建体中可生物裂解的连接基的用途，其中它们被用于在单个寡核苷酸内连接多个反义构建体(例如间隔聚体区域)。
在一个实施例中，本发明的寡核苷酸除构成间隔聚体的连续核苷酸序列外还包含区域D'和/或D″。
在一些实施例中，本发明的寡核苷酸可以由下式表示：
F-G-F’；特别是F1-8-G5-18-F’2-8
D'-F-G-F'，特别是D'1-3-F1-8-G5-18-F′2-8
F-G-F'-D″，特别是F1-8-G5-18-F'2-8-D″1-3
D'-F-G-F'-D″，特别是D'1-3-F1-8-G5-18-F'2-8-D″1-3
在一些实施例中，位于区域D'与区域F之间的核苷间键是磷酸二酯键。在一些实施例中，位于区域F'与区域D″之间的核苷间键是磷酸二酯键。
缀合物
如本文所用，术语“缀合物”是指与非核苷酸部分(缀合物部分或区域C或第三区域)共价联接的寡核苷酸。缀合物部分可以与反义寡核苷酸共价连接，任选地经由连接基(诸如区域D′或D″)基团。
寡核苷酸缀合物及其合成已在Manoharan于Antisense Drug Technology,Principles,Strategies,and Applications,S.T.Crooke编辑，第16章，Marcel Dekker,Inc.,2001中所作综述和Manoharan,Antisense and Nucleic Acid Drug Development,2002,12,103中报导，上述文献各自通过引用整体并入本文。
在一些实施例中，非核苷酸部分(缀合物部分)选自由以下项组成的组：碳水化合物(例如半乳糖或N-乙酰半乳糖胺(GalNAc))、细胞表面受体配体、原料药、激素、亲脂性物质、聚合物、蛋白质(例如抗体)、肽、毒素(例如细菌毒素)、维生素、病毒蛋白质(例如衣壳)或它们的组合。
示例性缀合物部分是那些能够结合脱唾液酸糖蛋白受体(ASGPR)的缀合物部分。特别地，三价N-乙酰半乳糖胺缀合物部分适用于与ASGPR结合，参见例如WO 2014/076196、WO 2014/207232和WO 2014/179620(通过引用并入本文)。此类缀合物用于增强肝脏对寡核苷酸的吸收。
接头
键合或接头是两个原子之间的连接，其经由一个或多个共价键将一个目标化学基团或区段与另一个目标化学基团或区段联接。缀合物部分可直接或通过联接部分(例如接头或系链)连接到寡核苷酸。接头用于将第三区域，例如缀合物部分(区域C)，与第一区域共价连接，该第一区域为例如与靶核酸互补的寡核苷酸或连续核苷酸序列(区域A)。
在本发明的一些实施例中，本发明的缀合物或寡核苷酸缀合物可以任选地包含位于与靶核酸互补的寡核苷酸或连续核苷酸序列(区域A或第一区域)和缀合物部分(区域C或第三区域)之间的接头区域(第二区域或区域B和/或区域Y)。
区域B是指包含生理上不稳定的键或由其组成的可生物裂解的接头，该键在哺乳动物体内通常遇到的条件下或与之相似的条件下可裂解。生理上不稳定的接头经历化学转化(例如裂解)的条件包括化学条件，诸如pH、温度、氧化或还原条件或试剂，以及在哺乳动物细胞中遇到的盐浓度或与之相似的盐浓度。哺乳动物细胞内条件还包括通常存在于哺乳动物细胞中的酶活性，诸如来自蛋白水解酶或水解酶或核酸酶的酶活性。在一个实施例中，可生物裂解的接头对S1核酸酶裂解敏感。在一个优选的实施例中，核酸酶敏感的接头包含介于1个与5个之间的核苷，诸如1个、2个、3个、4个或5个核苷，更优选地包含介于2个与4个之间核苷，并且最优选地包含2个或3个连接的核苷，该核苷包含至少两个连续的磷酸二酯键，诸如至少3个或4个或5个连续的磷酸二酯键。优选地，该核苷是DNA或RNA。包含磷酸二酯的可生物裂解的接头更加详细地描述于WO 2014/076195(通过引用并入本文)中。
区域Y是指不一定是可生物裂解的但主要用于将缀合物部分(区域C或第三区域)与寡核苷酸(区域A或第一区域)共价连接的接头。区域Y接头可以包含链结构或重复单元诸如乙二醇、氨基酸单元或氨基烷基基团的寡聚物。本发明的寡核苷酸缀合物可以由以下区域元件构建：A-C、A-B-C、A-B-Y-C、A-Y-B-C或A-Y-C。在一些实施例中，接头(区域Y)是氨基烷基，诸如C2至C36氨基烷基基团，其包括例如C6至C12氨基烷基基团。一些实施例接头(区域Y)是C6氨基烷基基团。
治疗
本文所用的术语“治疗”是指既存疾病(例如本文所指的疾病或疾患)的治疗或疾病的防止即预防。因此将认识到，在一些实施例中，本文所指的治疗可以是预防性的。预防可理解为阻止HBV感染转变为慢性HBV感染或阻止由慢性HBV感染引起的严重肝病，诸如肝硬化和肝细胞癌。
患者
为了本发明的目的，“受试者”(或“患者”)可以是脊椎动物。在本发明的上下文中，术语“受试者”包括人和其他动物，特别是哺乳动物和其他生物。因此，本文提供的手段和方法适用于人类治疗和兽医应用。优选地，受试者是哺乳动物。更优选地，受试者是人。
如本文其他地方所述，待治疗的患者可能患有HBV感染，诸如慢性HBV感染。在一些实施例中，患有HBV感染的患者可能患有肝细胞癌(HCC)。在一些实施例中，患有HBV感染的患者不患有肝细胞癌。
具体实施方式
感染的肝细胞中的HBV cccDNA负责持续的慢性感染和再激活，是所有病毒亚基因组转录本和前基因组RNA(pgRNA)的模板，以确保新合成的病毒后代和cccDNA池通过细胞内核衣壳回收而得到补充。在本发明的上下文中，第一次显示A1CF与cccDNA稳定性有关。这种认知为HBV感染受试者体内的cccDNA去稳定化提供机会，这反过来又为彻底治愈慢性感染HBV患者创造机会。
本发明的一方面是一种A1CF抑制剂，其在乙型肝炎病毒(HBV)感染，特别是慢性HBV感染的治疗和/或预防中使用。
A1CF抑制剂可以是例如与A1CF蛋白特异性结合的小分子，其中所述抑制剂防止或减少A1CF蛋白与cccDNA的结合。
本发明的一个实施例是A1CF抑制剂，其能够减少感染细胞，诸如HBV感染细胞中的cccDNA和/或pgRNA的量。
在另一个实施例中，A1CF抑制剂能够在HBV感染者体内降低HBsAg和/或HBeAg。
在HBV的治疗中使用的A1CF抑制剂
不受理论束缚，据信A1CF经由与cccDNA的直接或间接结合来参与细胞核中cccDNA的稳定化，并且通过防止A1CF与cccDNA的结合/缔合，cccDNA被去稳定化并且变得易于降解。因此，本发明的一个实施例为A1CF抑制剂，该抑制剂与A1CF蛋白相互作用并且防止或减少其与cccDNA的结合/缔合。
在本发明的一些实施例中，抑制剂为抗体、抗体片段或小分子化合物。在一些实施例中，抑制剂可以为抗体、抗体片段或小分子，该抑制剂与A1CF蛋白(诸如由SEQ ID NO:1、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQID NO:10或SEQ ID NO:11编码的A1CF蛋白)特异性结合。
本发明的核酸分子
治疗性核酸分子可能是出色的A1CF抑制剂，因为它们可以靶向A1CF转录本并且经由RNA干扰途径或经由RNA酶H裂解而促进其降解。或者，寡核苷酸诸如适体也可以充当A1CF蛋白交互作用的抑制剂。
本发明的一个方面是一种A1CF靶向核酸分子，其在乙型肝炎病毒(HBV)感染的治疗和/或预防中使用。此类核酸分子可以选自由以下项组成的组：单链反义寡核苷酸、siRNA和shRNA。
本章节描述了适用于在乙型肝炎病毒(HBV)感染的治疗和/或预防中使用的新型核酸分子。
本发明的核酸分子能够在体外和体内抑制A1CF mRNA和/或蛋白的表达。通过将寡核苷酸与编码A1CF的靶核酸杂交来实现抑制。靶核酸可以为哺乳动物A1CF序列。在一些实施例中，靶核酸可以为人A1CF前体mRNA序列，诸如SEQ ID NO:1的序列或选自SEQ ID NO:4至SEQ ID NO:11的人成熟A1CF mRNA序列。在一些实施例中，靶核酸可以为食蟹猴A1CF序列，诸如SEQ ID NO:2的序列。
在一些实施例中，本发明的核酸分子能够通过抑制或下调靶标的表达来调节靶标的表达。优选地，与靶标的正常表达水平相比，这种调节产生至少20％的表达抑制，更优选地与靶标的正常表达水平相比，至少30％、至少40％或至少50％的抑制。在一些实施例中，通过将25nM的核酸分子转染至PXB-PHH细胞，本发明的核酸分子可能能够在体外将A1CFmRNA的表达水平抑制至少50％或60％，就选择与cccDNA减少具有良好相关性的核酸分子而言，靶标减少的这一范围是有利的。合适地，实例中提供了可用于测量A1CF mRNA抑制的测定(例如实例1以及“材料和方法”章节)。A1CF抑制由寡核苷酸的连续核苷酸序列(诸如siRNA的前导链或反义寡核苷酸的间隔聚体区域)与靶核酸之间的杂交来进行触发。在一些实施例中，本发明的核酸分子包含寡核苷酸与靶核酸之间的错配。尽管错配，与靶核酸的杂交仍可能足以显示出所需的A1CF表达抑制。由错配导致降低的结合亲和力可以有利地通过与靶核酸互补的寡核苷酸中核苷酸数量的增加和/或能够增加与靶标结合亲和力的修饰核苷数量的增加来补偿，该修饰核苷为诸如存在于寡核苷酸序列内的2'糖修饰的核苷(包括LNA)。
本发明的一个方面涉及长度为12个至60个核苷酸的核酸分子，其包含长度为至少12个核苷酸，诸如长度为至少12个至30个核苷酸的连续核苷酸序列，该连续核苷酸序列与哺乳动物A1CF靶核酸(特别是人A1CF核酸)至少95％互补，诸如完全互补。这些核酸分子能够抑制A1CF mRNA和/或蛋白的表达。
本发明的一个方面涉及长度为12个至30个核苷酸的核酸分子，其包含长度为至少12个核苷酸，诸如12个至30个核苷酸的连续核苷酸序列，该连续核苷酸序列与哺乳动物A1CF靶序列至少90％互补，诸如完全互补。
本发明的另一方面涉及根据本发明的核酸分子，其包含长度为14个至22个核苷酸的连续核苷酸序列，该连续核苷酸序列与SEQ ID NO:1的靶序列至少90％互补，诸如完全互补。
在一些实施例中，核酸分子包含长度为12个至30个核苷酸的连续序列，其与靶核酸的区域或靶序列至少90％互补，诸如至少91％、诸如至少92％、诸如至少93％、诸如至少94％、诸如至少95％、诸如至少96％、诸如至少97％、诸如至少98％或100％互补。
如果寡核苷酸或其连续核苷酸序列与靶序列的区域完全互补(100％互补)，或者在一些实施例中，所述寡核苷酸与所述靶序列之间可存有一个或两个错配，则是有利的。
在一些实施例中，寡核苷酸序列与SEQ ID NO:1和/或SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10和/或SEQ ID NO:11的靶序列的区域100％互补。
在一些实施例中，本发明的核酸分子或连续核苷酸序列与SEQ ID NO:1和SEQ IDNO:2的靶核酸至少90％或95％互补，诸如完全(或100％)互补。
在一些实施例中，本发明的寡核苷酸或连续核苷酸序列与SEQ ID NO:2和/或SEQID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ IDNO:10和/或SEQ ID NO:11的靶核酸至少90％或95％互补，诸如完全(或100％)互补。
在一些实施例中，本发明的寡核苷酸或连续核苷酸序列与SEQ ID NO:1和/或SEQID NO:2以及/或SEQ ID NO:3的靶核酸至少90％或95％互补，诸如完全(或100％)互补。
在一些实施例中，本发明的核酸分子的连续序列与SEQ ID NO:1的区域至少90％互补，诸如完全互补，该区域选自如表4所示的由靶区域1A至2001A组成的组。
在一些实施例中，本发明的核酸分子的连续序列与SEQ ID NO:1的区域至少90％互补，诸如完全互补，该区域选自如表5所示的由靶标区域1C至178C组成的组。
在一些实施例中，本发明的核酸分子包含长度为12个至60个的核苷酸，诸如长度为13个至50个、诸如14个至35个、诸如15个至30个、诸如16个至22个的连续核苷酸或由其组成。在一个优选的实施例中，核酸分子包含长度为15个、16个、17个、18个、19个、20个、21个或22个的核苷酸或由其组成。
在一些实施例中，与靶核酸互补的核酸分子的连续核苷酸序列包含长度为12个至30个，诸如13个至25个、诸如15个至23个、诸如16个至22个的连续核苷酸或由其组成。
在一些实施例中，寡核苷酸选自由以下项组成的组：反义寡核苷酸、siRNA和shRNA。
在一些实施例中，与靶序列互补的siRNA或shRNA的连续核苷酸序列包含长度为18至28个，诸如19至26个、诸如20至24个、诸如21至23个的连续核苷酸，或由其组成。
在一些实施例中，与靶核酸互补的反义寡核苷酸的连续核苷酸序列包含长度为12个至22个，诸如14个至20个、诸如16个至20个、诸如15个至18个、诸如16个至18个，诸如16个、17个、18个、19个或20个的连续核苷酸或由其组成。
在一些实施例中，寡核苷酸或连续核苷酸序列包含的序列选自由表6(“材料和方法”章节)中所列序列组成的组，或由其组成。
应当理解的是，可以修饰连续寡核苷酸序列(基序序列)以例如增加核酸酶抗性和/或对靶核酸的结合亲和力。
将修饰的核苷(例如高亲和力修饰的核苷)掺入寡核苷酸序列中的模式通常称为寡核苷酸设计。
本发明的核酸分子可以使用修饰的核苷和RNA核苷(特别是用于siRNA和shRNA分子)或DNA核苷(特别是用于单链反义寡核苷酸)设计。
在有利实施例中，核酸分子或连续核苷酸序列包含一个或多个糖修饰的核苷(诸如2′糖修饰的核苷)，诸如包含一个或多个独立地选自由以下项组成的组2′糖修饰的核苷：2'-O-烷基-RNA、2'-O-甲基-RNA、2′-烷氧基-RNA、2′-O-甲氧基乙基-RNA、2′-氨基-DNA、2′-氟-DNA、阿糖核酸(ANA)、2′-氟-ANA和LNA核苷。如果一个或多个修饰的核苷是锁定的核酸(LNA)，则是优选的。
在一些实施例中连续核苷酸序列包含LNA核苷。
在一些实施例中连续核苷酸序列包含LNA核苷和DNA核苷。
在一些实施例中连续核苷酸序列包含2′-O-甲氧基乙基(2′MOE)核苷。
在一些实施例中连续核苷酸序列包含2′-O-甲氧基乙基(2′MOE)核苷和DNA核苷。
有利地，反义寡核苷酸或其连续核苷酸序列的3′最末端核苷为2′糖修饰的核苷。
在另一个实施例中，核酸分子包含至少一个修饰的核苷间键。合适的核苷间修饰描述于“定义”章节的“修饰的核苷间键合”下。
有利地，寡核苷酸包含至少一个修饰的核苷间键，诸如硫代磷酸酯或二硫代磷酸酯。
在一些实施例中，连续核苷酸序列中的至少一个核苷间键是磷酸二酯核苷间键。
如果在寡核苷酸的5’或3’端的至少2个至3个核苷间键是硫代磷酸酯核苷间键，则是优选的。
对于单链反义寡核苷酸，如果连续核苷酸序列内的至少75％(诸如所有)的核苷间键是硫代磷酸酯核苷间键，则是优选的。在一些实施例中，单链反义寡核苷酸的连续序列中的所有核苷酸间键是硫代磷酸酯键。
在本发明的一个有利实施例中，本发明的反义寡核苷酸能够募集RNA酶H，诸如RNA酶H1。有利的结构设计是如“定义”章节中，例如在“间隔聚体”、“LNA间隔聚体”和“MOE间隔聚体”下描述的间隔聚体设计。在本发明中，如果本发明的反义寡核苷酸是具有F-G-F′设计的间隔聚体，则是优选的。
在所有情况下，F-G-F′设计可进一步包括区域D'和/或D”，如“定义”章节中“寡核苷酸中的区域D'或D”下所述”。
在另一方面，本发明的核酸分子(诸如反义寡核苷酸、siRNA或shRNA)可以通过将该核酸分子共价连接至能够与脱唾液酸糖蛋白受体(ASGPr)结合的缀合物部分(诸如二价或三价GalNAc簇)来直接靶向肝脏。
缀合
因为HBV感染主要影响肝脏中的肝细胞，所以将A1CF抑制剂缀合至缀合物部分是优选的，与未缀合的抑制剂相比，缀合物部分将增加抑制剂向肝脏的递送。在一个实施例中，肝靶向部分选自能够与脱唾液酸糖蛋白受体(ASGPR)结合的胆固醇或其他脂质或缀合物部分。
在一些实施例中，本发明提供了缀合物，其包含共价附接于缀合物部分的本发明的核酸分子。
脱唾液酸糖蛋白受体(ASGPR)缀合物部分包含一种或多种能够以等于或大于半乳糖的亲和力结合脱唾液酸糖蛋白受体(ASPGR靶向部分)的碳水化合物部分。许多半乳糖衍生物对脱唾液酸糖蛋白受体的亲和力已经进行过研究(例如：Jobst,S.T.和Drickamer,K.JB.C.1996,271,6686)或使用本领域典型的方法容易地确定。
在一个实施例中，缀合物部分包含至少一个选自由以下项组成的组的脱唾液酸糖蛋白受体靶向部分：半乳糖、半乳糖胺、N-甲酰基-半乳糖胺、N-乙酰半乳糖胺、N-丙酰基-半乳糖胺、N-正丁酰基-半乳糖胺和N-异丁酰基半乳糖胺。有利地，脱唾液酸糖蛋白受体靶向部分是N-乙酰半乳糖胺(GalNAc)。
为了生成ASGPR缀合物部分，可以将ASPGR靶向部分(优选地GalNAc)附接于缀合物支架上。通常，ASPGR靶向部分可以在支架的相同端。在一个实施例中，缀合物部分由连接至间隔物的二至四个末端GalNAc部分组成，所述间隔物将每一个GalNAc部分连接至可与反义寡核苷酸缀合的支链分子。
在另一个实施例中，缀合物部分相对于脱唾液酸糖蛋白受体靶向部分为一价、二价、三价或四价。有利地，脱唾液酸糖蛋白受体靶向部分包含N-乙酰半乳糖胺(GalNAc)部分。
GalNAc缀合物部分可包括例如那些WO 2014/179620和WO 2016/055601和PCT/EP2017/059080(通过引用并入本文)中所述的缀合物部分，以及附接有GalNAc部分的小肽，诸如Tyr-Glu-Glu-(氨基己基GalNAc)3(YEE(ahGalNAc)3；与肝细胞上脱唾液酸糖蛋白受体结合的糖三肽，参见，例如，Duff等人,Methods Enzymol,2000,313,297)；基于赖氨酸的半乳糖簇(例如L3G4；Biessen等人,Cardovasc.Med.,1999,214)；和基于胆烷的半乳糖簇(例如，脱唾液酸糖蛋白受体的碳水化合物识别基序)。
可以使用本领域已知的方法将ASGPR缀合物部分，特别是三价GalNAc缀合物部分附接于寡核苷酸的3'端或5'端。在一个实施例中，ASGPR缀合物部分连接至寡核苷酸的5'端。
在一个实施例中，缀合物部分是三价N-乙酰半乳糖胺(GalNAc)，诸如图1所示的那些。在一个实施例中，缀合物部分是图1A-1或图1A-2的三价N-乙酰半乳糖胺(GalNAc)或者两者的混合物。在一个实施例中，缀合物部分是图1B-1或图1B-2的三价N-乙酰半乳糖胺(GalNAc)或者两者的混合物。在一个实施例中，缀合物部分是图1C-1或图1C-2的三价N-乙酰半乳糖胺(GalNAc)或者两者的混合物。在一个实施例中，缀合物部分是图1D-1或图1D-2的三价N-乙酰半乳糖胺(GalNAc)或者两者的混合物。
制造方法
在另一方面，本发明提供了用于制造本发明的寡核苷酸的方法，该方法包括使核苷酸单元反应并由此形成包含在寡核苷酸中的共价连接的连续核苷酸单元。优选地，该方法使用亚磷酰胺化学方法(参见例如Caruthers等人,1987,Methods in Enzymology，第154卷，第287-313页)。在另一个实施例中，该方法进一步包括使连续核苷酸序列与缀合物部分(配体)反应以将缀合物部分共价附接于寡核苷酸。在另一个方面，提供了一种用于制备本发明的组合物的方法，该方法包括将本发明的寡核苷酸或缀合寡核苷酸与药用稀释剂、溶剂、载体、盐和/或佐剂混合。
药用盐
根据本发明的化合物可以以其药用盐的形式存在。术语“药用盐”是指保留本发明的化合物的生物学有效性和特性的常规酸加成盐或碱加成盐。
在另一个方面，本发明提供核酸分子或其缀合物的药用盐，诸如药用钠盐、铵盐或钾盐。
药物组合物
在另一个方面，本发明提供了药物组合物，其包含本发明的化合物中的任何化合物，特别是前述核酸分子和/或核酸分子缀合物或其盐以及药用稀释剂、载体、盐和/或佐剂。药用稀释剂包括磷酸盐缓冲盐水(PBS)，而药用盐包括但不限于钠盐和钾盐。在一些实施例中，药用稀释剂是无菌磷酸盐缓冲盐水。在一些实施例中，核酸分子以50μM至300μM溶液的浓度在药用稀释剂中使用。
用于本发明的合适的制剂可见于《雷明顿药物科学(第十七版)》(Remington'sPharmaceutical Sciences,Mack Publishing Company,Philadelphia,Pa.,17th ed.,1985)中。对于药物递送方法的简要综述，参见例如Langer(Science249:1527-1533,1990)。WO 2007/031091(通过引用并入本文)提供了药用稀释剂、载体和佐剂的其他合适的和优选的实例。WO2007/031091中也提供了合适的剂量、制剂、施用途径、组合物、剂型、与其他治疗剂的组合、前药制剂。
在一些实施例中，本发明的核酸分子或核酸分子缀合物或其药用盐为固体形式，诸如粉末，诸如冻干粉末。
可以将本发明的化合物、核酸分子或核酸分子缀合物与药用活性或惰性物质混合，以用于制备药物组合物或制剂。药物组合物的组成和配制方法取决于许多标准，包括但不限于施用途径、疾病程度或施用剂量。
这些组合物可以通过常规的灭菌技术进行灭菌，或者可以进行无菌过滤。所得的水溶液可以包装后直接使用或冻干，在施用前将冻干的制剂与无菌水性运载体混合。制剂的pH通常为介于3至11之间，更优选地介于5和9之间或介于6和8之间，并且最优选地介于7和8之间，诸如7至7.5。可以将固体形式的所得组合物包装在多个单剂量单元中，每一个单元包含固定量的一种或多种上述试剂，诸如在片剂或胶囊的密封包装中。固体形式的组合物也可以灵活的量包装在容器中，诸如在设计用于局部适用的乳膏或软膏的可挤压管中。
在一些实施例中，本发明的核酸分子或核酸分子缀合物为前药。特别地，对于核酸分子缀合物，一旦前药被递送至作用位点例如靶细胞，缀合物部分就被从核酸分子上切割下来。
施用
本发明的化合物、核酸分子或核酸分子缀合物或药物组合物可以局部施用或肠内施用或肠胃外(例如静脉内、皮下或肌肉内)施用。
在一个优选的实施例中，本发明的寡核苷酸或药物组合物通过肠胃外途径施用，包括静脉内、动脉内、皮下、腹膜内或肌肉内注射或输注。在一个实施例中，活性核酸分子或核酸分子缀合物在静脉内施用。在另一个实施例中，活性核酸分子或核酸分子缀合物在皮下施用。
在一些实施例中，本发明的核酸分子、核酸分子缀合物或药物组合物以0.1mg/kg至15mg/kg，诸如0.2mg/kg至10mg/kg、诸如0.25mg/kg至5mg/kg的剂量施用。施用可以是每周一次、每二周一次、每三周一次或甚至每月一次。
本发明还提供了如所述的本发明的核酸分子或核酸分子缀合物用于制备药物的用途，其中所述药物是皮下施用的剂型。
组合疗法
在一些实施例中，本发明的抑制剂诸如本发明的核酸分子、核酸分子缀合物或药物组合物在与另一种治疗剂的联合治疗中使用。治疗剂可以例如是上述疾病或疾患的护理标准。
举例来说，本发明的核酸分子或核酸分子缀合物可以与其他活性物质联合使用，诸如基于寡核苷酸的抗病毒剂(诸如基于序列特异性寡核苷酸的抗病毒剂)，其通过反义(包括其他LNA寡聚物)、siRNA(诸如ARC520)、适体、吗啉代物或任何其他抗病毒剂，核苷酸序列依赖性作用模式作用。
作为进一步的实例，本发明的核酸分子或核酸分子缀合物可以与其他活性物质，诸如免疫刺激性抗病毒化合物，诸如干扰素(例如聚乙二醇化干扰素α)、TLR7激动剂(例如GS-9620)或治疗性疫苗联合使用。
作为进一步的实例，本发明的核酸分子或核酸分子缀合物可以与具有抗病毒活性的其他活性物质诸如小分子联合使用。这些其他活性物质可以是例如核苷/核苷酸抑制剂(例如恩替卡韦或富马酸替诺福韦二吡呋酯酯)、衣壳化抑制剂、进入抑制剂(例如Myrcludex B)。
在某些实施例中，另外的治疗剂可以是HBV剂、丙型肝炎病毒(HCV)剂、化疗剂、抗生素、镇痛剂、非甾体抗炎(NSAID)剂、抗真菌剂、抗寄生虫剂、止吐剂、抗腹泻剂或免疫抑制剂。
特别地，相关的实施例中，另外的HBV剂可以是干扰素α-2b、干扰素α-2a和干扰素αcon-1(聚乙二醇化和非聚乙二醇化)、利巴韦林；HBV RNA复制抑制剂；第二反义寡聚物；HBV治疗性疫苗；HBV预防性疫苗；拉米夫定(3TC)；恩替卡韦(ETV)；富马酸替诺福韦二吡呋酯酯(TDF)；替比夫定(LdT)；阿德福韦；或HBV抗体疗法(单克隆或多克隆)。
在其他特定的相关实施例中，另外的HCV剂可以是干扰素α-2b、干扰素α-2a和干扰素αcon-1(聚乙二醇化和非聚乙二醇化)；利巴韦林；Pegasys；HCV RNA复制抑制剂(例如ViroPharma的VP50406系列)；HCV反义剂；HCV治疗性疫苗；HCV蛋白酶抑制剂；HCV解旋酶抑制剂；或HCV单克隆或多克隆抗体疗法。
应用
本发明的核酸分子可作为研究试剂使用，例如用于诊断、治疗和预防。
在研究中，此类核酸分子可用于特异性调节细胞(例如体外细胞培养物)和实验动物中A1CF蛋白的合成，从而有助于靶标的功能分析或对其作为治疗干预靶标的可用性的评估。通常，通过降解或抑制产生蛋白质的mRNA从而防止蛋白质形成，或通过降解或抑制产生蛋白质的基因或mRNA来实现靶标调节。
如果在研究或诊断中采用本发明的核酸分子，则靶核酸可以是cDNA或衍生自DNA或RNA的合成核酸。
本发明还包括用于调节表达A1CF的靶细胞中的A1CF表达的体内或体外方法，所述方法包括以有效量向所述细胞施用本发明的核酸分子、缀合物化合物或药物组合物。
在一些实施例中，靶细胞是哺乳动物细胞，特别是人细胞。靶细胞可以是形成哺乳动物组织的一部分的体外细胞培养物或体内细胞。在优选的实施例中，靶细胞存在于肝脏中。靶细胞可以是肝细胞。
本发明的一个方面涉及用作药物的本发明的核酸分子、缀合物化合物或药物组合物。
在本发明的一个方面，A1CF抑制剂，诸如本发明的核酸分子、缀合物化合物或药物组合物能够降低HBV感染细胞中的cccDNA水平，并且从而抑制HBV感染。特别地，反义寡核苷酸能够影响以下参数中的一个或多个：i)减少cccDNA和/或ii)减少pgRNA和/或iii)减少HBV DNA和/或iv)减少感染细胞中的HBV病毒抗原。
例如，抑制HBV感染的核酸分子可以i)与对照物相比，将感染细胞中的cccDNA水平降低至少40％，诸如降低50％、60％或70％；或ii)与对照物相比，将pgRNA的水平降低至少40％，诸如降低50％、60％或70％。对照物可以是未处理的细胞或动物，或用适当的对照物处理的细胞或动物。
HBV感染的抑制作用可以在体外使用HBV感染的原代人肝细胞进行测量，或在体内使用人源化肝细胞PXB小鼠模型(可从PhoenixBio获得，也参见Kakuni等人,2014Int.J.Mol.Sci.15:58-74)进行测量。对HBsAg和/或HBeAg分泌的抑制可以通过ELISA测定，例如使用CLIA ELISA试剂盒(Autobio Diagnostic)根据制造商的说明进行。细胞内cccDNA或HBV mRNA和pgRNA的减少可通过qPCR测定，例如，如“材料和方法”章节所述。评估测试化合物是否抑制HBV感染的其他方法是通过例如WO 2015/173208中所述的qPCR测量HBV DNA的分泌，或使用Northern印迹杂交、原位杂交或免疫荧光测量。
由于A1CF水平的降低，本发明的核酸分子、缀合物化合物或药物组合物可用于抑制HBV感染的发展或用于治疗HBV感染。特别地，与仅减少HBsAg分泌的化合物相比，本发明的核酸分子、缀合物化合物或药物组合物通过对cccDNA的去稳定化和减少作用而更有效地抑制了慢性HBV感染的发展或治疗慢性HBV感染。
因此，本发明的一个方面涉及A1CF抑制剂，诸如本发明的核酸分子、缀合物化合物或药物组合物用于减少HBV感染者中的cccDNA和/或pgRNA的用途。
本发明的另一方面涉及A1CF抑制剂，诸如本发明的核酸分子、缀合物化合物或药物组合物在抑制慢性HBV感染的发展或治疗慢性HBV感染中的用途。
本发明的另一方面涉及A1CF抑制剂，诸如本发明的核酸分子、缀合物化合物或药物组合物在降低HBV感染之人的传染性中的用途。在本发明的一个特定方面，A1CF抑制剂，诸如本发明的核酸分子、缀合物化合物或药物组合物抑制慢性HBV感染的发展。
用A1CF抑制剂，诸如本发明的核酸分子、缀合物化合物或药物组合物治疗(或预防性地接受本发明的核酸分子、缀合物化合物或药物组合物)的受试者优选为人，更优选地为HBsAg阳性和/或HBeAg阳性的人类患者，甚至更优选地为HBsAg阳性和HBeAg阳性的人类患者。
因此，本发明涉及一种治疗HBV感染的方法，其中该方法包括施用有效量的A1CF抑制剂，诸如本发明的核酸分子、缀合物化合物或药物组合物。本发明进一步涉及预防由慢性HBV感染引起的肝硬化和肝细胞癌的方法。在一个实施例中，本发明的A1CF抑制剂不旨在用于治疗肝细胞癌，仅旨在预防。
本发明还提供了A1CF抑制剂，诸如本发明的核酸分子、缀合物化合物或药物组合物用于制备药物的用途，特别是在HBV感染或慢性HBV感染或降低HBV感染之人的传染性中使用的药物。在优选的实施例中，药物被制备成用于皮下施用的剂型。
本发明还提供了本发明的核酸分子、缀合物化合物、药物组合物用于制备药物的用途，其中所述药物为用于静脉内施用的剂型。
A1CF抑制剂，诸如本发明的核酸分子、缀合物或药物组合物可以用于组合疗法。例如，可以将本发明的核酸分子、缀合物或药物组合物与其他抗HBV剂诸如干扰素α-2b、干扰素α-2a和干扰素αcon-1(聚乙二醇化和非聚乙二醇化)、利巴韦林、拉米夫定(3TC)、恩替卡韦、替诺福韦、替比夫定(LdT)、阿德福韦或其他新兴的抗HBV药物诸如HBV RNA复制抑制剂、HBsAg分泌抑制剂、HBV衣壳抑制剂、反义寡聚物(例如，如WO2012/145697、WO 2014/179629和WO2017/216390中所述)、siRNA(例如，在WO 2005/014806、WO 2012/024170、WO 2012/2055362、WO 2013/003520、WO 2013/159109、WO 2017/027350和WO2017/015175中所述)、HBV治疗性疫苗、HBV预防性疫苗、HBV抗体治疗(单克隆或多克隆)或TLR 2、3、7、8或9激动剂联合来治疗和/或预防HBV。
本发明的实施方式
本发明的以下实施例可以与本文描述的任何其他实施例联合使用。以上在本文中(特别是在章节“发明内容”、“定义”和“具体实施方式”中)提供的定义和解释比照适用于下文。
1.一种A1CF抑制剂，其在乙型肝炎病毒(HBV)感染的治疗和/或预防中使用。
2.根据实施例1所述使用的A1CF抑制剂，其中A1CF抑制剂以有效量施用。
3.根据实施例1或2所述使用的A1CF抑制剂，其中HBV感染为慢性感染。
4.根据实施例1至3所述使用的A1CF抑制剂，其中A1CF抑制剂能够减少感染细胞中的cccDNA和/或pgRNA的量。
5.根据实施例1至4中任一项所述使用的A1CF抑制剂，其中A1CF抑制剂防止或减少A1CF蛋白与cccDNA的缔合。
6.根据实施例5所述使用的A1CF抑制剂，其中所述抑制剂为与A1CF蛋白特异性结合的小分子，其中所述抑制剂防止或减少A1CF蛋白与cccDNA的缔合。
7.根据实施例6所述使用的A1CF抑制剂，其中A1CF蛋白由SEQ ID NO:4、SEQ IDNO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10或SEQ ID NO:11编码。
8.用于根据实施例1至7中任一项所述使用的A1CF抑制剂，其中所述抑制剂是一个长度为12个至60个核苷酸的核酸分子，其包含长度为至少12个核苷酸的连续核苷酸序列或由其组成，所述连续核苷酸序列与哺乳动物A1CF靶核酸至少90％互补。
9.根据实施例8所述使用的A1CF抑制剂，该抑制剂能够降低哺乳动物A1CF靶核酸的水平。
10.根据实施例8或9所述使用的A1CF抑制剂，其中哺乳动物A1CF靶核酸为RNA。
11.根据实施例10所述使用的A1CF抑制剂，其中RNA是前体mRNA。
12.根据实施例8至11中任一项所述使用的A1CF抑制剂，其中核酸分子选自由以下项组成的组：反义寡核苷酸、siRNA和shRNA。
13.根据实施例12所述使用的A1CF抑制剂，其中核酸分子为单链反义寡核苷酸或双链siRNA。
14.根据实施例8至13中任一项所述使用的A1CF抑制剂，其中哺乳动物A1CF靶核酸选自由以下项组成的组：SEQ ID NO:1、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ IDNO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10和SEQ ID NO:11。
15.根据实施例8至13中任一项所述使用的A1CF抑制剂，其中核酸分子的连续核苷酸序列与SEQ ID NO:1和SEQ ID NO:2的靶核酸至少98％互补，诸如完全互补。
16.根据实施例8至13中任一项所述使用的A1CF抑制剂，其中核酸分子的连续核苷酸序列与SEQ ID NO:1和SEQ ID NO:2以及SEQ ID NO:3的靶核酸至少98％互补，诸如完全互补。
17.根据实施例1至16中任一项所述使用的A1CF抑制剂，其中当与对照相比时，HBV感染细胞中的cccDNA的量减少了至少50％，诸如60％。
18.根据实施例1至16中任一项所述使用的A1CF抑制剂，其中当与对照相比时，HBV感染细胞中的pgRNA的量减少了至少50％，诸如60％。
19.根据实施例8至18中任一项所述使用的A1CF抑制剂，其中当与对照相比时，哺乳动物A1CF靶核酸的量减少了至少50％，诸如60％。
20.一种长度为12个至60个核苷酸的核酸分子，该核酸分子包含长度为12个至30个核苷酸的连续核苷酸序列或由其组成，其中连续核苷酸序列与哺乳动物A1CF靶核酸至少90％互补，诸如95％、诸如98％、诸如完全互补。
21.根据实施例20所述的核酸分子，其中核酸分子是通过化学方法产生的。
22.根据实施例20或21所述的核酸分子，其中所述哺乳动物A1CF靶核酸选自由以下项组成的组：SEQ ID NO:1、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQID NO:8、SEQ ID NO:9、SEQ ID NO:10和SEQ ID NO:11。
23.根据实施例20或21所述的核酸分子，其中该连续核苷酸序列与SEQ ID NO:1和SEQ ID NO:2的靶核酸至少98％互补，诸如完全互补。
24.根据实施例20或21所述的核酸分子，其中连续核苷酸序列与SEQ ID NO:1和SEQ ID NO:2以及SEQ ID NO:3的靶核酸完全互补。
25.根据实施例20至23中任一项所述的核酸分子，其中核酸分子的长度为12个至30个核苷酸。
26.根据实施例20至25中任一项所述的核酸分子，其中核酸分子为RNAi分子，诸如双链siRNA或shRNA。
27.根据实施例20至25中任一项所述的核酸分子，其中核酸分子为单链反义寡核苷酸。
28.根据实施例20至27中任一项所述的核酸分子，其中所述连续核苷酸序列与选自表4或表5的靶核酸序列完全互补。
29.根据实施例20至28中任一项所述的核酸分子，该核酸分子能够以低于-15kcal的ΔG°与SEQ ID NO:1和SEQ ID NO:2的靶核酸杂交。
30.根据实施例20至29中任一项所述的核酸分子，其中连续核苷酸序列包含至少14个连续核苷酸，特别是15个、16个、17个、18个、19个、20个、21个或22个连续核苷酸或由它们组成。
31.根据实施例20至29中任一项所述的核酸分子，其中连续核苷酸序列包含14个至22个核苷酸或由其组成。
32.根据实施例31所述的核酸分子，其中连续核苷酸序列包含16个至20个核苷酸或由其组成。
33.根据实施例20至32中任一项所述的核酸分子，其中核酸分子包含长度为14个至25个核苷酸或由其组成。
34.根据实施例33所述的核酸分子，其中核酸分子包含长度为16个至22个核苷酸的至少一个寡核苷酸链或由其组成。
35.根据实施例20至34中任一项所述的核酸分子，其中所述连续核苷酸序列与选自由SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:15组成的组的靶序列完全互补。
36.根据实施例20至35中任一项所述的核酸分子，其中较之于与其互补的哺乳动物A1CF靶核酸，连续核苷酸序列具有零至三个错配。
37.根据实施例36所述的核酸分子，其中与哺乳动物A1CF靶核酸相比，连续核苷酸序列具有一个错配。
38.根据实施例36所述的核酸分子，其中与哺乳动物A1CF靶核酸相比，连续核苷酸序列具有两个错配。
39.根据实施例36所述的核酸分子，其中连续核苷酸序列与哺乳动物A1CF靶核酸完全互补。
40.根据实施例20至39中任一项所述的核酸分子，该核酸分子包含一个或多个修饰的核苷。
41.根据实施例40所述的核酸分子，其中该一个或多个经修饰的核苷为高亲和力修饰的核苷。
42.根据实施例40或41所述的核酸分子，其中该一个或多个修饰的核苷为2'糖修饰的核苷。
43.根据实施例42所述的核酸分子，其中该一个或多个2'糖修饰的核苷独立地选自由以下项组成的组：2'-O-烷基-RNA、2'-O-甲基-RNA、2'-烷氧基-RNA、2'-O-甲氧基乙基-RNA、2'-氨基-DNA、2'-氟-DNA、2'-氟-ANA和LNA核苷。
44.根据实施例40至43中任一项所述的核酸分子，其中该一个或多个修饰的核苷为LNA核苷。
45.根据实施例44所述的核酸分子，其中修饰的LNA核苷选自由以下项组成的组：氧基-LNA、氨基-LNA、硫代-LNA、cET和ENA。
46.根据实施例44或45所述的核酸分子，其中修饰的LNA核苷为具有以下2'-4'桥–O-CH2-的氧基-LNA。
47.根据实施例46所述的核酸分子，其中氧基-LNA为β-D-氧基-LNA。
48.根据实施例44或45所述的核酸分子，其中修饰的LNA核苷为具有以下2'-4'桥–O-CH(CH3)-的cET。
49.根据实施例48所述的核酸分子，其中cET为(S)cET，即6'(S)甲基-β-D-氧基-LNA。
50.根据实施例44或45所述的核酸分子，其中LNA为ENA，具有以下2'–4'桥–O-CH2-CH2-。
51.根据实施例20至50中任一项所述的核酸分子，其中核酸分子包含至少一个修饰的核苷间键。
52.根据实施例51所述的核酸分子，其中该至少一个修饰的核苷间键为硫代磷酸酯核苷间键。
53.根据实施例20至52中任一项所述的核酸分子，其中核酸分子为能够募集RNA酶H的反义寡核苷酸。
54.根据实施例53所述的核酸分子，其中反义寡核苷酸或连续核苷酸序列为间隔聚体。
55.根据实施例54所述的核酸分子，其中反义寡核苷酸或其连续核苷酸序列包含式5'-F-G-F'-3′的间隔聚体或由其组成，其中区域F和F'独立地包含1个至4个2'糖修饰的核苷或由其组成，并且G为介于6个与18个核苷之间的能够募集RNA酶H的区域。
56.根据实施例55所述的核酸分子，其中1个至4个2'糖修饰的核苷独立地选自由以下项组成的组：2'-O-烷基-RNA、2′-O-甲基-RNA、2'-烷氧基-RNA、2'-O-甲氧基乙基-RNA、2'-氨基-DNA、2'-氟-DNA、阿糖核酸(ANA)、2'-氟-ANA和LNA核苷。
57.根据实施例55或56所述的核酸分子，其中区域F和F'中的1个至4个2'糖修饰的核苷中的一个或多个核苷为LNA核苷。
58.根据实施例57所述的核酸分子，其中区域F和F′中的所有2'糖修饰的核苷均为LNA核苷。
59.根据实施例56至58中任一项所述的核酸分子，其中所述LNA核苷选自β-D-氧基-LNA、α-L-氧基-LNA、β-D-氨基-LNA、α-L-氨基-LNA、β-D-硫代-LNA、α-L-硫代-LNA、(S)cET、(R)cETβ-D-ENA和α-L-ENA。
60.根据实施例56至59中任一项所述的核酸分子，其中区域F和F'由相同的LNA核苷组成。
61.根据实施例56至60中任一项所述的核酸分子，其中区域F和F'中的所有2'糖修饰的核苷均为氧基-LNA核苷。
62.根据实施例55至61中任一项所述的核酸分子，其中区域G中的核苷为DNA核苷。
63.根据实施例62所述的核酸分子，其中区域G由至少75％的DNA核苷组成。
64.根据实施例63所述的核酸分子，其中区域G中的所有核苷均为DNA核苷。
65.一种缀合物化合物，该缀合物化合物包含根据实施例20至64中任一项所述的核酸分子，以及共价连接至所述核酸分子的至少一个缀合物部分。
66.根据实施例65所述的缀合物化合物，其中核酸分子是双链siRNA，并且缀合物部分共价连接至siRNA的正义链。
67.根据实施例65或66所述的缀合物化合物，其中缀合物部分选自碳水化合物、细胞表面受体配体、原料药、激素、亲脂性物质、聚合物、蛋白质、肽、毒素、维生素、病毒蛋白质或它们的组合。
68.根据实施例65至67中任一项所述的缀合物化合物，其中缀合物部分能够与脱唾液酸糖蛋白受体结合。
69.根据实施例68所述的缀合物化合物，其中缀合物部分包含至少一个选自由以下项组成的组的脱唾液酸糖蛋白受体靶向部分：半乳糖、半乳糖胺、N-甲酰基-半乳糖胺、N-乙酰半乳糖胺、N-丙酰基-半乳糖胺、N-正丁酰基-半乳糖胺和N-异丁酰基半乳糖胺。
70.根据实施例69所述的缀合物化合物，其中脱唾液酸糖蛋白受体靶向部分是N-乙酰半乳糖胺(GalNAc)。
71.根据实施例69或70所述的缀合物化合物，其中缀合物部分相对于脱唾液酸糖蛋白受体靶向部分为一价、二价、三价或四价。
72.根据实施例71所述的缀合物化合物，其中缀合物部分由两个至四个末端GalNAc部分和将每一个GalNAc部分连接至可与反义化合物缀合的支链分子的间隔物组成。
73.根据实施例72所述的缀合物化合物，其中间隔物为PEG间隔物。
74.根据实施例68至73中任一项所述的缀合物化合物，其中缀合物部分是GalNAc部分，诸如三价N-乙酰半乳糖胺(GalNAc)部分。
75.根据实施例68至74中任一项所述的缀合物化合物，其中缀合物部分选自图1中的三价GalNAc部分中的一者。
76.根据实施例75所述的缀合物化合物，其中缀合物部分为图1B-1或图1B-2的三价GalNAc部分或者两者的混合物。
77.根据实施例75所述的缀合物化合物，其中缀合物部分为图1D-1或图1D-2的三价GalNAc部分或者两者的混合物。
78.根据实施例65至77中任一项所述的缀合物化合物，该缀合物化合物包含位于核酸分子与缀合物部分之间的接头。
79.根据实施例78所述的缀合物化合物，其中接头为生理上不稳定的接头。
80.根据实施例79所述的缀合物化合物，其中生理上不稳定的接头为核酸酶敏感的接头。
81.根据实施例79或80中任一项所述的缀合物化合物，其中生理上不稳定的接头由2个至5个连续的磷酸二酯键组成。
82.根据实施例65至81中任一项所述的缀合物化合物，该缀合物化合物显示经改善的在肝脏(相比于肾脏)之间的细胞分布，或者与未缀合的核酸相比，改善了肝脏对缀合物化合物的细胞吸收。
83.一种药物组合物，其包含根据实施例20至64中任一项所述的核酸分子、根据实施例65至82中任一项所述的缀合物化合物或其药用盐以及药用稀释剂、运载体、盐和/或佐剂。
84.一种识别预防、改善和/或抑制乙型肝炎病毒(HBV)感染的化合物的方法，包括：
a.将测试化合物与
i.A1CF多肽或
ii.表达A1CF的细胞接触；
b.在存在或不存在所述测试化合物的情况下，测量A1CF的表达和/或活性；以及
c.识别降低A1CF表达和/或活性并减少cccDNA的化合物。
85.一种用于在表达A1CF的靶细胞中调节A1CF表达的体内或体外方法，所述方法包括向所述细胞施用有效量的根据实施例20至64中任一项所述的核酸分子、根据实施例65至82中任一项所述的缀合物化合物，或根据实施例83所述的药物组合物。
86.根据实施例85所述的方法，其中与未经任何处理或经对照物处理的水平相比，靶细胞中的A1CF表达降低了至少50％，或至少60％。
87.根据实施例85所述的方法，其中所述靶细胞被HBV感染，并且与未经任何处理或经对照物处理的水平相比，在所述HBV感染靶细胞中，HBV感染细胞中的cccDNA减少了至少50％，或减少了至少60％。
88.一种用于治疗或预防疾病，诸如HBV感染的方法，其包括向患有或易患所述疾病的受试者施用治疗或预防有效量的根据实施例20至64中任一项所述的核酸分子、根据实施例65至82中任一项所述的缀合物化合物、或根据实施例83所述的药物组合物。
89.根据实施例20至64中任一项所述的核酸分子，或根据实施例65至82中任一项所述的缀合物化合物，或根据实施例83所述的药物组合物，所述核酸分子、所述缀合物化合物、所述药物组合物以用于用作用于治疗或预防受试者中的疾病，诸如HBV感染的药物。
90.用于制备治疗或预防受试者中的疾病(诸如HBV感染)的药物的根据实施例20至64中任一项所述的核酸分子、或根据实施例65至82中任一项所述的缀合物化合物的用途。
91.根据实施例88至90中任一项所述的方法、核酸分子、缀合物化合物或用途，其中受试者是哺乳动物。
92.根据实施例91所述的方法、核酸分子、缀合物化合物或用途，其中哺乳动物是人。
现在将通过以下实例说明本发明，所述实例不具有限制性。
实例
材料和方法
siRNA序列和化合物
表6：被siRNA池的各个组分所靶向的人A1CF序列
siRNA池(ON-TARGETplus SMART池siRNA产品目录号LU-013576-02-0005，Dharmacon)含有四个单独的siRNA分子，该四个单独的siRNA分子靶向上表中列出的序列。
表7：对照化合物
寡核苷酸合成
寡核苷酸合成是本领域公知的。以下是可以实施的方案。就设备、载体和所用浓度而言，本发明的寡核苷酸可以通过略有变化的方法来产生。
使用亚磷酰胺方法在Oligomaker 48上以1μmol规模在尿苷通用载体上合成寡核苷酸。合成结束时，使用氨水在60℃下将寡核苷酸从固体支持物上裂解5-16小时。通过反相HPLC(RP-HPLC)或通过固相萃取纯化寡核苷酸，通过UPLC进行表征，并通过ESI-MS进一步确认分子量。
寡核苷酸的延伸：
通过使用5'-O-DMT保护的亚酰胺在乙腈中的0.1M溶液和DCI(4,5-二氰基咪唑)在乙腈(0.25M)中用作活化剂，进行β-氰基乙基亚磷酰胺的偶联(DNA-A(Bz)、DNA-G(ibu)、DNA-C(Bz)、DNA-T、LNA-5-甲基-C(Bz)、LNA-A(Bz)、LNA-G(dmf)或LNA-T)。对于最后的循环，可以使用具有所需修饰的亚磷酰胺，例如，用于附接缀合物基团或这样的缀合物基团的C6接头。通过使用氢化黄原素(0.01M，在乙腈/吡啶9:1中)进行硫醇化以引入硫代磷酸酯键。可以使用碘在THF/吡啶/水7:2:1中的0.02M溶液引入磷酸二酯键。其余试剂是通常用于寡核苷酸合成的试剂。
对于固相合成后的缀合，可以在固相合成的最后一个循环中使用可商购的C6氨基接头亚磷酰胺，并且在脱保护并从固体载体上裂解后，分离出氨基连接的脱保护的寡核苷酸。使用标准合成方法通过官能团的活化来引入缀合物。
通过RP-HPLC纯化：
粗制化合物在Phenomenex Jupiter C18 10μm 150x10 mm色谱柱上通过制备型RP-HPLC纯化。0.1M醋酸铵pH 8和乙腈以5mL/min的流速用作缓冲液。将收集的级分冻干以给出纯化的化合物，通常为白色固体。
缩写：
DCI：4,5-二氰基咪唑
DCM：二氯甲烷
DMF：二甲基甲酰胺
DMT：4,4’-二甲氧基三苯甲基
THF：四氢呋喃
Bz： 苯甲酰基
Ibu： 异丁酰基
RP-HPLC：反相高效液相色谱
Tm测定：
将寡核苷酸和RNA靶标(磷酸酯连接的，PO)双链体在500ml无RNA酶的水中稀释至3mM，并与500ml 2x Tm缓冲液(200mM NaCl、0.2mM EDTA、20mM磷酸钠、pH 7.0)混合。将溶液加热到95℃持续3分钟，然后在室温下退火30分钟。使用PE Templab软件在配备有Peltier温度编程器PTP6的Lambda 40UV/VIS分光光度计(Perkin Elmer)上测量双链体解链温度(Tm)。温度从20℃上升到95℃，然后下降到25℃，记录在260nm处的吸收。使用一阶导数以及解链和退火的局部最大值来评估双链体Tm。
克隆生长培养基(dHCGM)。dHCGM是DMEM培养基，其包含100U/ml青霉素、100μg/ml链霉素、20mM Hepes、44mM NaHCO3、15μg/ml L-脯氨酸、0.25μg/ml胰岛素、50nM***、5ng/ml EGF、0.1mM Asc-2P、2％DMSO和10％ FBS(Ishida等人,2015)。将细胞在37℃的培养箱中于具有5％CO2的潮湿气氛中进行培养。接种后24小时更换培养基，并每2天更换一次直至收获。
HBV感染的PHH细胞
新鲜原代人肝细胞(PHH)由日本东广岛市PhoenixBio以96孔板格式、70,000个细胞/孔来进行提供(PXB-细胞也在Ishida等人2015Am J Pathol.185(5):1275-85中描述)。
到达后，使用HepG2 2.2.15衍生的HBV(批次Z12)，通过将PHH细胞与HBV在PHH培养基中的4％(v/v)PEG中孵育16小时，以2GE的MOI感染PHH。然后，细胞用PBS洗涤三次，并且于具有5％ CO2的潮湿气氛中在新鲜PHH培养基中进行培养，该培养基由补充有以下项的DMEM(GIBCO,Cat#21885)组成：10％(v/v)热灭活的胎牛血清(GIBCO,Cat#10082)、2％(v/v)DMSO、1％(v/v)青霉素/链霉素(GIBCO,Cat#15140-148)、20mM HEPES(GIBCO,Cat#15630-080)、44mM NaHCO3(Wako,Cat#195-14515)、15μg/ml L-脯氨酸(MP-Biomedicals,Cat#0219472825)、0.25μg/ml胰岛素(Sigma,Cat#I1882)、50nM***(Sigma,Cat#D8893)、5ng/ml EGF(Sigma,Cat#E9644)和0.1mM L-抗坏血酸2-磷酸酯(Wako,Cat#013-12061)。将细胞在37℃的培养箱中于具有5％ CO2的潮湿气氛中进行培养。接种后24小时更换培养基，并且每周更换三次直至收获。
siRNA转染
在感染后四天，细胞用A1CF siRNA池(参见表6)一式三份转染。无药物对照(NDC)、阴性对照siRNA和HBx siRNA被包括作为对照(参见表7)。
对于每个孔，用2μl阴性对照siRNA(原液浓度1μM)、A1CF siRNA池(原液浓度1μM)、HBx对照siRNA(原液浓度0.12μM)或H2O(NDC)与18.2μl
(Thermo FisherScientific减血清培养基)和0.6μl/>
RNAiMAX转染试剂(ThermofisherScientific目录号13778)制备转染混合物。在转染之前，将转染混合物混合并且在室温下孵育5分钟。在转染之前，将培养基从PHH细胞中去除，并替换为100μl/孔William's E培养基+GlutaMAXTM(Gibco，#32551)，并以不含P/S的HepaRG补充剂(BiopredicInternational，#ADD711C)补充。将20μl转染混合物添加到每个孔中，使阴性对照siRNA或A1CF siRNA池的最终浓度为16nM，或者使HBx对照siRNA的最终浓度为1.92nM，并将板轻轻摇动，然后放入培养箱中。6小时后用PHH培养基替换该培养基。如上所述，在感染后的第6天重复siRNA处理。在感染后的第8天，收获上清液并且存储在-20℃处。如果需要，可以从上清液中确定HBsAg和HBeAg。
HBV抗原表达的测量：如果需要，可以在收集的上清液中测量HBV抗原表达和分泌。根据制备商的方案，使用CLIA ELISA试剂盒(Autobio Diagnostic#CL0310-2，#CL0312-2)测量HBV传播参数，HBsAg和HBeAg水平。简而言之，将每孔25μL的上清液转移至由各自抗体包被的微量滴定板，并添加25μL的酶缀合物试剂。将该板于室温下在摇床上孵育60分钟，然后使用自动洗濯器用洗涤缓冲液将孔洗涤五次。向每一个孔中添加25μL底物A和B。在使用
发光读数器(Perkin Elmer)测量发光之前，将该板于室温下在摇床上孵育10分钟。
细胞活力测量
由细胞计数试剂盒-8(CCK8，来自Sigma Aldrich,#96992)对无上清液的细胞测量细胞活力。对于测量，CCK8试剂在正常培养基中以1:10进行稀释，并且以100μl/孔添加至细胞。在培养箱中孵育1h后，将80μl的上清液转移至透明平底96孔板并且读取450nm处的吸光度。吸光度值针对设定至100％的NDC进行了归一化，以计算相对细胞活力。
细胞活力测量用于确认病毒参数的任何降低是否都不是由细胞死亡引起，该值越接近100％则毒性越低。
用于cccDNA和HBV DNA定量的qRT-PCR
在细胞活力确定后，细胞用PBS洗涤一次并且随后用来自
GeneExpression Cells-to-CTTM试剂盒(Thermo Fisher Scientific,#AM1729)的50μl/孔裂解溶液来进行裂解并且储存在-80℃处。
在cccDNA qPCR分析之前，用T5酶(15U/4μL细胞裂解物；New England Biolabs,#M0363L)消化一部分细胞裂解物。消化在37℃下持续30分钟。
为了cccDNA的定量，对于每个反应使用了2μl的T5消化的细胞裂解物、0.5μl的20xcccDNA_DANDRI Taqman引物/探针(下表中列出的Life Technologies,custom#AI1RW7N,FAM-dye)、5μl的
Fast Advanced主混合物(Applied Biosystems,#4444557)和2.5μl的DEPC处理的水。对每个样品运行了三次技术重复。
为了细胞内HBV DNA的定量和归一化对照，人类血红蛋白β(HBB)，对于每个反应使用了2μl的未消化的细胞裂解物、0.5μl的20x HBV Taqman引物/探针(LifeTechnologies,#Pa03453406_s1,FAM-dye)、0.5μl的20x HBB Taqman引物/探针(LifeTechnologies,#Hs00758889_s1,VIC-dye)、5μl的
Fast Advanced主混合物(Applied Biosystems,#4444557)和2μl的DEPC处理的水。对每个样品运行了三次技术重复。
qRT-PCR在QuantStudioTMK12 Flex上运行，其中快速加热块为标准设定(在95℃下持续20秒，然后进行40个循环，其中在95℃持续1秒并且在60℃下持续20秒)。
通过排除与对每个样品的所有9个生物学副本和技术副本的中值Ct的差值超过0.9的值，从数据集中去除任何异常值。cccDNA和总HBV DNA的倍数变化通过2-ddCT方法从Ct值确定，并且作为管家基因归一化为HBB。表达水平呈现为平均无药对照样品的％(即，值越低，则抑制/减少越大)。
用于测量A1CF mRNA表达的实时PCR
为了定量A1CF RNA水平以及归一化对照，GUS B，使用了
RNA-to-CtTM1-Step试剂盒(Life Technologies,#4392656)。对于每个反应，使用了2μl的未消化的细胞裂解物、0.5μl的20x A1CF Taqman引物/探针(Life Technologies,#Hs00205840_m1,FAM-dye)、0.5μl的20x GUS B Taqman引物/探针(Life Technologies,#Hs00939627_m1,VIC-dye)、5μl的2x />
RT-PCR混合物、0.25μl的40x />
RT酶混合物和1.75μl的DEPC处理的水。对每个样品运行了技术重复，并且包括负RT对照，以评估由于DNA存在而可能产生的扩增。
qRT-PCR是在QuantStudioTMK12 Flex上运行的，其中在48℃下持续15min，在95℃下持续10min，然后进行40个循环(其中在95℃下持续15秒并且在60℃下持续60秒)。
使用比较周期阈值2-ΔΔCt方法分析A1CF mRNA表达水平，该方法针对参考基因GUS B和未转染的细胞进行了标准化。表8列出了用于GUS B RNA和靶mRNA定量的引物。表达水平呈现为平均无药对照样品的％(即，值越低，则抑制/减少越大)。
表8：GUS B和A1CF mRNA qPCR引物(Thermo Fisher Scientific)
| A1CF引物 | Hs00205840_m1 |
| 管家基因引物 | Hs00939627_m1 |
实施例1：对由siRNA处理导致的HBV感染的PHH细胞中的A1CF mRNA、HBV细胞内DNA和cccDNA的减少的测量
在以下实验中，测试了A1CF敲低对HBV参数、HBV DNA和cccDNA的影响。
用来自Dharmacon的siRNA的池(LU-013576-02-0005，参见表6)处理HBV感染的PHH细胞，如“材料和方法”章节“siRNA转染”所述。
在4天的处理后，通过qPCR测量A1CF mRNA、cccDNA和细胞内HBV DNA，如“材料和方法”章节“用于测量A1CF mRNA表达的实时PCR”以及“用于cccDNA和HBV DNA定量的qRT-PCR”所述。结果显示在表9中，作为相对于无药物对照样品的平均百分比(即，值越低，抑制/减少越大)。
表9：用siRNA的池敲低A1CF后对HBV参数的影响。值作为三次生物重复和三次技术重复的平均值而给出。
ND＝未测定
由此可以看出，A1CF siRNA池能够相当有效地减少A1CF mRNA、cccDNA以及HBVDNA。阳性对照如预期的那样减少了细胞内HBV DNA，但对cccDNA没有影响。
序列表
<110> F.霍夫曼-罗氏公司 (F. Hoffmann-La Roche AG)
<120> A1CF 抑制剂用于治疗乙型肝炎病毒感染的用途
<130> P35530-WO
<150> EP20192212.7
<151> 2020-08-21
<160> 20
<170> PatentIn 版本 3.5
<210> 1
<211> 86267
<212> DNA
<213> 智人 (homo sapiens)
<400> 1
tttgatatga cgattagagc ataacccgag tgacacgttg aattcgccat aatcaaggaa 60
accttttccg ggtggggatc tctgaaatta ctcaggtatg atccatgtgt tttgcttttt 120
tctatttcaa ctctgtgaaa ctgtgtattg tggtatcagt gggaatgcag tgaaaacagc 180
ttttaccctc ttctgttatc gagcctaatt caaagaatta tctagcttgt ttttagacta 240
atgaaacaac cagaaaacaa aagaatatat tggaattatt atataatctc taaatgagat 300
agctgccagg atttaataaa tttctgtaga cttaccacgg agggttcaag agtggagcca 360
atgttgtgag aagtttattt agctctaacc agacagcagg gagagttgtg gttgagtgcc 420
tgtcccaatc ctaggaccct gagaaacaaa aatataatta acaaaagaaa tagtattaac 480
atcaccagca gattttgagt tctgtgtgtg ggtcataatt cctatcatac tttagacttc 540
atatattcaa ttatctccag agctactacc accataaaaa agaaagtctt ggtacaactc 600
ttgcgattcc gcctgccatt atcttgctaa ccaaaggaat gtttaaacta ttcacttttg 660
attctgacca aaaaaatatt atggaaaatg actggttttc agtgtgttaa atctgaacct 720
tggaatggct aattattata ttgtttccac aatttgggca actgtgctga ggtggatata 780
ttttcacata ttttttttgt gtactccaaa aacattataa tggtatttta gctaaagaaa 840
gaaatcaatc tggacattta ccaaaaatat cccattttta ccagaaaccc cctaaactct 900
ctgacttttt gtcatgatta cctatgtaaa ttccaagaag aaaggattcc aaactaaaca 960
attttattta ctataggact tttcagatat gtattgtata tctccaagaa gatgaagaac 1020
acagcattat ttgcacattg tgcaggatta gtgttttata gatcgtattt tggcaaattc 1080
agctctagtt atagtttagg agcatcaaaa aatgtgttgg tctgctctga aattttcttt 1140
ataacgtgtg ctatggagca tgcaatggga gcacaggtct ggaaatgaca gtgatatcac 1200
ttatttgtca aagcagtaag gttttgccct gctaaataca gagaaagaga caaatgactt 1260
ataaggttca tactttctgg aataacattg actctgccca tttcagacaa ctcttaacat 1320
tttactgttc tattttacta tttatcgatt tcaagggaaa aaagaagaca gctggcaagg 1380
aaaagaaata ttgttgtggg caaacattat aaaatgacat aatggatatt aaaacactat 1440
aaatactttg ttcttatttt ctactgcact aatgccaagg tggttttatg tcatttcaaa 1500
tatcaacatt tcctacacta tattcagtgg atgttaataa atgtggctca aaagaaaagc 1560
aactccattg tcaagtaagt tgaggaaaca gtgttagaaa agttatagca ggttttgtta 1620
ccacatgagt gttttgagta ataatgataa caagcatctg tgaagcacta tattatcggg 1680
tctacttcta agttctctcc atgcattatc tcatgttatt cttggaacaa ctctatggtg 1740
tgatactatt ataacagttt ataaatggga aaatggaggc acagacaaat tacctaacag 1800
gctcagctac tcagttagca agtggcagag ccaggctcct ttgtctggta gtctgatcca 1860
gagcccaagc acgtaaccat tatatcatac gctcgagcac tggggactca tgacacatgc 1920
aaatattgtc atttatcaca actatctaag agagtaggca acgttttgtt tcctgggctt 1980
aatttacaac agaacatctt ctttcaggaa catctatcaa tatctctcaa aattggcatt 2040
tctcagaata cagaacaaga aagaccaaat cgcttttata gcccatgtcc agcattcaga 2100
acaatcagaa tccattgaaa taatcacagt tgaaaaatct aaaggacttt agagtctagt 2160
cttccaccaa ataggactat gcctatctga gaaactttta aaattaatta cggaaagaac 2220
actaggcttt gtgcctcgac acagctaagt ggaaacgcct attgtaaaac tccctaggtt 2280
tgtgaccttg ggcatattgt ttgactccac tgaatctcag attcctcaaa tgtgaaatgg 2340
gggtaagatc tgacccatag tattttgtga agtttaaatt agatgataaa gcaaaggaga 2400
gaaatgtggt ccccggtact taagaattca gcaaaaaccc cacttccctt ttcattttcc 2460
tatttgtaac aacctccaga aaaattttct aaaattgccc aagtatacct attaggcctt 2520
gtttttcaaa acaatactaa taaagttgaa atcacaaact gtacataaaa aattttgatt 2580
aatcacaaat agtagcacta ttccatttat tcagagaaag acagtctgta aattttttta 2640
gtattaaagc acacacacag agtatatttt tattttagag attattgctg aagaaaactc 2700
ttagttataa aaccccaaca ccttttcacc caaacccatg ggacaccctg acacagtgca 2760
tgctcatttc atcatggagg cagttgatgt taaaaatctg tttcagtaac tgtcttttaa 2820
aaattgtcat cccttagaaa gctgagtagt actgtgggta ctattgcaca atggttttca 2880
ttaccttatg tgtctctaaa atgactcaat aagttcaaac aagacagtat tgatcgacag 2940
aggataaaca ccattttatc ttattcacag aaacagtaac caggctcctg caaagtgcag 3000
ctctcacaat ccaactgccc ccaggaaaag catctggaaa aggagcagca ctcttgcggt 3060
gacattctgt attagaaatc tgtatcccat ctgctccttg gcctgatcct gtaaaatctg 3120
gagagttatt aacaaatgtt tgctgctgat tcaaccagga aagctagttc atcatttcat 3180
ttcatcaaat ctactccaac taggttatca gttttttgtt gttgatgatg gtttgtttgt 3240
atgagatgga gtatcgttct gttgcctagg ctggagtggt ggtgcaatct cagctcatca 3300
caacctccac ctcctggatt caagtgattc ttgtgcctca gcctcccgag tagctgggat 3360
tacaggcaca cgccaccatg ccaggctaac ttttgtattt ttagtagaga cggggtttca 3420
ttatgttggc taggctggtc tcgaactcct gaactcatga tctgcctgcc tcagcctccc 3480
aaagtgctgg gattacaggc atgagccaac atgcccggtc taggttatca gttttaatga 3540
ccacttagaa tttttaattt aataaactaa aattttgtat tgaatatttt tgattgatgc 3600
aatccaaaaa ttaaaacatg cccttttgta aaaaatcatc gtcctgtata agatatgctg 3660
gtatcttgag agctctaatt tgatttcttt taaacatatg taagctaaga tttttatcct 3720
atatagattt atatgtggag ttttatgcat atatgtatta acaatcacat ggagaacatt 3780
ttccaagttt gtttattcaa taggaattgg tccctggtaa tattaagaga gaaatactaa 3840
taaggatgta agataaatcc ttctgatttg cacagttaag tgcaatgctc tgctccagat 3900
gtaatatgac taaagagaat taacacatga caatttaggc agacagaatg tctaagtgag 3960
cagattggtt tataattcta taaaatccca cctgcagtag tgatgtagtg atgccttccc 4020
tccctccagc aattaaaaac tattcattgt tttaggatgc ccaattgatt taaaaatcac 4080
taggtttaag tagtagaact aactacaata tcttatttcc ataggatatt ctagtttata 4140
aagcttttca tatacaagaa cttataaaga tttttaatgg caaatttctt atagttgatg 4200
tcaattcagt atgcctagtt tcttcaaggt aactgtgtca atattcacca ttccaattgt 4260
acaaatctga ttaactgaaa gatgctccca cctatcgttt ataagcccaa ctctgtttat 4320
gtaacacaat gatgtccaac ttcactggac attaactaat gtacctatca gttaagaggc 4380
tagatgaggc cgggcgcagt ggctcacgcc tgtaattcga acactatggg aggccaaggc 4440
aggcagatca cctgaggtca ggagttcaag accagtctgg ctaacatgac gaaaccccac 4500
ctccagaaaa atacaaaaat tagccaggca tggtggtggg tacctgtaat cccagctacc 4560
caggaggctg aggcgggaaa atcacttgaa cccaggaggc gaaggttgca gtgagccgag 4620
atcgcaccat tgcactccag cctaggcgac agagtgagac tccacctcaa aaaaaaaaaa 4680
agagtctaaa tgaaaacagt gaagagagga cataaaggtc catgtggaag gtgagagaag 4740
aaccaccccc atatgggacc tagaagaaaa cagccctaaa aagatgtaat tataactcag 4800
tccagatgct gtgactaaca cagtgaaaga tataaaggaa cagaggttta taaaatctcc 4860
tacctgcctg gcaggggact ggcaaaacat tgtgcacaaa tgaaattttt tatttctatt 4920
gattttagta ttctatccag ctcttctact gggattctgc ttagtgctta tctttccatc 4980
tggggccttc agcatgaact aaaatgtact ttaaattatt agatgtaatt aaactctaat 5040
gcctctgatt atttgaaatg gaagtcagaa atcaaaatca ggttccatgg ggggaaaact 5100
gtgttggcac atatagatgt tcatctcagg aatcctcttt ctaaccttct tttccgaaga 5160
tccctaagag ttcctcgcca ttcatgtact tactaccaac taattataat tggcacccta 5220
cgatgatgat aacaatgatg ttaataaaat ctcttacatc ctcttacatc ctgccacatg 5280
ccaggcacat aggttaactc atttaatcct ccatcactct atggaatggg tactattgct 5340
acgccatttt tccaataaag cagctacagc ttagggacac agagaaattt gccccaggtc 5400
acaccactaa taagtggtgc aggagtgagt ccgggcagtc tggcacaggc caccctgtga 5460
acaaaggaca aatggaacac tgggaagcat caaggcttag aactgaagaa aacttttgag 5520
atcctttatt tgacagagaa aagcaagttg ggttccccag cttgggtttt tgttagaatg 5580
agaacccaag agcagaacct gaaccctctg tggatacttt tccattatac cacttcccac 5640
tgtaaagcat ttctaattca gcctgattct ctgtgaaaat tctgagagac gaattaatag 5700
aatccctata gttaaacagg aatactccct tcactccaag tctcaccttc cttgctgtgc 5760
ccagactcat ggactgacct agccagagac tcagttaaag gagacccatt ttgtgacttg 5820
gagagactga caggcccaca tcacagagga aatacatgca gacacagaca tggatatggt 5880
ttagcttttt gtccccaccc aaatctcatc ttgaattgta atccttaggc ctgaaggaaa 5940
gaatctggtg agaagtgata ggattatggg ggtggtttcc cccatgctgt tttcatgata 6000
atgagtgaat tctcatgaga cctggtggtt ttataagtgt ttgacttttc cttctgtaca 6060
cactacttct ctcccctgct gtcacataag aaggcctaag cttgcttccc ctttgccttc 6120
caccatgatt gtgagtttcc tgaggcctcc ccagccatgc agaactgtga gtcaattaaa 6180
cctctttctt tataaattac ccagtctcag gtatttcttt gtagcagtat gagaacagac 6240
taatacaggc accatgaaca tagtgacagg ataaaccatg gaggcattga taaaaataaa 6300
aagtaattgt gatgaatgac ttggttgcaa ttacactcaa attctgttag tgtctgaaga 6360
ggacatagca cctcctacct ggaggacata cccttttccc catggaaaaa ataattgggc 6420
tgctaggtct gtgtctgcta agggagtccc atatttaaac tgacctaatt cagaacttta 6480
aattgagact cagatgctcc caaatagcag ctccaccaac ctgaatagag ttactcattt 6540
agaataagag tttgttccca caagttttgt taaaatacaa attagttggg atgcggggtg 6600
tgagtgatag ggactaaaat cgcttaacag actagcctgg caaagccctg tgggaagcaa 6660
gttttgatga tagggaagag aagatgtcaa gagcagatgg tccagggagg aagtgtcaca 6720
agtaacttgg gggtgatata agggacttga gtagcaggta tttgtctgat ctttaaggaa 6780
ttaacttatt aaagaatttt gttagtaaag tcatttgagt atcacacttg caacatacta 6840
attcatccat gtctagtttt ctcattaaat cacagatatt taacaggtgc attaacttga 6900
attgacatca tgcagcaaat gccattatat ggacccttaa gatattttaa gagaaaaacc 6960
tataatgcct ggaaactctt agttttctct gacatttaaa aacaagccgt aaaatcaaat 7020
cctttctata ataatttagt aactcagaat tgcaaaggat ttcctaaagc ccaatgatcc 7080
aaagctctga cctgtgatgt tggcatagca gagtgggaga caaatcatat gttaaagcag 7140
aaggctctgg atctggaatg cttggataca aattctggct ctaccacttg ctacaattta 7200
actctaggca aattactgaa ctctgtgact atttcctctt ctgtaaagtc agggttgttt 7260
caataattag atcagaaatt gtaaagtgct tagaataata ccaagcaagt gtgcataaac 7320
tttagccatt tagctataac tctcatcata tttctgtgtt gattacaaaa tgctttacta 7380
gaggaaaata gatgagaaag aggccatgag gtaaaaatgt acagtgcttt ttaaagtaga 7440
atgaggtggc ttagaaatta attctatccc catcactggc ttgtagtaga aatttgaaac 7500
agtctctccc tgattctctg gcagtttttc tctttttttc ttttttttct ttttgagatg 7560
gagtctcact ctgtcaccca ggctggagtg tagtagcgtg atctcagctc actgcaacct 7620
ccgcttcccg ggttcaagcg attctcctgc ctcagcctcc tgagtagctg ggactacaag 7680
catgtgccac cacaactggc taattttttg tatttttggt agagacaggg tttcaccttg 7740
ttagccagga tggtctcgat ctcctgacct cgtgatcctc ctgcctcagc ctcccaaagt 7800
ggggggatta caggcgtgag ccacggcgcc cggccctctt tcagtttttt ctaagacaga 7860
gacactccct atcacagaca gggtcttcta aattagtaga gaatgatttg aaggaaactg 7920
ggtaattatc agaggaagta aaagagaaat acagatcctc acaccagaat gcaaatctct 7980
aagactttat tattttcatc actatgaaag aaaagatcag tactcaaagc cacttatgat 8040
gatgcatgta aattagcata aaatcagaac aaatataata tggcttttaa aatagaaaca 8100
taaggctatc tttccttaca agtgtcagat tgcttctgtg ccactgtaac acagagcttt 8160
agatggattt tttaaagctt cactcagaga tcaaatgtac tccattagtc agtgattggc 8220
agacttggtg aaaattgagt tttcaactta aatttctcca aattggtctg aggaaaccag 8280
atgcagcaac taagttcaga aggtcagagt ctcaataagg ttaaaaagag agggagaaac 8340
ataacactag aagtatgaat gaatgaaata gaccacacac agctcatcag gtctctataa 8400
tataccacgc aaataattgg taccaggact attgaataat caactgcttt taagctgaag 8460
aatatctaca ttgtatacca tgattaccac tttaccaatt caaaagacaa cttaaaaatt 8520
aaacatatat acaaagacat tctgcttttt tcattaggcc atgtcattct ataatttcta 8580
aattctgtca actctcttcc ccaggaatct tctagaagtc aggcattttg ggaatagttg 8640
agtatcataa ttgaataaag atagcacaac agtcacctgt agtagtctga tcttacaggt 8700
actagaacaa taacagcaca aaaacagagt tacgtgtatg tattattcag tgttctctag 8760
aagaaaacat agtatatgta tatataggca atacatttat aaatgcataa aacaaatata 8820
aatttgtgta agtatgcata taaatatgta agtctacaca tataaataca aataaagaga 8880
tttattctat gggattggct catgcaatta tagaagcagg agtcccaaga tttgcagtaa 8940
gcaagctgga gattcagggg agcccatgca tagttccagc ccaagtccaa aggcttgaga 9000
cccagaaaag caatagtgta agttccagtc cagaagccat caggttagag acgcaagaag 9060
agccaatatt tcaagtccga agatcaggaa aggccaatgt ccctgctctg tcatgcaggc 9120
ccagctccct cttactcagc ttttatgttt tattcaggtt ttcaattgat tggatgaggc 9180
ccactcacat tgcatctgct gttaaaattt tccaagatct ttttggggtt aaaaacctat 9240
cattcatctc tcaatcttca gtgttgacaa ggacagagca cttatgagta ttcctgtttc 9300
tgagtttctg ataagcttgt ccaagtggag cacaggctgg acaatttata agacagtatt 9360
gaagtcagag caattacaaa aggaaagggg taggtttctt gtgtgatgtg ctgcaaacac 9420
tgacctctca gaatttattc ggccctgtgt gtatatacgt attcatgtct gcacatatgt 9480
gctagttcac ttatacatct atacatacac acaatcacat atacccaaga tctgatggaa 9540
tagacatgaa tttggcttag ccagggaaat tatagaaaga ataatgggaa tcctaggcat 9600
gtgggaaatg ggaaacaagg acaaaggcgc ctaggtaaaa taaaaagcaa ctggtgtgcc 9660
taggagacct gatggacttg agcatggaat agctccagac ttgtattgaa agaaaatcag 9720
gaaagtcaag ttacgaccag gtcatggcag gcactgaatg tcaggttaag gggctgaact 9780
gtttctttct agttagtgat gggtccagtg aaggatttgg ggcaggagaa tactagaagg 9840
aatattttag ggagattgat cttccagtgg tgtgcagaac agatatgcca tgcctagagg 9900
gtagtaagca gtgacatttc tttcactcta cactttagct gagctcaggg taagtccagt 9960
aatggaagat ggggtgggaa atagagctag gagtgtagag agggcaacag gtaaggatac 10020
atatgtacca aaagcagaaa acaagttaag atccaggctt catgaggtgc ctatattgaa 10080
gattgctctg gataaagaga ctgttaggac ttcagagtta gaattcatag caattcacag 10140
aactgctcag gctcttcatt attcacctga ctcaactctc ctacatctgc tcctttctcc 10200
taagagattt ccttgctctc tgtcctttct ctaccccaca gcttttgctt cctttccgta 10260
catagaacca cacaacaagt actagtttta tgcatgcagt ggtcatataa atatcttatt 10320
ggcgagtcct catcaaaact gagttgaaac aaaccatttg agccagaatt tagtaagagt 10380
cagatttttt aaggtacttc aaggatttta tttataaata caactaggaa aacatttact 10440
cattagaaat gatgaaacca tagacaaaac aattattaga gaaaattttg aattattctt 10500
ttctcctgct gtctaatttc tacctttctc atgtagtctt tttcttttta attagatttt 10560
ttatgtgagt atatggtcca tgtatttggc tggtggaata aattcaatta ttctcaattg 10620
ttttgtttga cctgtcacgt gtgtaaatta gagcttcagt cagctgttct agatgcaact 10680
gcatattgtt atcacctgag aagctttaaa atctgtcatt tcctgggccc cattccaaac 10740
cagctgaatc agaatccttc cgggagggta agatgatgcc taagcacagg tgattctacc 10800
atgagtccag gcagggagtc tggtttttgt gcacagcttc tgtatgtcat ggctattggc 10860
acctggctct gctacggcgg ttcttaagtg atcttttaat gccgattggg agtatgtttt 10920
aatagtggca caatatttta agaataaggc tttaaaggaa gttattgcaa gtaacagtta 10980
agggatttac tcaaactgga cacaacctct gttggagcag attacagtga agttttgggg 11040
gcatgggata aaaaagagga aggagagatt taatggagcg aatattattt gctaaaattt 11100
aagaacgttt gcagttaaat ctcgtactat tgcaacaaga tgtgcacagg tgcataggtg 11160
aatgcttcct cttctggtat ttccttgtgt catttatagt tcaagttaaa tcctagggat 11220
ttaaagtgct tctcattgat atttaaaggg catttttaac aaatggagaa atgtctttcg 11280
aaacagataa aatgtacctt tataaaatcc actttatgag aatatgctaa aaaggaagat 11340
gtgtttctat tggatcataa attatacaat tttaaacaga tttttatatg aaagtaaatt 11400
gttccaacta tttgaaatta ctttttcctc aaacaaaaca aaaaagattt ctagatgcca 11460
ggattgtttt gcaaaaatga tgatctgatg atctgtgggc cagatgaata tgcttaactt 11520
tcctaagagt taaggtaaca tttttccttt aatgagcctg tatctgattt ctgatttgat 11580
gtagtttttt aaaaattgag aaaatatgcc tcctctaccc cttgcatgtt ttaatgccct 11640
gatttaatgc cggtgtgtgt acatatgtgc atatacacag atatatacat atatacacaa 11700
acacatatta aaattataat aaaataatca tttgttcatt ttatacctgc ttgttctttt 11760
tctctgataa actctaagac agtggttcct atggtatttt ttctctgata tagtttttct 11820
tttctctata gatattttca ttacagtgca atttttccag tgtcttaggt tttgctattt 11880
taatttactc tacttaggac ttagaatgat tccatatagg atggtatata gattttaaac 11940
ttcaacaaac agtaatcaaa catcagctag ccctacgcat ccttgcaaaa ataacaattt 12000
atttagaaag ttgtatcagc attactcctc tacaacattt aatatcttgc cttaaaagtt 12060
caatatacat gtcagatgga ttcagaaact tctttagcca tgggtgtcac caaaagagca 12120
ggaaagggaa caaaaaatta aagaataaaa cagaaaaaga gaaaaaggaa aaatgaatta 12180
tatggtcatt tgaggatgga gagtgagaag accttactca ttccctgtgt gtagctgtgt 12240
gtaacacaac tacacatagt tgtgttagct gtcttgagaa gcacttgggg ctttgattac 12300
ctccattgca acctcatgag atatttggtc tatagataat ttcttcttct cttgctatct 12360
acaatccaga agaactaaag atcagtggaa agaagaatca acactttaaa gaatttaaat 12420
ggctgggcga ggtggctcac acctataatc ccagcatttt gggaggccaa ggtgagtgaa 12480
tcactggagg tcaggagttc gagaccagcc tggccaaaat ggcaaaaccc tgtctctact 12540
aaaaatacaa aaattagcca ggcatagtgg cacacatctg taatcccagc tacttgggag 12600
gctgaggcag gagaatttct tgaacccagg aggagaaagt tgcagtgagc tgagatcacc 12660
ccaccacact ccagcctggg tgatagagcg agattctgtc tcaaaaaaaa aaaaaaaaaa 12720
aaaaaaaaag gaacttaaat ataagaataa aagtaagcat gaaagctgag ccagatcttg 12780
ccaaatgata catcatttgg taaaccatga aggcgccaca cttgccaagg agtaacattt 12840
caatgagata tgactctgca tagcagacag ctgggtccat ttggaccata tccacagggg 12900
atcaatcctt gatgtgtccg agtgaagcat cagacaatcc acccacacca ctcctcgaag 12960
gagctattac aatagctcac tttcattccg gcaaagaggc taagttacca tagtgcttca 13020
gatgctccag accatgtgtc cctatggaag agaatgggga ccacagcatc cccctcattg 13080
gttcattatg gtgtcctgtg ttcttcacag caacacttta aggcaggcag ggtagatata 13140
atttccacac cccctgccta ttttttttta agatgaggaa actggaaaga agtaaaatta 13200
gtaattagga acacaatctc agcctccagg ctacctaaat tcaaatcatc tgtctgccac 13260
tcattaccag tgtaaccttg ggcactttag cctctctcta ccttgattta ttacccatat 13320
cataggaata ataatagcta catcactgag cttttatgag gattaaatga attatgttta 13380
aaattttcag aacatagcat atgtgttcag taaatgttag ctatgtttat tatccttatt 13440
taaaatattt ttacatattg ccacataata ggcaaaaaaa tgttatcttg gttttttgtt 13500
ttaatttgcc ttttcctgat cactaaagat taccattttt aaatcatgtt tataagctat 13560
tttgatttct ttaaattgac agttcatttc ctttgctcat ttgtccactg atatgtgtct 13620
attatttaaa agtaatctgt atattacaga taatatttct ctatctatta tataaataac 13680
aattattctc ttcctgtctg tagactcttt ttaacttcat ttattttgcc attacagaag 13740
tttgtaatat ttttgtagtc aaatctgcta gtcttttcat ttatggttct taatatgctt 13800
ggtttagaag accttctgta ccatgagatt ataaaaacac tctactatat ttacttctgg 13860
aagttacaca atgtttttaa aggttatttc tttattccat ttagaatgct ggcatgttat 13920
gaggtgatat gcccacttta ttttttttct caaattgttt atgatccccc tatgaatttg 13980
aaatagcacc tattggtgaa ttccagtata aacaaaacta tgggtccaga gtttttattt 14040
tactccatta atctggttct ctatttctat gcttgtttta atctaaactg ttaattaggg 14100
ctgttccaaa tcattataca ctttcaatat atgttgtggc atttattgca cattgttcct 14160
gcccggtgaa ctatgaaatc aatttgtcaa atttcagaat aatttcattg gactttaaat 14220
tagaattgca ttaaagtaat aatttgggaa aaactgatat ttttacatca gcaaaacttc 14280
catttactaa ggcctttaga tctttcagtc aaattttatc atttttttat ataggtttta 14340
aacttttctc gttaagttta ttcaactttt atgtttttat tctattgttt agaccttatt 14400
atacttcact tgttatttct attaaataca gaacatttat tttataattt tccttgtagt 14460
aatctttcat tagtttcaat catattatat agttgattta cttgttttta atgagaataa 14520
atgattgtgg tgtttcatta ctaagtataa tgtttgtttc atgtttctga gagatgctct 14580
ttatcaattt aaggatgttt tgttctattg ttcacttatg aagatttttt ttaaaccaat 14640
actgggtatt aactttcatt aagtgccatt tttagattta ctgtgatgat cacgtgtttt 14700
ctttttaaca gtgaaatgaa ttaaacttcg ataatcccta atgtttaata aactttatat 14760
ttttgtagtg atcccatctt gttcattgta tattattatt ttggatgctt tttcatatgt 14820
agttcatatc tatactccta tgatactggt ctagtgttct actttgtagt atatttttct 14880
ctatcagata tgatgagttt gtagataatt tcagaagttt tctattattt tctactcttc 14940
aaaaggcttt acatggcaaa ggaataattt gcttttaaag agatttataa aacttgccta 15000
ataaaaccat ctggatctgg tgttatttgg gaggaaaaca ttgaatgttt tcaatataga 15060
ttatgattac tagtttattc aaatttttaa cttatccttg agattaaaaa ttcacacttt 15120
tctaaggttt tgtccactac atgtatattt ttcaaattat tggtaaaagt attctctttt 15180
ttaaaagtct atgaatcttt ggttatatcc aatttttctc ttgttttgaa aatttatttt 15240
ctccttttta ccttgtcagg attgccagct gaatgctaat ttactactac actcagctgt 15300
tacatacatt tatcaagtct acaaatttgt tttattaatt ctacttttat ctttgattcc 15360
ttccaatttc tttttgtcca tttcattctt ttcctagctt ctttagttga atgcttattt 15420
tcagtgttta ttgtcttgta attaataata aacagactat cgtttacaaa aatctagtgt 15480
acatttcaaa atagctagag aaaatgattt taatgttttt agcataaaga agagacaaat 15540
gtttaaagtg atagatatcc caattatact tctttaagct ttacaaatta tataaatgga 15600
ttaaattatc acatgtaccc tcaaaatatg ttaaatctat tatgtattaa ttaaaaaaga 15660
aaaacaagaa tagaaacttg accacatctt catgaaaagt atgatatttt cattaacatc 15720
catttattaa cataatttta acttttatat tttatattat gagcaagagc tatatatcat 15780
aggaagctaa aaatagtcaa ataagcaaga atgaagaaaa caaaaataat ttgttaatcc 15840
actcacccag agataacaaa ttagccttgt gtaatcaaag catatttgaa tataaaaatt 15900
aatacaaatg aaatcagacc atacattctg ttttgtaacc tgccttttct actttattat 15960
atttcacaag tatctgtcta aattattata tattcttcta gaacattgat ttgattagct 16020
gtactgtatc actgcttatt caaatatttc tttatcatta gatatttcag ttgtgcctac 16080
ctttcataac aatactaata tattctatga gaggtgacaa acatgaacag tcttaggacc 16140
ttaacaactt ttctactagg tagcaaaaac aaagataaat gaaataactg gatccattag 16200
taaggcaata taaaagagct caagataatg cattcgaaat tgaatttttc tctgcattgg 16260
agaaacagga ggagaataac caatgagaaa atcacaggtc atggctaaga tgagttaaac 16320
aaagcagcaa ataaagaata agaatagaat atttctacag caccttctat atgccaggta 16380
ctatgttagg cgctctcaca ttcattacct tatttattcc atgcttaaaa gaaccttcaa 16440
gttaggtatc agtattctta tcctttttta gactagaaaa ctagacctca gaaaagttaa 16500
aatcatggtg gcagaactaa atttttttta actttttttt ttaagttcag ggatacaagt 16560
gcagatttat tacacaggtg aacttgtgtc atgggggttt gttgtgcaga ttatttcatc 16620
acccaggtgt taagcctagt acccactagt tatttttcct gttcctctcc ttcctcccac 16680
cctgcatcct ctgaaaggtg ccagtgtgtg ttgtccccct ctatgtgtcc atgtgttccc 16740
atcatttagc tcccacttat atgtgagaac atatggtatt tggttttctg ttatcctcct 16800
ctgcagcagg ttccacaatt ttaaagatgc ttacatttac atttcagttc tgtccctgtg 16860
taagtttgct acagttaatt caagaacaga actgaaattt cagtgtaagc ttgttcttct 16920
ttaaaaatgt ggaaacctac tacagaggaa aatttttgtc aatacttaca agtaaaatta 16980
acatgtccac tatgaacaac ttttacattt cttttctttc tttaatttaa gccttgtctt 17040
ggcttaaatt gacaagttcc aaattaatat atgatttttt gctaatgcct gaaaaacata 17100
gaggaggttc tggttagttt tttttctagt attgttttaa aaaactaaga tgttgcacat 17160
tgggactttt tgtgatgtct tcatggctat attttgaaat tttatgtata catattctct 17220
attaattttg ctatggctca tgatccatga ccaaagtgca tgctaccaca agaattaatt 17280
tccaaaatag acttaagatc aattgtaaat atttttccaa ggtggatatt agagctttgt 17340
atcaagcaat gcaaagcaat atttacttag catcatcagg caaatatata gacttcagtc 17400
ataaatcctt caccaaccat ttcagtacta tctagaattt ctttcacgta aaattcccag 17460
gagatactca agggctgaaa ttcgtgctaa aaccacttgt acaacttgca tgttacataa 17520
aagttatgtc cagcctacat catgtaatgt caaggcacaa ctaaacattg aggaaagact 17580
aggttcagtt tggagaggtc ccagaggcaa gtgaagccat catggatttg aaatgcacgt 17640
ggagcacctc actgtacggg ccccagtggc ttctcattca attatgaaag aacacttctc 17700
tgcttaccaa gtcagaaata gtctttgtcc ccattcagtt tccttatcca atttcttccg 17760
aaaaatcaaa tcaagatagt aaacatacta ttaacagaat gccttcattt cctaactcta 17820
aattgtctac cacgttgcag atattaaatt aatatttgct gatccttttg ttaaagtcga 17880
ggataattac tttaattttt aaccaagaaa tcttctaact ttaattctgt ctttatcttt 17940
tgtctccttt ctgttcctct ctgcctgtca ttcacaatga ccatttcttt tgtttgtata 18000
aacttatagg gtgcaagtgt aattttgtta tatgcctaga ttgcagagtg gtcaagactt 18060
ttagggtatc catcatccaa ataatgtaca ttgtaaccat taaggaatcc ctcatcatcc 18120
accacctttt cacttcatta cccttccaaa tctccattgt ctatcatttc actctctacc 18180
tccatgtgta cacattatgt agctcccatt tatgaatgag aacagatttg tttttctgtg 18240
tctgacttgt ttcacttaag aaaatagcct ccagttccaa ccaggttgct gcaaaatata 18300
aaataaaata aaagaatttc attctttttc atggctgaat aaaattctac tatacatata 18360
taatattata taaaattttc tttatccaat tgttgatgga tacttaggtt gattccatat 18420
ctttgccatt atgaatattg ctgctataaa catatgagtg caggtatgtt tttgatatat 18480
tgatttcttt tcctttggat agatacccag tagtgcccaa ctacgatttc tagttctgtt 18540
tttgccaagc tatgctttca tgactcgtta aatgtgtttt tctagtatgt actcctctta 18600
cctttgtctt gtatcttccc caatttacca tttgaaagac attaagaaaa aaaaaaaaac 18660
aggccaggca tgttggatca cgcctgtaat cccagcagtc taggaggccg agatgggaag 18720
actgcttgag cccaggagtt cgagaccaac ctgggcaaca tagctagccc catctctatt 18780
ttcttttaaa aacttatata catatattac tcattttccc tctttgtctg tttccctagc 18840
tgccaactta tggtctgcta gggcagtaag accttctacc attctcataa cttcaggcaa 18900
atctagataa caaatctcac ttaaaatcct cgcttagttt tctttccatg acttggttct 18960
tcatgtggga tcagctttta ggtacaagat aaatgtgttt cctctttcta gctcagggtt 19020
ataatcaaag agcaggacat actatccagc taacaggtct agatttagaa aagtcagaat 19080
gtactacact gcctgtgtct ctcttccaac ttccttctca tctgtttccc tgccaacttc 19140
cctgaaactg gacccactgg cacctgaggc caacagggtc gggaactgca gctctaactt 19200
tgcccaatag tgaactatgg caatttccat tgagcagctg cagccaagtg acgaggtgag 19260
ctattcattc caatccctct ctgcctctca agaaggcaga agtcttgaac ccccaagaat 19320
ttctagatct ttgttttctt ggtcaaatag gcactgatgt tgcaaatata aaaccagaaa 19380
gagatagaaa agtgtataca aatatcaact ttatatttta atcactctgc actctgaatt 19440
tttttacttt tcttgtctct ctcacaagta tgatgacata ttcataaatg cagagaaaca 19500
acaaaaatca atttcttata taaaacaaat tcattccagg atggaaattt caggaaggaa 19560
ctggaaaaag agaaataata agtattagga ctttcaattc agattaaatt taattctgat 19620
tgactgcaag tctctgtaat ttataaaatt gctgatccaa agttttgcat ttcttctaaa 19680
agtatcaatt aagcacttag cataatgtca agctgagcct tctgggcaaa caaagatgag 19740
gtacaagata gtccctgtgc tcagaaagct cacagtttag tgaaaaagtt agacatgtaa 19800
gccaataaat acagtcatgt gcgaaacaat acaaggatgt acaggttttt ttgagaggac 19860
tgaggagctg acacttgaag gttacctaca gaggttgtca aagaaagaaa gcatcacaga 19920
gcaaagaaga tgttaatcaa gtctagaagg atcagtaagg ccaatgtggc aaagttagga 19980
ggcatgggaa ggaaaagaga ttccaagcag agaaactgga agtgtaagaa agcatgggaa 20040
ggccaagtgg cagggcatgt gaatgacact ggaaggggag tctagggtct agtcctgaag 20100
ggacaatgtg tcatgctaag aacctgggac tttatccttc acacagttgg ttttgaaatt 20160
ctgcctcttg gagttagaga ttgataatta taataattaa aatgatataa tagctaatat 20220
ttattggatg gttattaaat tccagaaacc attttaagta ttttaaaggc atattcatta 20280
tttagctccc aatattaata ttgaatcctc aaagaaccct atgatggaat tatcatcatc 20340
ctaattgtat ttattttagt agtagtagta gtagtagtaa tagcagcagc agcagcagta 20400
gtagtaggag tacctttgag acagggtctc attctgtcac ccaggctgga gtgcagtggc 20460
ctaatcgcag ctcactgtaa gctcaacctc ccaggctcag gtgatccacc tcccaggtag 20520
catgactaca gatgcatgac actacacctg gctaaatttt tgtatttttt gttgaaatga 20580
gcttttgcca tgttacccag gctggtctgg aactcctggg cctcccaaat tgctggaatt 20640
acagggatga gccactgcac ccggccccat cgtaatttta tatgtaaaga aacaggctca 20700
gatagcttcc tctagggtga aagtggaaga agaaaagagg agacctgccg ggaggattgg 20760
ccaggcacgg tggctcactc ctgtaatccc agcactttcg gaggccaagg ctggcggatc 20820
acctgaggcc aggaggtcga gaccagcctg accaacatgg agaaacccta tctctactaa 20880
aaatacaaaa ttagccaggc gtagtggtgc ctgcctgtaa tcccagcttc tcgggaggct 20940
gaggcaggag aatcgcttga acctgggatg cggaggttgc ggtgagctga gatcatgcca 21000
ttgcactcca gcctgggcaa caagagcaaa actccatctc aaaaaaaaag taaagaaaag 21060
aggggaccat ttttacatag caggtttggt ggtgaggata catttaaacc aagtgttcca 21120
ttgctaataa aaacacagtg tctgagagga caagaagact ctgatcgcca gttaatggaa 21180
gctgtaagaa ctagaggaag ccctggcttt caatactttg tgtcctttgc tcatcccatt 21240
gttagaaggg atataaagga gaagggaagg gaaaggggag gaaattatac aaggaggagt 21300
tgacatttca tcaggccctt tctggagtcc ttttgctgtt cctctactct gcttctctcc 21360
tccaatatga gatattagca aacctagggc aatgcttcac aggtgttttc tcatttcatc 21420
ttcacaacaa tatgttgcac agcctgctca tcaccccaat tcacaaatga ggaaattgat 21480
gcttagagac agtatgtgaa tatatgattc tttcctgtaa tactaaccgt agccttcccc 21540
tccatccaat ctccatcttt tttgaccctt tctgctctca cccatcctca actagataac 21600
agtgctgtgc caaaaacctg tggattttct ctacaaaaat tatgtaagta tactatattt 21660
tacttactgt gtattggcat atattagttg tacatattct gagggtatat gtgatattgt 21720
gatacctcta tacaatgtgt aatgatcaaa tcagagtaat tggaatatca catcaaacat 21780
ttattttctc tttatgtttg gaacattata aatcttctag ttattttaaa atatataatt 21840
attgttaact ataatttccc tactatacta tcaaatagta gaacttctgt ctcactgtat 21900
tttgtacccc ttaaccaact tctattcatc tccttctccc cactaccttt ctcagcctct 21960
agtaaccacc tttctacttt taacctccat gagatccact ttttgtattc tacttattga 22020
tcttatttat tacctctctc atcccctgta aaactccatg atattttggg ggatgagagg 22080
tttggtttta ttttttctca tctacatccc tatgtcttga aaattcttag aagacagtag 22140
atactcaata aataatttct gaattaatag gtgataaata ctcatgaaag cttttctcta 22200
tctttccaaa gtcttaatgc ctgctctatt tgttttaaat tctattgctt caataagata 22260
ctttaagaac tattctttca taattctgat ctgaagaact tacaaggtgc taaattagaa 22320
gatgtattgc aaaggcttta tttcaatttg gccaagcttt ttaataaaag tttgacttgc 22380
ttaaaagaaa tatttatctg ggattcgagt tcactcctta gactaggtca acactttgag 22440
agggggttgt ttttgcaaaa taaaaattaa agattaagtg tttctcatga caaattttga 22500
attttatttc catgccctga ttcccaatga cttgacacta taattgagat attatacaga 22560
ttttctcaat aacttcagag tgcatttata tgtgatcaaa agacctttct gatttcaaga 22620
tacctttaat aacctttact aattattaac caaaactaaa ggcagatttt gcaaatataa 22680
acttgtcatt tcagcatgac tgttatcttt ttgatggaaa agatgaagtt cagcgaagaa 22740
caaatctaca acttggccag aagactgtag actttgcctt caaagaggtg taacacatac 22800
gtaaataatc ccatcagacc ccatccacag cctccctgct cttgcaattt aattaagcac 22860
agtgagaggg tttgagagta tcctcacgaa aagacaattt tggtagcatt tgggaaaaaa 22920
gcaagagtta atttttatct gaaagactag tttcctttgt aagtcttcaa aatgttttgc 22980
cttttgcaaa gtacagacac tgaagctggc atgttaactt actaagttag cagattcccc 23040
ctaaaatgca atgccctaaa gctggacaga gggtagaaat agcaaacaga gagcattaac 23100
tatatgcttc ttcaaacaat cagtgaatgc aaactgaatt gccctgagtc agcagcaggc 23160
aagaaccatc agaaaggtga aggcaagaat atccatgttt atataaagag gatgacattg 23220
ttctgtccct aaaaacagct aactcttgat aatctcattt tttcctttga tgttctaaat 23280
tataatgaaa atatacttcc tttttttttt gaaacagagt ctcactctgt tgcccaggct 23340
gcagtgcaat ggcatgatct cagcttactg caaccttcac ctcccaggtt caagcaattc 23400
tcatgcttca gcttcccaag tagctgggat tacaggcatg caccaccact cctggctaat 23460
ttttgcattt ttaatagaga cagggtttca ccatgttggg caggctggtc tcgaactcct 23520
gacctcaggt gatctgcctt ccttggcctc ccaaagtgct gggattacag gccagagcca 23580
ctgcacctgg ccaaaatatc actttctaaa tgatgcttat ctattagctt ggggacattt 23640
atttaattct actacttcag tagtagaata cccattgcta ttactaatag tagtactatt 23700
agtattacta tagtattact attattacga ttagtattgc taatcataat atatatagta 23760
ttagcatact atatgcacta ctatagtaat actatactag tatactaata gtagtattat 23820
aaatactatt aatattacta ttgctactat catagtatta ttataattac tagtaataat 23880
tactattact attattatga ttagtattac tataatcata atagtagtaa tagtaataat 23940
taccagtaat tataacaata tattactatt gctactacta ttactatatt ggtattacta 24000
ctattagtaa tactagcact gtcattatta atagtgctac aattagtaat actagtgtta 24060
ttagtaatat tggtactaat attggtgcta ttagtaatag tagtactatt aatactaata 24120
ttagtaggta gtcctaataa tattgttatt gttactaata gtatatctta ttactattct 24180
gttattcaag taatagtaat tttagtaata gaatacctct actttagtaa tagaatacct 24240
attactatat tgttatcatt actactatta gtgatactag cactgtcatt actactagtg 24300
ctgcaattag taatactagt gttagtaata ttggtactaa tattagtgct atcagtaata 24360
gtagtactat taatactaat attagtaggt agtcttagta atattgctat tgttagtaat 24420
attctattac tattctgtta ttcaagtaat agtaatttta gtaatagaat accttaaagc 24480
tgcatttttc agaaacgatc acttcagctt cacttttttc tttcacccaa attttcaccc 24540
agtttcttat attattaatg gtgtcttcat tctgagtctt taaaggacaa tgtgaagcag 24600
tacaggaatt ctcaacgcat atgacagaaa attttcaaaa gtacctatat tcaaatacat 24660
tctagttgca tttgattcag atcattgtaa aacatattcc tctgtcctgg ttggcagagc 24720
acattaagca gggtgaaaac ccagcaaaga accttccctg agccactaat aactagaacc 24780
cagtgtggca gccttcacct ctgtgtatgt gggaacttcc agggcctcac actcctacag 24840
cctagaacct tcaaaatgga cattatcttg ttctgggaac ttgtggatgt gagcaaccat 24900
catatttgga atgtgattca aatcatgttc ccaaaataga aaatgtagac aatgaaatgc 24960
tgaaattata catttatatc tgtacacaca aacgtgaaca tatgtaaact ttcatcattt 25020
tttaaaattt acaaaagttt tcatgtactc tactgaacat gtctgtggta tgtgatctgg 25080
gtgttagcaa acccttccca cgtcaagtca aaagcatcca ttgttcttgt tttgttaaaa 25140
ttaatgtcac atttttatta catagagtac tttgcatgat gacttctgtg tatgtgatac 25200
tggcatattt tgctctaaaa atttatcttt ggagaataag tagataacta tcttagctga 25260
cacacagact aaaactcaat ctctgagaat tctgatttct tatcttagtg gttagaatga 25320
gcgacagtgt cctcttctca cgtctgtaag gaacattctt catattcttt taatagatgt 25380
gagctgatct gtttttgagt atttggtgac atcctgagat aagtggattc agaattacta 25440
atctgcatta taattggaga atgggtattg ttcatttttt tttgtttcta aatttcaacc 25500
aatattgtgc atttttaaaa gttttttttt aagagcacat ttacacagcc ttgtttgtat 25560
gtaactctta gttgctctaa ctttaatgac gcatttacag agaatatttc ctaaagatgt 25620
ccttcatgaa aaggagaagt ttggacttga caacagtaat ttacttaatt tatcttaaat 25680
ttggtttcag tgagcaaccc taattaacct gattttttgc tgataatcac tctcaatgga 25740
atcaaatcac aaatccgggg atggattgag cggcactcag aaggaagcag ccctccgcgc 25800
actggtccag cgcacaggat atagcttggt ccaggtagga acttgtgaaa tctgctgaga 25860
ctcaccactg aatttgcaca gtggtgggaa tattggaggt cctaagatgc aaaatgggaa 25920
tggtcagtta catagctctt tagagaaatg tccctttcta aaagagaagg aaattgcaac 25980
atttctgttt tgtagatgac actgaatgta accttctttc tactctaggt tatcaattca 26040
accttaactt gtcacagaat cagtgtccac agttatagag actatcccaa aaaggcagct 26100
agaatttgcc acccaaggct atgaagtaga accacattgg tgtttcagga atcagcagaa 26160
aataaactac agcaggaacc aggcttagtt tccagagaga tcactgcaca cctaagactt 26220
ctagatgtgg gatccaagga atgaactttt tgtgtctagc tgctgcagtt tgttctctca 26280
gaacacttgc tcatccagtc taggatatgt aatactaact tgtctccatg cttagcattt 26340
tgtaaaagga aaaaagaaaa caccacaatc ttaaaactgt ctatttatag acactgcctt 26400
ttagaaatta tctgtatatt attattatct ttatgatatc ttcttttaga gaacttatgc 26460
tgcatttaaa aaaatgtagt gttagataca tatattatct tatttaaaga aaaaaatgtt 26520
gctgttttta cagtaggaca aagtatttta atttctcagc tattttcttt cactcacata 26580
ctttcccaac ttaaccaaat cttgaattca aactactatg aattcaaatg tcatgtgtga 26640
ttagcaataa aatatgcaag agtgtccttc cattagatgc tcctttgtca gttgcaaaat 26700
atacatttat tttttaatta attttataaa tcatggcatg ctttgttaga catagtaata 26760
gttattttct tcatcctaat gaagagcgtt agtctttttt aagatttcaa aaagtttcta 26820
ttatttcata gttgactttt tgaagtttca cttaagtcca tggagatact gacatattag 26880
tttttttaat acttaaaatt caaattattt tagactcatt aaacttttga aaagagggtt 26940
ttctttcttt ttgcaatcaa cacttccata gatgttatac aatcaagaat gtttttgaat 27000
ctttttaaaa ttttgaactt cttgatatta gaaacatttg tgcaaagaca gtagaaatag 27060
aaagcatttc aaccctttca aacagcaatc tgttaatatt tatatatgag tgttcctttt 27120
ctggaactgt atttctaatg acccataata taagatagaa atatgtataa atctgtcaag 27180
ggtgacatta gctgtaatgc atatcacaaa cttaaatgta taaatacaag aaaattatta 27240
agtaaattat gaatgtataa ttattatacc caacaagcag aatttatgaa aaataatcct 27300
aaaacaatat aaattatcaa ttacatttca ttcaattctg gatactggtt cttccttttc 27360
cccccacatg aaattcaggt aaagtctcat aacttttctg gtaacgttca ggtaataaaa 27420
atccttcatt taaaaaaatt gatatttttt tcatattgat gttattccaa actagattgt 27480
ttggaataat agtaaagaca taaaatcatt caaagttgca gttatttccc tttctcaagt 27540
atgtcagggt ggaggataat ttcttttctg tttttctgca ctatgttttc ctctttcaac 27600
accagtttgg taactacaat ttctgactcc tgattgaagc agaagggaga aataaaagca 27660
aagaaaatgg taaaggaaag tttttactga gctaccttca ttgggctctc aggcctgaca 27720
ggtatcgaag cttgtgagat tctttttacg atcttcagac acccagcctc ctgctgggtt 27780
ctctttgata tttgaagcag ccctcatgga gaggatggaa gataatcatt aatttctaca 27840
cgtggccaaa ctctgatccc cggaaacaca cattccctga cccaacaaaa tctggaaatt 27900
gaggtgacac aaagcaacca cttctccttg ccaacaacaa agctgcaggc caacccattg 27960
ttcacagtga gagatttcag gagtgagtta gatccaccag cttagtgtgt tccccaaaca 28020
caaaggcagg gaatacacat caagctgtct aagtggtttc tcctgcttta ggcaaaatga 28080
caggcgcctc ccaattcctc ccacttaggg ggaactaaga gtcacaacac aacagcagtc 28140
atctccaaat atctttgtgc aaattccaaa aacttctctc aaactctcca atctcttttc 28200
taagcttagg gtgttgggtg acagttaaca atggaaaaat agtttcctgc taccttctca 28260
tcctgcttgg tgctctagtc acttggtttc atacctaaat cagaggctag agttaatgat 28320
aatttattac atatttcaaa acagctagaa gagaagattt gaaatgttcc caacacaaat 28380
aaatgtttga ggtgagggat atcctaatta ccctgatttg atcattacat attgtacgcg 28440
tgtattaaaa tatcatacat ggactcctta aatgtgtaca attattatgc accaatttta 28500
aaagtccaat tccgtcttaa aatcctgtca cagatgaaat agtattcagt aactaacagt 28560
aatcatataa aaaaatctga aggacaattg taacacatta ttgttaaagc tatgaagaaa 28620
cctttcaaat aatttttttg aaaagagacc caaataacaa tggagataat cttactccat 28680
ttaaaaattt tgctccattg taaggtcaaa tgttatgatt taaggacatt tatctgatag 28740
agaaaataat gatatgtata attgaaaatg ttaacatata aaatactcct aaaatatatg 28800
gccaatcttt attttacttt gatcttatct attaaatgat attcagaaaa tgcttataat 28860
aaggacctag accacaagtt aattgtaata ataataataa caaaaaatat tctatctgct 28920
ttgtgtatat taactcatct agtccttact atacactgtg tgatagctac tatgtttatc 28980
cccaatttcc tgatgaagaa aacaaggcac agacagttta gataacttgt gagattaaga 29040
ttctgttgtt attggccaaa atttttggtt agactcagaa aactgagagt tgttataatg 29100
tgacttttaa gattgcaatt ttagagatca gcatcctaga gcatgtgaca aacatttttt 29160
tggaacctaa actttgtaac atgattcact ttaagtaata ttgactagca gcgtgactgt 29220
tgaatcagaa gtgcttcaat aatgtagaag cttaatgttc caaaagctag ttatctatac 29280
ctaaggcctc taatcaaaat gtaaatacct atataactca atcattttga atgaattaaa 29340
gaatccctcc tgattttggc tacagagtgt ggaaaattat ccaagacttt aaatcagaag 29400
gcctgtaatc taatctagtc cctatgacat atgagttgta tgatctttaa aaagtccctt 29460
aacatctcca ggccataatc tcctggaaga tcaggtacgc aatacccaac tatttgtcca 29520
tgatttttgt gattctagta tcttctgaat ctagtcactg gttagcacac tggactattt 29580
ggtcgaaagg gtagcctaaa tatgtagaaa cacaacttca aactctttgt aacttaggga 29640
aaatccttta gtcttactaa tacttcagcc ttcctactct ggattataca aaagatcaat 29700
atgattatcc aaaaagaaag aaagaaaggc aacattaaga acatcaagtt tactttttaa 29760
aaaagttttt gtacaaaaat taagataaag aaacatccta atacaatcca agcagcatac 29820
ccataaaatg atagtttaga attttataga ttagggtttg aaggatttac ttttgctgta 29880
tctttgcagt ctctgatatt gaatgttgaa tatttacaga acaagaattc aaaaaacaga 29940
gggtgatgaa tttgtgctct cttatcacta gcaggacaaa tacagctatc aaaaatagaa 30000
ttttgtgagt tacttaataa cgtgacccag gcttttatgt agcaactgat gcaataatgc 30060
ctgcttctaa gggtttggaa atatgctttg tgatcttttt aaaataatca aacatctttg 30120
gatattgatg actgaagttt ttatcaaagt actgtagaga aaaaagagat ataatgtagt 30180
accccacata tagtatgtat ttaatacata ctcttgttga aaattgtata atattactaa 30240
gttaaacttt aagcttcata attgtattat gccttataaa aatattttgt aaggaagtgt 30300
gctgcagtat taacatgtga acagtctttg tctctgtgta atggaattat gtgtggggat 30360
tcttttctct acttttttat tcttaactgt acttcctgat ttcgaaagct agcatatact 30420
tctttgatag ctaaagacaa aaaaaattac attatgatga gtctttcctc aagaatgcat 30480
taatgatgtg ggtcataaac tatgatatgt gatgctcctc tcacctgaaa ttttctcctt 30540
agaactagaa aaatatattc tcatatgtga gcatattcag aaaaatatac acttccaccc 30600
aacgtggtgt ctgttgacat caagtttaat tctattgcaa ctaaacctaa atatatattt 30660
aataaaaatc accctcaggt agtcttaatt ttttaaaaat agactcatta tatctaatat 30720
atataaaatt taaaatgtgg tgtgtattag ctttgtttat ctagttatcc tattggtagt 30780
ctgttttcta aaaatcatta cagcacaatc aatttttctg aggtgtgata gtccccttgc 30840
tttcgtaaac caatgatcat cctaaataaa catcaatatt ttttgttttg ttttgttttg 30900
ttcttctgtt ttgcttcctt agtccctatt attgagaaaa atgtattagt gctgggtctc 30960
gggattatag agtataaaaa tgcagtgcct gacctaaagt tcatataaag tgggtgaaat 31020
gaaaaagaat gtatctaaaa tttacaacaa cataaggcag cctcaaatga gcaatacagc 31080
tgtgggtacc aaaaagatca gcattttcta tatagagcct taaaattgac aatgctcttt 31140
gacctgagga atgaggacaa atatttagac ataatgatgt tattatagtg aaatgtataa 31200
ttttttagaa atttaaactt aaacatatcc taaatatcca atgtaatatt aatggtcagg 31260
caaattatga tcattcttat attttcaaat tatacagtaa tataaaatta tgatttcaaa 31320
gaattttcaa agacatggag aagtattcaa ttttaacatt tagttaaaaa tctgaaggct 31380
acatataaat ttgtgaagaa tattttaaaa aattattcac atacagtaaa gaatattgta 31440
aaataacaaa gtataatctc taagtttttc ttgcctgatg ctcttcttca ttttctaaat 31500
tttctataat aaatgcagat cgtttttatc acaaggaaaa aatctcataa ggtagaaaag 31560
atttctaagg gtcagtcagg agttaaaaaa aagaaaagaa aaaaatcatg gaaaaaaact 31620
ttattattaa atttgggtga taggtcccta ggttcactag actattcttt ctaattctac 31680
atatacatga aatttgttta atattgatat agtccaatcc ttttgttctg cagttagaaa 31740
ataagcccca gaattacaca attattaatc aggggtcaac aaactatgcc ccatgaacca 31800
aatgtggcta cagcttgttt atgtagtaat tgcaagatat gatttttttt ttacatttta 31860
agcatttttt ttaaaaaaaa gcctaaaata tcaactattt ggccttttac aaaaaaaaaa 31920
aaaaattgct gactccaact cgattcctta gcctactgct ctatattaga agcgaatcta 31980
gtttttaaag aaaattcttt aatttagtat ttaatctccc ttaaaagaag taggtgcatc 32040
ccttcttgtg ctgcccattc acaccacctc aagcactggg ccctcactcg ttcatgtatt 32100
aattcatttc ttgattccac cacaaagaga gacatgtttc tacctttatg aagattagtc 32160
tcatagaaaa gatagaaaat taacagataa agaaacaagc aaagtaatta cagatcatgg 32220
taagtgtcaa gaatgtgata aaccaggctg tgtaaaagtc aaagccaggt gaccttcttt 32280
aggaaaaatt acattgaagc taagacttac cagatgagag caaacaaact ctgcaaggag 32340
ccaagtatcc ctgggagatg gagcacacag gcagtactcc ttaaacaaaa tatttataca 32400
gtgcagaaca cttttgggta gtgaagacat taatgtgtct tactttcaaa gatctagtga 32460
gattacagca gataagtcgg tggatttcat ctttcccttc ctctgttaat cagccatgaa 32520
cctggtgtcc tgggaacaat ctcctcaaac taggaacaaa atacagtatt caattcccac 32580
ccctcacact ttcctttata tgcattctct cttgtatgga atttcaatga aatcacatgt 32640
tttgattcta atttgttcag ttcttcagca aatacaagcc atcaggtaca aagaatggag 32700
ctagatcaag tctaattaga ataccgttcc tcttctaaga gtgccccaaa ttaagctaac 32760
tctccatctt tccggtttga gataatgtac ttaggtaatt ttaattgaat gttcctcaaa 32820
tggcattttt tcctataaat aatacaataa aaataacctg agggtctcag gtttactaat 32880
tggcttcatc tagactggct ccgagaggag cagatggaaa aacactgtgg cattgacatt 32940
ctttttcaac cactgcacaa aaaatcctag ggacagaaat aggaatttga cttcatggca 33000
aaatatagct cctgggtcct actttttcct ctattgcctg ttttcaccac ctgctcacat 33060
ccctgctatc caaggactta ggtcattcac caagtgcacg gataccaatt ctttaaatag 33120
gtagcaataa gcattagaac aggatgggac cagtagatta tcacaggctc atgcttccct 33180
aagcttatca ccccagccac ccacaggcca actttatttt aaagctcaga agcagtctta 33240
cttctactag ccagagatgc catagcgtgg tgtgaaagac tccaaatgaa ggagcagttc 33300
tgtgaatccc tttgtggagg gggtgtgtgc ccaacatttg tgggaacttc attatcccaa 33360
ggaacacaga tatgttccag aagctattat ttccaaatag caatgaattt ctcctcgaat 33420
agcctcatag ggtgttgact atatatgaag tgtttgatat aagattcaaa atcttcataa 33480
acgacacaag gtagtgcttt cccttaagct agaagcacag actttttcta ttttatcagc 33540
ttaaaaattg gtgtgacctc atgacccaaa tatgcagaag catgagcagg tcttgtggac 33600
tttggactgc gcacgctgac aaattcacac tttttcttaa agtgctattc atttgtgagt 33660
actgattggc aactaaaatt aagtgactct tcatcttcag aacctgaaag cttagcatta 33720
tgagatgcaa aagacagctt tcaaacaagc taggcaaaga agaaattatt gagatcacag 33780
ttccttgcaa tcatgaattt gtataggatt tcagcagctg tgatcctttg taacattgtt 33840
aaagaagtgc tgagcaggga accaagatga tgttaaatgg cacattgtcc acatcattaa 33900
ataacatcca atcccatata gagagaatta ttccactttc agttctctct caggcttcca 33960
ggtgaggaaa gttagttgtt ggaggtatga tttaaacacc tcttcaggcc ctgctaacct 34020
ttttaagtcc cgagagcaga actagagtgc agagctttta gtagacagtg tctatgtaga 34080
agttgaccat gatttccctt gtttgcaatt gtttttataa tcaccgacca tttatgggaa 34140
atgatactga tattccactt ataagaacaa tatattttct ttttgatata agcttattta 34200
agtaacaaag tgaatcaatg cataaagtca ttaggtaatt aacagaatag atgtcaattg 34260
gacatggaat tgaagataca ctgattttta aaattacaat atcctcttaa ggctccaatt 34320
gactaactca caaaacatcc tatgaacatt ttcctccatt aaacatgata tcaaagtcag 34380
ccttcctttt acaagcaccc tcacacccct acaggactac tgcaatcacc tagtcaaccc 34440
tcctactcct tcatagatga aataattaaa gtcagaatag atttagtgcc ttgccaagtc 34500
cctcagcttg tcagaaatta aaattcacaa gagtgttgta aggagaagaa tgattataca 34560
aaattcctta catgcctcaa acccggtgca ttggatggga ttatgtttgg catatgttga 34620
actaggaaaa gatagaagag caattaccca aaccaaatgt tctttattat gtctttatct 34680
gcacatggga agttttgcat aacttaatca gatctagcgg ccataataat agttaattca 34740
aaaaggcaaa ttgtaagtaa acaaaaaagt tagatgggcc tattgaataa attacacatt 34800
ctttaaggat aaaagctcca aacggattaa ggaatgacta aagctgtcac ctaattactt 34860
cttgaaagga atttagaggt tcctatagat ggaagcagtg tgtctgggca catgcccaga 34920
gccagaagcg agcatgagca cagcaattcc tggcctcaaa aaaggaaata atgctttgca 34980
gtccatcatt ttgcaaactt tgctggaaaa ggtaagcaga gggtcttaga agtgagttgg 35040
cattttactc gttctctttt acagaaacac acacacacac acaaatgctt tttgttttct 35100
aattttgaaa aacactcgaa taagttttct gttttgtaat tttgaaaaac actgacaaaa 35160
tgttttctgt tttctaattt tgtctatttt caaattcaat attcttatga atgaccaaaa 35220
tcttacatta taaaaagctt tgcaaaacac atcatttaaa aaagcctatt tgcttttgaa 35280
tgcttcaaac gttgatactg aataatcctt aaacataaag ggaaattatt aaaagatatt 35340
attaaatgca tcaacttgaa aacataaatt acttctgctt ccataagata gttaacaact 35400
tcaagtgaaa ttgggattaa tttccttgga aatagacttt caatggtcaa tcttccaaag 35460
tgaaacagga aggtgactca taatttactc atagttgttt ccttagaaga accatatcat 35520
acatttttta aagataaaat gtcagggctt tgtaaaaagt gaaaccaata aatgaaagtc 35580
aagagccaag agccatttgc atctttcttc atgatttttg ccatagatac atgccaccaa 35640
tattatttat ttagaattca ttaaatctcc tggctaacac agtgaaactc cgtctctact 35700
aaaaagtaca aaaaattagc caggcatggt tgcaggcgcc tgtagtctca gctactgggg 35760
aggcagaggc aggagaatag cgtgaagcca ggaggcggag cttgcagtga gctgagattg 35820
cgccactgca ctccagcctg ggcgacagag cgagactccg tctcaaaaaa aaaaaaaaaa 35880
aaaaaaaaag aattcattaa atcaactcac tatttttagt cgtttatgtt aaaagcaaac 35940
tttttctcac atatgtaaga aacccacagg ttttgtgtgc taattatact ttttctaatg 36000
tacattaaaa taaatgcata attattaaaa taagaaatac tgacctataa accatctaat 36060
atcatcctca catattttga gaaacactag gctatatgat gataaagcta aattaatatt 36120
tgataatgtt catatcgtag cttttcctgt ctttgtttct aatctacatt tccacaaaat 36180
ttcaacaact catttagtct ttatacacaa tttttattat tcttcctact ttaggaacat 36240
tatatctggc attcaagttg catacatctt gtaaaaattg tagaaaaata gccaatagaa 36300
ataatgccaa cttctacagt atattaagcc aaataaattc tgctttctaa attccagtct 36360
aaaaacagat tttaccaaca tgaagtcact gattttaaca agatgtgaag gtgaacaaac 36420
tatacaaaat agataattat tttatataca atttagaaat gaatattccc tgcagcactg 36480
tgtgttgttc tcaggcaaca aaaactttag aagagaccaa aggtaaaatc acattgaaga 36540
ggatcctgtt ggtacctttt atggccccat agactttcct taaactatct atcacataat 36600
gaaggatcta gtatataggt ggaatacaat agaaataatg tctaataaat acttttattc 36660
aatttcacaa atcaacaact aggaaaatac agtatagact catgaaacac aagtgacaca 36720
gtcaagagtg atgtcctcca tgccttgttg tcaactttaa gaaccatgca caggagtctg 36780
atcacagaac cactgttctg ggtatggtcc tggtgactgg caagctggta aaatcttgaa 36840
atgctactaa gcaagggtag atttggctag gacccaaggg aacaggagca ggaataaata 36900
ctaacctggt caattggaaa atgtacagga aaacatctga aacaagttta gttatgaaaa 36960
atacacagtt tcttccctct tagagagagg ggagaaaaag aaacaaagaa tcaaagagaa 37020
ccacaaagac gattacaaac ttgaaatatg aactttccaa agagccatta aagaaactga 37080
aattactact caggaaaaaa caggctgaat gagggttcat taattaatgt ccttccggtt 37140
atgaatgggc tcatttatgg gaaacaataa ccatctggtg tccatgattg gtgaagttga 37200
gcaggaaaat aaatgtaaca cacaacatga ggatttatga ggctgataag cctgagaaga 37260
ataatcatca caatttttga gtactatata tgccataaag ttcaccaaat tgagaatgat 37320
aggaccttta ttctagtctt ttctacaata aattaaacca gtgtgatatt agacaagtta 37380
tgtatctctg gacttagttt cctcatctat aaagttagta tattgtgtta atgtaaaaat 37440
gaaggaaaga taatggaact acaagcgtct tcatattttt tctctgctgt ttactgcttg 37500
tatgaatttg gacatatttt atgccttgga ttccttgcct ataaaatgga agtaatagta 37560
gtagcatcct catagatttg ttgagaagat taaataaatg taaagcactc agaaaaatac 37620
ctaattcaat tggagatagt tgttgttttt tgctgtcatt actgtcatgt gcaagtaaca 37680
gaagctaact ctgactggct aagtataaaa gagtttatta aaagggtact ggttcacaga 37740
aactttagat gtggagaatc caattcaagg gtaagctttt aagaacaaaa cccaaaacca 37800
catcacataa ttgtcatgat aaggaaatgt tatctgccat cacagaatgc tcaacattaa 37860
agtttgcacc atttgtggct tttgcatcag aactcaattt tagtaaggga aaccatgatt 37920
gtccatggtt tagtaaagga aaccatgatt ttccaataac catgatggcc ccagctgcaa 37980
ggaaggctag aaaaatcaag tatctgtcat ttttaagttc tataggagaa ggcaattttt 38040
gcccagattc cccaggtata taacaagttc aaacgctcag tggccaaaat taactcagtt 38100
cattcaatct tcatgctaag acttactgct tagaatgatt tattgaggaa ggttttgtgg 38160
cttttatcca aggtcaagaa gatggtagac aaaatctctt gaagactcaa tggcttcatc 38220
atgaaggact tgaaatatct gtgataggag gaaatttcca agtactcttg acatataaac 38280
tgagtaactg ggtaggctca gcatccaata tgtaaattaa agccactgga tttatagtta 38340
gaattgtgtc ctcaattgtt aatttacata ggtgaagact ttccacctat ttgtatatga 38400
ctctagagag acaacggttt gtaagtcttt ggaaaaataa aagtttccag agtttaataa 38460
acattctctc atgaaaaaca aaaatctata ttcttttagt ctgaactatt aatacatttg 38520
tgctgctggg gagaatgctt cccttgagga agacatcagc taggagagaa aagagcagtt 38580
ataactgggc tttatctatt ttaaactcct caactatgaa aatagtacct gacatattag 38640
caacccagag cccaactgtc ctttctgagt aatggacagc tattctaacc ccatgactaa 38700
tgcccattgc ctgtcttaaa ttgatctgaa cttccattac tggtacattc caagaccagc 38760
gggtggctca cagagcaaat ctcccctact gagtgaacta cagggcatcc ctgaactggc 38820
cagactcttt acagtctcaa aaaatattct ttggattttt tttcaagtgt ttataaaaaa 38880
caaagaaaga caattaatat gctttcttgc ccagttattt cagattgtaa gcaggtaaat 38940
cttcctatat gcatcatatg cataaatagt tggatggcat ttttagcaat tatagcaatc 39000
aagaaagttg aagatatatt taaacaggtc aatctgctgg ttgcctattt attttcaaac 39060
tatcaaagct attcaaagca gaatttctgg aattaccatt ttactattat gagattaaag 39120
tttggtttcc tcaacttgaa gggtaaaaat accacccaat gtatagtaaa cttataatct 39180
gttgaatgtt acagacatca aagatacata aaaatgggct cagaagcatc attatcaccg 39240
aaatggaaag agtttgccca gggagaagga tggtaatttg gcaattcagg ttgagtatct 39300
tttatccaaa atgcttagga ccagaagtat tttggatttc agacgttttt aattttagaa 39360
tttttgcata tacattataa agatatcttg gagttgggac ccaaagtata aacacagaat 39420
acacttataa ttcatatata ccttatacac atagcttgaa ggtaatttta tacaatgctt 39480
ttaacgattt cgtataccca tcacatgagg tcaggtgtgg aattttctac ttgtggcatc 39540
atgttggcac tgaaaagttt tgaattttgg attttggggt tagaaatatg agatatgttc 39600
ttccaaatat tttatgtaat aaaatgatcg gaaattgaaa ggattttaaa ttgcagtaga 39660
gaatttgcta tttaatggca tgatacattt tttcataaat aaggagtttt tttttttttt 39720
ttgagacaga gtcttgctct atcacccagg tgggagtgca gtgacaacat ctcagttcac 39780
tgcaacctct acttcctggg ttcaagtgat tctcatgcct cagactccca agtagctgga 39840
attacaggca tgtgccacca tgtccagcta atttttgtat ttttagtaga gatggggttt 39900
caccatgttg gccaggctgg tctcgaactc ctagactcaa gccatccacc cacctcagcc 39960
tcccaaagtg ctgggattac aggcataagc caccatgcca gaccaataag gaatatttta 40020
atgtatgtat ctgttataag tggcttccac gtatcaaagg agcaaaatgc aaaaattaag 40080
ctgatgaact ttgatgcctg actgcctggg ttcaaattct ggcttctcca cttcccaacc 40140
atgtgacctt ggcaaattaa tttatctggg ctttgatacc ttatgtaaat gggataataa 40200
ctgtccttaa cccatgacat taagtaatga cagagcagta tctgacatat agtaaatgct 40260
atataggtat ttgtttgaaa agaagtaaat aaataaaact cattaatgtc tctgaaaatg 40320
tcaattgcac atttttaagg taattcttgg ttgagatata aaccactaaa ttaccaaggt 40380
tttggggttt ttttctataa gcataagtat ttcaatttct cagatttctc agtgatatca 40440
aagttttact aatggacaag aatattaggg taagaaaaaa gtacaggaac tctctaggca 40500
aaaatttaaa tattcaatta gattttaaaa atactcagtt gtttgaaaca aaaaaagtaa 40560
tccaggcaaa gtagaagact catatgatat ctttttaagt tattattttt aaaaaacgtg 40620
gtatgaatta ttagaaataa tgtgtgatca tgacccacag acaccacaga tatgaattaa 40680
atactgtgat ccaaagagcc tttgtgctaa cacttacaaa atataattga gaaagactca 40740
agttggtgta tatgaagatt taacagggac actacaagct gctttacttc aattttaaac 40800
aacagtcata caaagcagtg tatttaaaca actaacatat gtcttttaaa aatatacata 40860
gaaaaatatt tgaaaaggcc tatgaaattt ttgacagtaa ctacttctaa ggatggtaca 40920
gtgatacatt ggagaatttt tctttttact ttacatgtca ctgtgttttt tccacaactt 40980
gtatcatttt atagcatgaa acttcttaaa atattagttg tagaagttag tagtgaactc 41040
ttgggctcaa gggatccttc tgcctcagtc agagtaagtt ctattgttct atagcactgc 41100
aggatgacta cgtttaacaa taatatatta ttaatatgta gttgtaaata gctagaagaa 41160
ggctattcct tgtgttccca acacaaagaa atgataaatg tttgagatga tggatatact 41220
aattaccctg atctatttac tctttaatgt ggtaagaaga tagatctctt aagtgttctt 41280
actcaatgaa attaaaaaag aaaaaaaaaa tatttgccta gcagtttaca agttttcaca 41340
atgtttatct caagcaagct gctgaagcac agagtgtggt actataatcc acataaaaag 41400
ctttaatttt tctcctttaa ccagtccact attattactt gtcaatgata aatacattca 41460
ttaatgtgaa attattttga aaaatactca gggaaattga attaaagtct tgatcatttt 41520
ctcctctcct tcacacctgc cctggatttg caggaaaatg gacaaagaaa atatggtggc 41580
cctccacctg gttgggatgc tgcaccccct gaaaggggct gtgaaatttt tattggaaaa 41640
cttccccgag acctttttga ggatgagctt ataccattat gtgaaaaagt gagtccaaat 41700
ttaacattta atttttctta tcgttcaagg gaaaaatact gttctcttca ctttgctttc 41760
attctcagcc ttcttggtca gtggctgttt ccattccaat taccattcct caattataga 41820
caaagtttct agtgattatc tctttataat cactgccttg acctagctct tgtcctgtta 41880
ctgacagctt gaattgctac aatttctaat gactgtcaaa tctatatctt gttccccaat 41940
ctttccactg tcatgccatc tgactacaaa ctatccatca acaataaccc tacaataacc 42000
tgtctaaaat tagatattgc tccaacttga aattttaata cagttttata aagtacaaca 42060
ttttcatttt aaaagaatgt gtatgtttga caaggctcaa catgtatcta taatccagaa 42120
tgaaatctcc aggtctgaat tttttgtcta cctaaatgca tcaagaagat taagaacatg 42180
gcttttcagt taaaggaaga atacaaaatt aaattttatt tttaataatt taccaagtag 42240
tttttagcaa caagcacatt cctgaaaaat ttagtaaata taagaattta gctctctgcc 42300
tgaatgccaa aatcaatttt gtgtgtgtgt gttaacagcc tcagattcag aactgcacct 42360
aattttacac atacaatccc tcttggcatg aggacaaatg atgaggactt aattctgtaa 42420
gaatcttata tactgaatct gaaaatgagc atcaagaaac acctgaaaca tagagatgta 42480
acatgttcaa actatttcct aatgagccca gaagaaatag gtgttcatta ctgaatacgt 42540
gagggtgggc tagggtaagg ctgagctgag aagtgaccaa ccacaaatgg catgtgctta 42600
atggcacttc tctccagaca tgcgccatca tatttatttg ggcaaccctt cttaaagcag 42660
ccagtgatag taaattgctc agtctagatt gctgcaggac agttgtggag tagaagggag 42720
tattacatgg gcaagtagag tcactatagc caggggaata gagtgttctc ctgctctgga 42780
ggccctagcc ctgagttagt agtatttagg ctagcattta cattcagcca gcagacagag 42840
aaaatgacaa gcctcccaga tcatcccctg aaacatatct gtgttcattt tgatgtcatg 42900
gctgaggaaa aagactgcta agaagttagt ttggcgaatg agcattcttg gattttattt 42960
taaacatcaa tgatagaata ggaccaactg gaaattaaac tatggagatt tcagaggaca 43020
atttagagga aatggacata tacatcaaaa aattgcactt tttttgagac agtgtcttgc 43080
tctgttttcc aggctggagt gcagtggcac aattatggct cattacagcc tctattgcct 43140
gggctcaagc aattctccca cctccgcctt ccaagtagct gggactacaa gcacgtgcca 43200
ccacgctcag ctaatttttg tattttttgt agactcaggg tgtcaccatc ttgcccaaac 43260
tggtttcaaa ttcccagggt taagcaatcc acctgccttg gcctcccaaa atgctggaat 43320
tacaggtgta agaaactgta cttatgataa aatgtgtttt catgtctcta agatgttcca 43380
gataattatg tgataaaagg tcatttgccc taccaaaaac acattctgtt aactcaggct 43440
gaaatgtcac ttgtacacat tttatttaac ttaacttctc tcatgaatca gataactgat 43500
ctgaacccac atgaaaatat gcaaaccatt ccacatggga tgcaaatgcc aaatagtact 43560
ggcaggaggc aaacttcaga aagcattgtg tgtgtgtgtg tttgtgtgtg tatcagcaca 43620
tgcacacata cattcagaag tacaaacgta taaatataaa tgttctattt ctattacttg 43680
cagatcggta aaatttatga aatgagaatg atgatggatt ttaatggcaa caatagagga 43740
tatgcatttg taacattttc aaataaagtg gaagccaaga atgcaatcaa gcaacttaat 43800
aattatgaaa ttaggtaagc tccgcctctt ctagattaaa agtgaaacaa acaatgcacc 43860
tgtgtctgtt tttctatcaa gtttatctaa tatggtgtat gccaaaaaaa aagccaagcc 43920
agaaatgaaa tagattagta tttttccttg gcaaaaataa atttgattaa atatttatta 43980
atatcaatac tatatgaata ccaaactaag ttctatgagt gttcaaagaa acaaaactta 44040
ataatttgcc tgtttcataa atatatattg ggcactgttc aaaatattgg gaatatatca 44100
aggtataatt tcctacttgc agagcaaata tataagatca ctcaaaatag tatgaaaaaa 44160
tcaaaccagg gatgggataa agttgtgtga gaaggtggct actctaattt ggtgtattta 44220
agaaaatact ctctggcaga gtgaaactta atctgagact tgaatgaaaa gagccagtca 44280
tgacagtcag accttgggaa ggttatttca ggaaaggaga gaacatcaag tataaagttc 44340
ccgaagtgaa aacaagcgtg atatgtttga ggggcagaaa gcaagcccat gtggccggag 44400
agggtaaaga gaggaggact gaaagcaata cagttggaga gctgtgcact gtgtgaggaa 44460
gtgtagatga agtacagaag tctctgtggt gatgaatttg aattttcttc taatagaagg 44520
gaggaaagag ttttgattac atttatagtt ttttaaacat tcctctgctg tttggttgag 44580
aatgtactat agcaggtgag gtttgaaaga ggacaccagt tagaaggctg ctgcagttgt 44640
ctagatttgg acaagagatg gtggtagttg gatgaggggg tccatggtgg acaagataag 44700
aaagggtgag atctgggata tacacaaatc tggctagaga ttggatttag actgagagag 44760
aattcagaat tcagggagga aacctaggat tttggtccga gtatctgtga acttgttagt 44820
gccattgcaa tggaaaagac tggaagaaca gcagaggaag gaccttttag ggcactttac 44880
atttgagatg cacattgaac atcccagggg aggtgttgag aaggtgactg tctgcattgt 44940
ggtggagtca ggagacaggt cacagttgga atataaattt gggggtcagc taaatataga 45000
tagcaattaa gaccatggga ctaggggaga gtcccatgta attgactttg tgcaaccaat 45060
tgcccgtttt gataaactgg aaataaaact gacatcatga aattgtctga tttctaaaac 45120
cttcacttgg agagagaacc gtcataaatt ctttcttaaa ggaagccctg agccacgtga 45180
gaggaagatt agtgcagcag ttaaagagca atagttttgg agtcagccat gcttcatttg 45240
agtgccacca agtaacttca ccattctaag cctcaatttc ctcatctata aaatggggat 45300
accatctatt tcataggttt attgctataa caactttaca gtgcttaacc cagtgtttgg 45360
aacacagtga taagccgaca aatgataaaa aaaaaaaaat tgtattttag cacagttcat 45420
caattctaga tgcagttttt ttttttacat cttatcccct tctgaaagag aactgcacct 45480
taaaatgggt agatcttaaa tttgatgaat gcagaaagag cagatttacc acaattattt 45540
ttctctcact ttctatagga ccaaaagaag tcatacatta tccttacagt ctgtaaatca 45600
attaactact ggcttatttt attaaaaatt cctgggccgg acacagtgac tcacgcctgt 45660
aatcctagca ctttgggagg ccaaggcggg cggatcacct gaggttggga gtttgagacc 45720
agcctgacca acctggagaa acctcatctc tactaaaaat acaaaattag cagggcgtgg 45780
tggcgcatgc ctgtagtccc agctactcgg gaggcaggag aattgcttga acctggcagg 45840
gtggagattg cagtgagccg agatcacacc actgctctcc agcctgggca agaagagcga 45900
aactctgtct caaaaaacaa acaaacaaac aacgccttag ccacaggaag atcagttgga 45960
ttcggcaact acttgtagtc taaccattca attccaaggc tggattctag aaaagagtct 46020
tggagaaaac ataaaggagg cttccctccc acaggtgcct ccatggaccc aaaagagctt 46080
tgtgtagtat gtggaggatt gtttgcagta ggaatcagga gatctggggt ccagcccagg 46140
ttcctttgga cgaatgcttt aacctctttg agcatcactt ttatcattgg cacctaaaca 46200
cagagatgtt ctgagcattc accatatgaa agaatatata ctaaagtgct ttgaaagggc 46260
tacaaaacgc tacattacag ttttatgatt tccagaattg gaagtttccc ccattccttg 46320
gtctttcatg gaaccttgac atcgtaacag taagggttat tcccaaaacg gtatttgagt 46380
tgagatagat atggaattgg ctatgtaggg aatcaagtgg atttactgta tctacttaac 46440
acattgttac ccaatagggc ctgtaaatac ttttggacag cagataggat atgaataatg 46500
aataaaatca atccactacg gccactgata attaacagta tcctctgtga attttagtgt 46560
ctttgtctgt gaaatagaga taaaaatata cctacctcat gaggtgtttt gaaaaataaa 46620
tgagataata tacatacatc tcagtgctga cacatactag gtgctctatg aatgtttgca 46680
gaaggttatg gtggtgatga tggaggagga gaagggaaaa gaaaaggaaa aatatgacag 46740
aaattaggaa gagaaagtta ctggccaaaa ttccagtcaa agcacaggtt ggatgccaga 46800
agcaaggtaa aggcagagtg ttaccttaaa aattaggggg tagaataaac ggaataagac 46860
aagccagaat aaacacccca tagacaacct cacctacttg cactctgcct tgggtcagtc 46920
ctgccaggga aagaactttt gttgcagaga agaaaccttc aatttgcttt tatccaccat 46980
ttctcaccca cctatcatta tatcagcttc tacttcatca gatattcact gatcgtcatc 47040
taaatgtctg gcttctagag acattaaagt tgtggcctca gcttttgaaa ggagatggct 47100
ctttgtctcc aaataattcc gggaaaggtg cctgacaaac cacaaccatt taaaaataaa 47160
atatggaatt ctaggctcct cctgctggta actgatatat gaccagcccc ctaactatca 47220
aaaataatat aatttctaaa tacattaata ctgtggaaaa caaggttttg gtgttttctt 47280
ttttaagtaa agtttaaaaa aaaacttgga agattatttt ttcaaccctt ccctcacctt 47340
gagaaccaca ctcctggcac aattcttact agactgagat ggacctgtca cagatctgac 47400
acacggtcct tggttcttca gcaaagcgta ggagacagct aggacagtgg cctaaccctg 47460
gtcagaaaac ctgccacaca accaagagcc attcgctcca tggatatcag accaatcgcc 47520
cactcacctg gctgagagct tttattcatg gcaaatgggt cgtttctgct aagcatactt 47580
cacccatttt taataactta gtgttattac aaaagtcata tagcctaata tgtaacacat 47640
ggaaaacatc aaaaagcata aagtaataaa agttaaaacc atttctccgc aactccattg 47700
ccccaaaata accactatgt tgatatttta ttgtctttcc agatttttct aaacattttt 47760
aatcaaaatg gccttcacat atacttattt tatagccttt taaagcctag cagccaattg 47820
tgaactgttt ttttaaacca atatatattc ttctacgtta ctctttttaa cgactgcaga 47880
gcgtgcaatg gtatgaatgc ctgtcttttg tttaccagtg attctcaatc aggagcagta 47940
ctgtccaccc aagggggcat ttagaaaggt ggggaggcac ttttgaatga tcagattggt 48000
cactattggc atgtagtacg caagaactag agatggtaaa cgtactacag tatgcaatga 48060
gaaaatgtcc aatccaaagc cagtaacatc tcagttgaga gacattaaac cagttcttta 48120
ccgtgaggta ttttgctcat ttccaatttg ggggagattt taaagagcag taataaatat 48180
ccttaaacat aaattctagg gctcactttt attttccagg gacatattcc cagaagatac 48240
tttatttggt caaaggttgt gcacacttaa gacttttgat acattttgcc aaatgttctc 48300
cagaatagtt taatccatgt gtactctgcc agtgaaggtg tacatacctc aacttgctaa 48360
gaagcaactc tgtacagtgg aagaaacagg aactgagatc ccacagctag gtttcattcc 48420
ttaaaatcta taacatttta agcaagtctt tttatttctt ggagtttcaa gttcatctgt 48480
aaatggaaat aacttctact ctgccgatct cacagtcttt ttgtgtgggg cagataaggt 48540
catatgtgaa aatgtgttca agtataaaag actgttttta acagagatca catcagaaca 48600
gcttttctct ttggctacaa aagaaaagga atgtcaggtg ttgcaaactc aagcgactgc 48660
agggccaggc aggtggcttc agtaacctgg gttaggtgta gggacctcag tgttggggat 48720
gcttcaggga gcggtgagga ttgacaactc ttgaatccac atctagccta aagaaagcag 48780
atgctatgca gccatgaaaa aggatgagtt catgtccttt gtagggacat ggatgaaact 48840
ggaaaccatc attctcagca aactatcgca aggacaaaaa accaaacact gcatgttctc 48900
actcataggt gggaattgaa caatgagaac acttggacac aggaagggga acattacaca 48960
ccagggcctg ttgtggggtg gggggagggg ggagggatag cattaggaga tatacctaat 49020
gcaaatgacg agttaatggg tgcagcacac caacatggca catgtataca tatgtaacaa 49080
acctgcatgt tgtgcacatg taccctagaa cttaaagtaa aataaaataa aaaaagaaag 49140
cagatgctac tcagcttcag ataacttttt tgtttgaaaa tgtagagcac atgttgacac 49200
atctaataat cttgcaaaag aagccacaac tctccaaaaa tggtttcaac actatgaacc 49260
caaacatccc acatcttcag gcaacatttg gcccacagcc atacattttc aacctgaatc 49320
ctacaaggat tctcatcaat caaaatccct gctctttttg cagaaatggg cgcctcttag 49380
gggtttgtgc cagtgtggac aactgccgat tatttgttgg gggcatccca aaaaccaaaa 49440
agagagaaga aatcttatcg gagatgaaaa aggttactga aggtgttgtc gatgtcatcg 49500
tctacccaag cgctgcagat aaaaccaaaa accgaggctt tgccttcgtg gagtatgaga 49560
gtcatcgagc agctgccatg gcgaggagga aactgctacc aggttagcaa tcccctcctc 49620
aaagatgaga cttctctgcc tatcctgcct gcctccgcaa agaaaataag catttttaat 49680
tttttttggc tatctttcat tacgctgtat tttaaatttt ttatccttct tcactgtctc 49740
acagttgatt ccattccctg aagttttcag actcagtttt gaaaaatatt cattctgtgc 49800
attgaggcta atttacatgc actaaagaaa cccagaactt taagtacagc aatcctttga 49860
tgaataaaga gtcttcttaa aattaagtat atcaatcaca gttacttttg tgtatagatt 49920
ttgttaccag gcttattaga attagggtat attctccatt acagtgtaga aataaaaacc 49980
tcaagtgata ccttattcca atgacaacta ggtgacatac tttcattatg actccctgtt 50040
gtctaataat ttctgtctaa tttgagagaa gagagataaa agctctcctt agaaagccac 50100
ctttatttgt tagttattac aaccacagga tagatcccat ttggtgaata actatcaaat 50160
tctctatcca ccccaacact gcctcggtca gatcaactta ggaaaatttt ttacagttct 50220
tggctcattc taaaacattt tctacaactt acacaggttt ttaaatgaat actaaaataa 50280
gaggatttca aaaatgacag actggacaca ctggaatgaa cttttctcat gaaaattatg 50340
ggagagccac cagaattcaa aacaaaacaa ccacaacaaa gatgtctaca tttatgttgc 50400
ctttgtaaac actcttcaaa acaaaccaat actagatcag ccccctagat atcttcaaaa 50460
ctaggagaca gtttctggct tggggaagat ctttcaataa tatcttcatg aaggcaactt 50520
aaagggaaaa aaaatgagac agtcccaaag gttgctgaat cttttagaga agtagatatt 50580
tttaatgttg aatctttcat tcacaacttc ttccctcttc actggccagc atttggtcaa 50640
gtcatctaaa tcacaggtcc atagatagac tcactaagac tcctcatggg ggcatacctt 50700
ttggtgacct ggacgtaata ttttgctatc tgcttcaatt cttctttctt cttcaacatc 50760
gacaactgta ccattgaaaa gtcttttgta tccatcctgt tcttaggcca ccactgaagt 50820
ctaaacacac atattctaaa ccttatgtaa tttttttcaa gatctaatta ttctcccagc 50880
tctgctttct cttccatgtg ccccaccctc cgacttctcc atcctgaaca ttaccaccag 50940
attaatgttt ccaaaatatc ctattatcct ttcaacacct tcttgcaaat agtaggaatt 51000
caatctctat ctataggctg aatgatgtct gtcactaact ggccagttca aaaatattca 51060
taactccttg ctgtgtgtaa gaactaaata tgtgatttca ttattcaata ccttttattc 51120
atttcctggt cttttatgac catatttgct accttctatt tcccaataaa aactcttcct 51180
tctatcagga cagacacctc aatgacctag acacttccat gcttatgtct gtctcgttta 51240
ttcctaatgc tatatcctct actaggaata cctgcccctc cgtcacttgt gacattcacc 51300
ccagcccagc cagcaccttc ttgagaaacc tacctccagt attccagccc gaattagtca 51360
ctttcctccc tcaatgcagg aagccattca ttatctgtaa aaacagatat gtgaaataat 51420
ttggggtgtg ggggagtagg acagtgaaag aaggtccaaa acaagtgaaa gacagtttcc 51480
agggtcaaga caatccagta atcccagaga agctccacct cctgaaagct tccctatctc 51540
ttcagggaga atggcacatt ggcccaccga aggaactcct ttttctaagt caagcagact 51600
agctagccag gtcctatcag ataagcttca gaaattttca agcacttcat taagcttcca 51660
cccacagtcc tgacttttcc ttgtggattc tctgtccagg atatgccata gggaggctgc 51720
ctcccctccc cgtccacaac tcatattcac tatgatccaa tgcaaccccc ttacctatgg 51780
ccctttgagc cagtctcagg tggatttcac tcagctggat tttagtcagc aactaactca 51840
tcagcaaact aacaagatga ggcacagtgg tgagtaagcc agccagagca aacttcttca 51900
cctctaatga gatctcagaa caaaacctat cacccatttg gatcactcta cctgttaccc 51960
cattgcagac tcacccacaa caaaggaatt ctttaattgc caaccctttg agaacctagt 52020
ttaaaagaac aaggagactg ttgagaaaaa tgataagtga agacaacaag aaacttttct 52080
ttcttaattg acccagactt ggagacagag agacaatagt tgtctaaagg gatgtaactg 52140
ctcctcagtc acttacctcc tctctaaaca gtggcagttc ccccttgaga aatctcacct 52200
ttattgagct ctttacagaa caaagttgct gcatcccact cagaaactag aaaggtgttc 52260
taagaatgct ctgaagaaaa gtcctggcag tgattctcaa tgtcaggctg catcagcatc 52320
acctggaggg cttgttatag cacagattgc tagatcccac cgccagagtt cttgattcag 52380
taggtctggt gtcaggccag gtaattcgca tttacaacaa gctcccagga tgctactact 52440
cccaggactg cacatttgaa aacccatgat ttgaatcaat gattttccat cctaggctgc 52500
acattggaat tacctgatgt tttcaaacaa tgtgagtacc catgtcagcc tctaatcaat 52560
tgaatctgca tcactggaat ataaagttag ggaactggtg ttttaagttt tccagatgat 52620
tctattcttc agtcaaattt tgtgattcac agctaaatct atcagctaat gatactgggt 52680
aatcatcttc atggcatgta aataggaata cctgggaact gctcagtcag taaatattta 52740
ttaagcatct agaacacata ttgctccctt ctgaatgaca tgagagattc taaaaataaa 52800
aaaaaaaaca tagtacctaa ccattgcact caaagagtgc atattctgag aaaactatac 52860
atacacaaaa acaggaaaaa ttattaagag gagagtgtat tgttaaatca taatttaaaa 52920
gttattaagt cttctctgca tcatcttttc ctgacctcac aacaatagta ggttgtagat 52980
aaggaaactg atgttagaaa ggatatgttt tctagccagg atgattgttc tgacatttga 53040
acttgtctta cttctagctc atgctctcaa atcactctgt aacactcact ttcaccagag 53100
gccttcacaa ggatgttggt ggaaatcact gcttcccata tttactctca tttctgttcc 53160
cttagcctta tgcagctctt cgtggtccta ggctgagaag actaaagcta gagcagtagt 53220
actcaactgt ggctgcattt tagaattaac taagctactt ttaaaactcc tgagatccag 53280
cccacttata tcagaattgg gaagggtagg tagtccagag gtcagtaacg agctggtaaa 53340
tctttaacag ccagctccca gaggaaaaaa caaaagccct gatttgtagc atttgccagt 53400
ttccatggta ttaacactcc cactgtggct gatttcaggc taccaatgcg actttaactg 53460
gctcacaaaa ttctgatact ttctttatct atttatctgt caatgaacat ttaggttgat 53520
tccataccat ggtaattgtg aataatgctt caataaacat gggaatgcag gaatctcttt 53580
aacataatga tttcatttgg ggtgaataca tacccagtat ggtgattgcg ggatcatatg 53640
gtagctctat ttttattttt ttgaggaacc tgcatactgt tttccataat ggctctacca 53700
acttacattc ccatcaacag tatgcaagta ttctcatttc tccaaatcct tgccaacatc 53760
atctttgatc tttttgataa tggccattct accaggtgtg aggtgataac tcattttagt 53820
tttgatttat atttgcctga tgattagaga tgttaagcat tttttcatat acctgttggc 53880
gatttatatt tcttcttttg agatatgtct attcaaatcc attgccctgt ttttgttttt 53940
tatttttgag acggagtttc actcttattg cccaggctag agtgcaatgg catgatcttg 54000
gctcactgca acctctgcct cccgggttca agtgattctc ctgcctcagc ctcctgagta 54060
gctgggatta caggcatgtg ccaccacgcc tggctaactt tgtattttta gtagagatgg 54120
ggtttctcca tgttggtcag gctggtctcg aactactgac ctcagatgat ctgccagcct 54180
tggcctccca aagtgctggg attacaggtg tgagccacca cgcccggcct tttgcccatt 54240
tttaattggg ttatctgttt tcctactatt gattgtttga gttctctata tatttgggat 54300
attaactcct tatcaaatgt atgctttgta aatatttttt tcccattcct taggttatct 54360
cttcactcca ttgattgttt cctttgctgt gcggaaagtt tagtttgatg caatcccatt 54420
catctatttt tgcttttgtt gtctgtgctt tgggggttat agccaaaaaa taactgccca 54480
gaccaatgtc aagaaacttt cccttatgtt tctttctagt agttttactg tttccagtct 54540
tacatttaag tctttattcc attttaactt ggcttatgtg tatattgtaa gataagggtc 54600
ccatctcatt cttttgcata tggatatcca attttcctta caccatttgt tgaagaggct 54660
gttccttctc cattgtgtgt tcttggcacc tttgtcaaag atcaattggc cataaatgtg 54720
tggatttact tctggactct attttgtttc attggcctaa atgtctgttt ttatgccagt 54780
atcatactat tttgattact atagctttgc agtatatttt gagatcaagt agtgtgatga 54840
ccccagcttt gttcttttgg ttcagatttc tttggctagg gtcttttgtg gccccataca 54900
aattttagaa ttgtattttc tatttctgtg aaaaacatca ctggaatttc gatagagact 54960
gcattgaatc tgtagattgc tctgagtagc gtggacttta taacaataat aatgcctcca 55020
atccatgaac ataggatatt tttccattta tttgtttctt ctttaatttt ttatcaatat 55080
tttacagttt taagtataca gatctttcat tttgttggtt aaatttattt ctaagtattt 55140
ttggggggat gatactataa atgagattgt tttcttgatt tctgtttcag ttttcttgat 55200
ttcttgttgt tagtgtatag aaaggctact tatttatgta tgttagtttt gtattttaca 55260
gctatactga gcttgtttat tagttacaat ggaatattag tcaatcttta caaagaagga 55320
aattctgtca tttgcaacaa catggatgaa actggaggac attatattaa gtgaaataag 55380
ccagacacag aaagacaaat attgcataat ctcacttata tgtggaatct aaaaagttga 55440
attcatataa gcagagtgta gaatggtggt taccagggct gggggcagag gtatggagag 55500
atattggtca aacgatacaa agtttccatt aaaatgaata atttctgcaa atctattgta 55560
taatatgact atagttaatg tatttgtata cttgaaaatt ggtaagagag tagatcttaa 55620
atgttatcac caccaaaaaa aagtattgag gtgatgcata tgttaattag cttcatttaa 55680
tcattttaca tgtatacatg tatcaaaaca tcatgttgta taccacaaat agatgcaatt 55740
ttgattgatc aattatacct ttaaaaagat gggaaggaaa aatgcaaaaa tttaatcatc 55800
tatttttgca agtagataag aactggctct agtacatcac tgggtggaac ccaggtttca 55860
ttatttttta aacctcaccc aatatggagc caaggctgag aaccactgag ctaccaaagc 55920
cagaattatg tgggagcctt ggggatcttg gaataataca aacaaaaaaa gtctatgtaa 55980
agcatacaag gggaaaggaa gagagtaatg aagaaaacta tcccctgaaa tgcaacacag 56040
aacaagatgg tcacagctag ggtaacaaga gccagcttct ccagggtcag ttatctctta 56100
agacatgcct attcttcatt tgggttttag aatgccaggg ccacggatgc ttttactgac 56160
tgcttttcaa ggaatataaa gatgcattct tattgaaaat aattgcttcc tatgtgtagt 56220
aattaaacaa ataaaccctt accaatactg agagttcctg attttgttct ctcaagcttt 56280
gtattgctta cgggataaag tttattccca aataacgaat aaaaaacaaa ctagatttcc 56340
aatcaaattt agaacttggg ttgactctca ctctcctctc atcacttcaa caagatctgc 56400
actgcgtagg ggtataggag cagagtcacc aaaaaacaaa acaaaacaaa acaacaacaa 56460
aaaaggggga ggtggttaag tagaacaggc ctgggaaagt tatcctctct aaagctcatt 56520
tcccattctg taaaattggg agtaattcac ctccccacag ggttactgtg agaagtaact 56580
gagatggcac atgggaaaca gatggtacag tacaagacac tcaataaaat gtgttcatag 56640
taatacaaaa atatatgtag ccatggagaa caactaccct ttacagaaga attaaaattc 56700
tcattataga ctcttccatt gcttgtcatc tgtcttctta attaggactt tttgaaaatg 56760
tctccagatt cccaatttat tcatgttgtg aaagaggatt aagagggaac acagctgatc 56820
taagccttga ccaagtgtga gggacagaga acaaattaag gatgcctgag tcccacccac 56880
ctttgcccaa acaccatttt ttgaacatct caattgtggt acctagccta attaacaaca 56940
cagattccag cagcagtaaa tgctcttcct agtaaccttc ttaatgttct gtggagtcag 57000
attctatatc tgggccctaa atccataatt ttcctatctc ccttgtgcta tcttacctta 57060
agtgactacc ttcacccaat gagtgttgtt ctaagagcca aatgtggcct ctgctgcctc 57120
atttctgttc aacctcaaac cacgtcctgg ttccctttat aatcgatagt tataacaagc 57180
caccggtcac acagaactcc cttctaatca gctactccac ttggaatgtc tcttaagatc 57240
aacactcacc agttttaatg gtcttcttgc tcattcaaga cctcaagggt caggtcaatt 57300
taaaagacca ttggtataaa ttgagatgat gttgtcctga ttcctacata attaatcata 57360
atggtgatca ttttcaacag gaagaattca gttatgggga catggtattg cagtagactg 57420
ggcagagcca gaagtagaag ttgatgaaga tacaatgtct tcagtgaaaa tcctatatgt 57480
aagaaatctt atgctgtcta cctctgaaga gatgattgaa aaggaattca acaatatcaa 57540
accaggtagg acatatatac aagattagtt tttcaaaaca ttctttgtcc tggtttagtc 57600
ttgggagggt gtatgtgtcg aggaatttgt ccatttcttc tagatttcta gtttatttgc 57660
atagaggtgt ttatagtatt ctctgacggt agtttgtatt tctgtgggat cggtggcgat 57720
atccccttta tcatttttta ttgtgcttat ttgattcttc tctcttttct tctttattag 57780
tcttgctagt ggtctatcaa ttttgttgat cttttaaaaa aaacagctcc tggattcact 57840
gatttttttg aaggattttt gtgcctctat ctcattcagt tctgctctga tcttagttat 57900
ttcttgcctt ctgctagctt ttgaatgtgt ttgctcttgc ttctctagtt cttttaattg 57960
tgatgttagg gtgtcaattt tagatctttc ctgctttctc ttgtgggcat ttagtgctat 58020
aaatttccct ctacacattg ctttaaatgt gttccagaga ttctggtatg ttatgtatgt 58080
ctttgttctc atcggtttca aagaacatct ttatttccac cttcatttcg ttgtgtactc 58140
agtagtcatt caggagcagg ctgttcagtt tccttgtagt tgagtggttt ggggtgagtt 58200
tcttaatcct gagttctagt ttgattgcac tgtggtctga gagacagttt gttataattt 58260
ctgttctttt acatttgctg aggagtgctt tacttccaac tatgtggtca attttggaat 58320
aagtgtgatg tggagctgag aagaatgtat attctgttga tttggggtgg agaattctgt 58380
agatgtctat taggtccgct tggtgcagag ctgagttcaa ttcctgaata tccttgttaa 58440
ctttctgtct cgttgatctg tctaatgttg acagtggggt gttaaagtct cccattatta 58500
ttgtgtggga gtctaagtct ctttgtaggt ctctaaggac ttgctttatg actctgggta 58560
ctcctgtatt gggtgcatat atatttagga tagttagctc gtcttgttga attgattcct 58620
ttaccattat gtaatggcct tctttgtctc ttttgatctt tgttggttta aagtctcttt 58680
tatcagagac taggattgca acccctgcct ttttttgttt tccatttgct tggtagatct 58740
tcctccatcc atttactttg agcctatgtg tgtctctgca tgtgagatgg gtttcctgaa 58800
tacagcgcac tgatgagtct tgactcttta tccaatttgc cagtctgtgt cttttaattg 58860
gagcatttag cccacttacc ttttaaggtt aatattgtta tgtgtaaatt tgatcctgtc 58920
attatgatgt tagctggtta ttttgctcat tagttgatgc agtttcttcc tagcctggat 58980
ggtctttaca atttggcatg tttttgcagt cgctggtact ggttattcct ttccatgttt 59040
agcgcttcct tcaggagttc ttgtagggca ggcctggtag tgacaaaatc tctcagaatt 59100
tgcttgtctg taaagtattt tatttctcct ttgcttatga agcttagttt ggctggatat 59160
gaaattctgg gttgaaaatt attttcttta agaatgttga atattggccc ccactctctc 59220
ctggcttgtc gagtttctgc cgagagatca aaacattctt taaaagcacc tatgcttgag 59280
atgacttccc ataactttaa atagaaatgc ttttatttag ttcatctcat aattccatgc 59340
agacctctca aactatgttc ctaactttgg attagaaaat caagccatgt ggtcctacaa 59400
catttatcaa tattataatt gcatacttat ctatgtgatt atttaatgaa tatctatttt 59460
cttcactaaa ctataaattt catgagtttt tcccctctta ttgtttcctc catcttcaga 59520
catttaatct ctgggcctgg ggtacaatga ttgctcaata aatatttact gtaatgaaga 59580
atgcatgcca taaccatagg tctgatgcag ggtttctcag cctcaccact attgatattt 59640
tggaacagat cattcttggc tgtgggggtc tgtccagtgg attgtaggat gtttagcagc 59700
atcccaggcc tgtctctgtt agataccagt agcaacctcc aagatgtgac aacgaaaaat 59760
gccttcagac attgcaaaat atactctacg ggtgggcaaa attgccccca gttgagaacc 59820
actggcctaa tggaatacac ttgtgacata agtaaaaagg tgacaatcct aggaaactga 59880
tttgagtgaa gaggaaggga aaggaataga gggaaggtgg aaggggatag ttagttgcta 59940
ctcatcttgt caatactttt cagtatcaat tctaagccat cagattgact ccccatctct 60000
ttcttctcca tataggagct acaacactga gagaggtaga gcatttcagg aaacaatatc 60060
caaattacca tttcccaaaa acagttcaga acattaattc tacaatcttt tggtggatgt 60120
tgctgataaa agggctccat ggtcaaataa gcttgtaaac accagattct gcaaaattaa 60180
atgaatttct tcattatgga acttatcaaa gtcttttgcc ttctaacatg ctttgaaatt 60240
ctccaagaag cgatgcagaa atcttcattt ttcaagtttc tgaaacatga ctgctctttt 60300
ttgccatatc attttgtggg attactgtgt ctttaaacac actctgggca gtagtggctt 60360
agggttatca tagtagtaat atcctttcat aactgagaat ttcccagtct cctggcaaat 60420
tatctaggtt gttaataagg gtgggccatg gtgctgtcat gttaaagctg cctaagaata 60480
ttcacttgca catactcaca tcgtctgttt ccaactctgg gtgctacttc agatagaaca 60540
gaatgataag ctgatgattt gctctgaagg acattcagga aggatgtcac tgctccattt 60600
tgaaagattc accaaagatc tttctccagc ctcagggact ctgccttccc tgaaatatta 60660
gtgtgagggt gtggctccac accaacagct gtgaatccat gactaagcta gaatctgcaa 60720
atgatggacc accttactgt gtgccaagca ttgcagtggg cactttcaca gcatgtgtca 60780
tttattcatc acaaccctat aatacaggtt gctttattca ttccattact ttctagataa 60840
gaaaaacagg acccagagta gttaagtagt ttgcccaggt tcacacagct agcaggtcgc 60900
agatcctgga tttgaactca ggtctggtaa agggcatgtt cttaaaaact ttaatactct 60960
catgccgcct ccttattcca ttcactcact cattcattca actgtctttc cttcagtagc 61020
tcctacatgc caggcactgt ggaaggaaca aacaagtatg atgtgtgcat ggaaaaagtt 61080
taagaaattc cagaaaaata cagctttgac agactactct tggagtgcag agaagacttg 61140
tgttttgaag cgacatctaa gctgagatct gaatgttgat gcagttgtag gcataggaac 61200
attatgtgtg tataaatatt gcccactatt ctcccctcat tccatgttga ctttctacct 61260
tcccagagtg aataatactt cttattttta tctaattaaa acagcacctt tttttgccaa 61320
gggctagaat gagaaactac taaaaggctg cttcctttcc tagtccctga ttatcagctt 61380
tcccagtctg cgtattggca tatattaaag agacatgtgt gcccggatcc tactaattat 61440
catgaaaata atgaacatca catatctctc tcttgctcac tctctcactt tctctttctt 61500
cttgggacta aagtgtgtcc agcgatttca gggcacagtc tgcagctggt ggcacaactc 61560
tcagggctat ataatgatgt atggcttgtt cttcgtggcc ctctgcaaaa aaaaatatga 61620
atttcagaac gtgaacaact agcagacatc tgctgcatta agagggaaaa gtcagagcta 61680
actagtttat cttggaaagt atgtactgtg ccaaggctat acttatctag aaaaatttct 61740
ggaaacaaac agaaaaatga ctctaaaaat tccatttaaa gtttaggtcc ctcagaggaa 61800
cctacatatt acctcaaaat atttgaccac gtatcagttt aaccatgatg aacttgaata 61860
atattatatt gccactgaga gacacaaaag ataattagaa caaaaattga gacctgaaga 61920
tggtttgttc ttccccactg tagcctaagg gtatctgctg aatttccaat tatagtcatt 61980
ctacaaaatc tgatcttcct acaagagttt agcagtatta gaatcacctg aagggcatgt 62040
taaatcactg attgcttggc ccatcatggg tgggttcaag catttccatt tctattaagt 62100
ttccaggcaa agtggattct gctggtcagg gcaccacact tcgggaacca tgaccctctg 62160
ataaccttcc ctttggcatg caggtgtgtt tctcctcagg tttatgtgtt gctgacaagt 62220
tgataagaaa cacagcaata attttccaat tccttgcatc atgatttcag aggatctttt 62280
tcttctttgc taatggatga ttgagtaata atgatcactc atattctatg gactcaccct 62340
ctgccaaatg aggatcaatt attaaacaaa ctcctatgca ctaaagaaga aacataataa 62400
aataagccat gtggtgaata ctattgtaga gaaaaccaac ttttatgaca cagactctaa 62460
ctttttaact tgtctgtttt atgaggctaa gtttttaaat atcaaatttt ccaaaaccag 62520
atgcatctgg aagttatcgt ccaacagtgt aagataattt cagatatctg caaacagaat 62580
ttcagaaaat ctaaattcat tatcatctca aatgccacta actggtgtaa atgacagaag 62640
ttgggatgtg aattaactga taatattccc ttattccatg tgtatttata gagtagctcc 62700
tgtgtccaag gcagtaggca ggaaccaggt gaagatgata ccaagaagtc tctgaagagg 62760
gtcctgttct cagggagata acagaccagt gagcctaggt ggagaatgac attgaaatat 62820
gaaccaagca aagactggaa aggtgaaggt catcattggc caacgtcttc cttctcagtt 62880
actaaaacaa gtcatgggat taagtcatga tcatcacccc atgtgacact gaaaggaatg 62940
aagagactat attggatatt cagttaatta tatgtctcat gcttcatggt ctcagagagc 63000
tttatttatc cttagcctgg ccagataatt ttgctctgta taaccattgc cataagaagt 63060
caagggtcga ctgttgaagg gagtgaaaag agaagtatca caatgtcttt aaattgtcct 63120
tatgttacag gccgactatc attccaaagg aagataattc ttagtcattg aaccacgtgg 63180
gagagtaaaa actctaatta cctttgttac cttgaatcta agaagataat gaaactttga 63240
taaggacaga aaggacttcc ccctcttctt ttccctggca taatgtctca tcctatgttg 63300
tctcccggca ctctcaaggt acacccaagt gagtgtaggg attaaagaag ataattggca 63360
tgctaaacta atagtggtta aacaaatttc caccttacct tcactctaag caaaaggtct 63420
atttttaaaa ttgagtaagg aaaaacattt taaaaatata acatccaact atctcggtac 63480
aactatcttt ttcattttta tatgttgcca tcatgttcag cagttccctt acataaaaat 63540
agatagttgg tttgtttggg ttttctacac aaataatata aataaacttt gcaaatattt 63600
gtaaaatacc aaatatatca attaaaatat gaaaacctcc ttcattcttc ccaacttttc 63660
tccccattcc tgaagtaacc tctgttaaga gtttggtctc tatcttttca gttcactttc 63720
tgtatgagtg tatttatatt tgtgtgcaca tatatatggt tttggattat taaaaacaca 63780
aatgctgtaa tattgtactt actattttat aactttttaa aaattaacaa taggtcttgg 63840
gccaggcacg gtggctcatg cctgtaatct caacattttg gcaggccgag gtaggcagat 63900
cacctgaggt cgggagttcg agaccagcct gaccaacatg gtgaaactcc ttctctacta 63960
aaaatacaaa attagccagg cacatggtga tgcatgcctg taatcccagc tactcgggag 64020
gctgaggcag aagaatcgct tgaaccaggg aggggtgggt tgcggtgagc tgagatcacg 64080
ccattgcact ctagcctggg caacaagagc aaaactccgt ctgaaaaaaa aaaataggtc 64140
tctaatcttt ccatgtaaca acatacaggt ctattttctt tatagactcc ttcgtgttgg 64200
tataaatgca gcggatttaa tcactcatga aaatagacat taaattgttt tatttttgct 64260
ctttcaacag tagtgtaatt gatatcctta tgcatgatcc ttgtacatgt gtgtgagtgt 64320
ttctgtaaga gacattactc aaagtagaat agtagatatt tacattgttt ccaatcttta 64380
gctatcatga cagcaaggca ggcaacttat ctttgttccc agatgttctt tcggaaacaa 64440
ctttcttttt cttctttttg ttttttattt aaagattatt ggataaggat atagagaatc 64500
cagttgtagt tcctctctgt gtgcactcta aatctcagtt cccttgtcag aactgtagtt 64560
acctaatatt taaattttta aaagtaattt aaagttaatt acataagaca aaagagataa 64620
agacattttg ctggggtgaa aagcaaaagt aatcacctaa atatatgttt gtaaaatgat 64680
caataattga gttcaactca attcaacaag tattttacca tgcaaaatgt actatctttt 64740
acattacata aaatgcaaaa gaagatggaa ttcccaccct tagacacctt gtaatctagg 64800
aagtggaaga cacaaatcca taacaaatta taataagtca gaatataaat tttattttaa 64860
aaactgcaaa aaaaatcttc tgttgaatgt tcttgatgag atccttactt aaatatgagg 64920
tatccataaa aaaaatcaaa tactctttgc agctagatgc taaaatatat cactttcaag 64980
gctctcttaa ttttgttaat ggggcaacct tcactctatt ttacaggtgc tgtggagagg 65040
gtgaagaaaa ttcgagacta tgcttttgtg cacttcagta accgagaaga tgcagttgag 65100
gctatgaaag ctttaaatgg caaggtaagg tagaagaaag aaaaaaatat gcagattaca 65160
tccaagtttg gtgtggatat tacatccaaa agcacagtcc tgcaagcctg tctcactcca 65220
gccttctctg acatggctgc ctcagtccat ttaagatgta ctaaagagaa atgatggaaa 65280
atacaatgga agttggagat gtacctaata tatccaactt tacctctatt tgttttttat 65340
aatttggaca agtcactggc cctcaatttc catggaaaga ggagatttaa gtagattatt 65400
tcaagatgtt tttcacaatt ccagttttct ctcattactt caaagagatt atcatcattt 65460
tagtgcagta ttttagaagc tgatgaatta aaaacatgtc aagatagctg ttattctgcc 65520
ttcatagttt gatcttccac ttggaaagct tagagtctct caccttgcca agagtagggg 65580
ctggggaagc ttctatatcc tcactactga gttgtctaca gaaagcaata taatatttat 65640
atatcaagcc aataaacatt taaaaccttc tgtagaccac ttatcatgct aggatacaaa 65700
gagaatcaaa gatgtttgac aaagagttaa aagttggttg gaggaataag acaactacac 65760
aaactcgtgc aaagtatagg caagtaaata tcataaagag agataaacgt ggtgagcaag 65820
ttcaaaggaa gaagtgggct ataaagaata aaacatcttc atggatatga gaagataata 65880
tttaagagaa gccacgaaaa ttgggtataa tttcaaaaat caaaatatgg aaagacagga 65940
agtcttagag gcacagaatt tgagaagagc aagacaagat tggagaacag gaaaatgtgg 66000
agtaacttgg ctggaacata atgcacgtgg gactgtgtta cctatcggat ctggcatcgg 66060
tcagggtccc aaaagaaaac aaatagcaaa ggaattaatt acaaaagtgc gagtggggac 66120
tagggaaatc aaaaaagagt gtcagaattt ggggctcaca gcattctgga gtcaaaggta 66180
caaggggctg gagaattaat agaaatcctg aaaggggaga gaattgtgta gagcagatct 66240
ctttgcaaga agttgctggg tgcagtggct cgcacctgta atctcagcac tttgggaggc 66300
tgaggtagaa ggattgcttg agcccaggag tgcaagacca gcctggacaa gatggcaaga 66360
cctcatctct acaaaaaatt agccgagcat ggtagcatgg actactacag tagtcccagc 66420
tactccgggg gctgaggtgg gaggatctct tgatcccagg aggctgaggc tgcagtgatc 66480
tatgattgtg cctttgcact ccagcctggg caacagagtg agaccccacc attaaggaaa 66540
gaaagaaaag agaaaagaaa gaagcagtga ttttggtcaa aggacacagt cagcccaagg 66600
tgacctctca aagacgggtc cagcagaata aatgccccga attcactgtt gtctcttctc 66660
caacctccta ccagtgttcc ccattggcta aatgcaatca caatctagaa ggctaaagag 66720
gaccccatgt agaacagctt cccagagcag agagcaggct ggagctggta ggtggtgaat 66780
tccataggca gtggatccag atggcaaagg gaggatctct tagcctaggc ccttcagaca 66840
ctgtggagcc tcttgcatat tagctcctca ggggcccact caaactcaaa aagtttgaat 66900
actggagggt ggggtggaga aagtattcac tctgaaatac aaaaaagaaa actgcaaaga 66960
aaaactaatg cataaataca tgtctataaa gaaaagcatt atttcatctt cattgatgat 67020
cacatttagt atcataaaag tgttattact tggaaaacaa tttgtaagtt agattttctc 67080
tatatggaaa cattcctgag tatacatgat gattgctggg aaggaacagc catcacaaat 67140
taaatgccaa aaattacgtt ggaataatta caattgaaac atattcaaat tcccaatttt 67200
tgcagctaga tatttttaga gtaattattt acacatatta tttagttaaa tatatattta 67260
atattatatt tgactataat gtggtatgga aaaatcaaaa gtaagttttc ctaggaacta 67320
tgaaggtttt tgagcatata tagagatatt tatatttaat ttgttagatg aagtgagatc 67380
ttgaaatttt ttctacgata attatcacat ttacaattta ggaaaattag cctagtaaga 67440
actgactttt taatacaggt gagagaaaca tgtcatagaa actagttata aagctattat 67500
agtcaaccaa atgggacaaa ataaagtctt gaacttaggt aggaatggaa tgtaggagac 67560
agccatatgc agaacagtaa gggataaatt caaaggacgc aggaactgat tggagatggg 67620
gtgaaaaaga aggacaagtc attataagct tccaatatgg taggttgtta tgaaagtcag 67680
gaagggaagc ctattcagag agaaaaatga tgaattgagc ttcagaatga ttattcattt 67740
attctttttg taagtctatg aagtgaaaga aattttacta agcttgggct atacagatta 67800
ataagatatt gtcctagctc tggaaatatc taaaccaaat aactaaaata caatattgaa 67860
tttaaaatgc ttttggatgg gacaaaggaa ggcagaacaa aatttgttac aagatatctg 67920
aatttgccgc aaagaatcat tccatgcaaa acatctcttg atatggaagt gcctataagc 67980
agagacctat ttgggtctct catcttcctc aagactggac tgaagatata aagaatctta 68040
tacccaagtt cctcccctat tttcagtatg ccaggtctac tttttctaat tacatcaaca 68100
tcaatataag attgttgaat atcagctgga ttctgtctgt ctctcagagt attccatcta 68160
acttatttga cactggctcc tgctactaaa aagtaaggta aatacataat actggggaca 68220
aattgaccaa gaggctgaac aaaatggtca ggatgaccat gaagcacaag ctttgtccag 68280
cagacttcaa taatccagga accactgagt cactgttgaa atcagagggt aagggtgcac 68340
actcagctgc tgtgaatggg aatttctgta gaaacacttt acataaaagt gttctttata 68400
taaaacagag gatcttcaca ttcttattca aaaacaaagc cacaaatgct ttcagacaat 68460
actttgttcc tttgataata aatacatcaa tctatcaaga atttcttgag agccatcatt 68520
gtttattgtg taggcaagca atacatagaa gttagtagca cacgtagatc tacatacatc 68580
cattatcttt gacatctgga gctgtttgca gtctcagaat ttgtgtcaga attcttaagg 68640
acaggtttta agcagtgcat gatctgagaa cctcaatact actctcactc ccaactactc 68700
ctgacccctg tcatccctgt ttattagctc ccaactgttc agcagatcaa aaggtggctt 68760
cacaaggaag aacctgtggc aggcaatgca acagcctccc agattcctct tcctttggta 68820
gagccacagt atgtctctct tctccagtga aaacttactt gtgtggctgc tctaaggagc 68880
aagacagtta gcgggctatc agctggaagg gcctgatttg gctgcccatg ctaaatgcta 68940
ataattgata agatttcttt attggtttcc tttcaccttc atcttattgt gcaaggtaat 69000
ggagatttta taccatccat aacaaaccta aattgtcttg tagttatata attatataaa 69060
tatgtaattt aaaacacata tatgacctaa taaaaatatt acataacttt ctgtctcagt 69120
gactgtaacc agattgtaaa tttataatga atatgtcaat ggacactggc caatatgtca 69180
ctgtcaaacc tgttggcatc ttatgcaact taccaacaaa atggctcaga aaaagttcaa 69240
ctggcataca aaacaaacct ataaaatgac aagatacaat caataaacct acagcaaata 69300
gtctaacact tagaaggagt catgttatta gggctcagcc acacttggtt atcttcatat 69360
catctcgcgt tgatatttct ttgctctcta caacaggtgc tggatggttc ccccattgaa 69420
gtcaccctag caaaaccagt ggacaaggac agttatgtta ggtatacccg aggcacaggt 69480
ggaaggggca ccatgctgca aggagagtat acctactctt tgggccaagt ttatgatccc 69540
accacaacct accttggagc tcctgtcttc tatgcccccc agacctatgc agcaattccc 69600
agtcttcatt tcccagccac caaaggacat ctcagcaaca gagccattat ccgagcccct 69660
tctgttagag gtaacaccag tcagatcttg ctttagagta atcccaagat ttcaaatgac 69720
tcaaattgca gtagccttag atacattgga tgggtccact tggagaaaag cactgaaaaa 69780
ttgtttatta aaaatcaact attatatcaa tagttttcct ttaataggaa tctttttcac 69840
attacaactg gttattgaaa aaacgtcatc agaacattgt gcaaatgagc ctagtgcaca 69900
gattcaaact ttgcatgggc ccataaaatt tgcacaaact aaaacctagt tctataattg 69960
ttagcttctt ctatatcact tgtccaccac tgtgtagtca tctgtggctc attacaacac 70020
ttctggaata gactagtata gtccagtgga aaccaattac ctcaaatagc aaaacccttt 70080
caaggcatgt gtgtatttga tggtgactca gtggcattgt cttaatatgt aaatcacaaa 70140
ttattataaa tataatctaa cagacatatg agatgttctc atctgacctc ctccaggaaa 70200
tatgttatac tttcttagaa gccaaataat taaggacatt actatatttc tttaatacat 70260
ggagaactga acaacaaata gaaaaaaaac cctcaatcag actgctaata aaacaataaa 70320
tatttcacat ttgaatcctg taagaattct aaatgtttga gcagttttcc aagctccatt 70380
tcttcaagaa agctagaaga taaagaaagc ctttattcta tttccaagaa actagcttgt 70440
ccctgtcttt ttggctcctt cagatgagtt tttctaggat gtggctaatg ccaactgaat 70500
cccagttcta tcctccaaat acgacatgaa tctgggcaat tcgataaact gtgcatttaa 70560
gtctattctt gggtttgact tagaagcaaa aaggcacatc tagattactg tggaaacaat 70620
tatcttacta tgttttacta cttttcagta taactaaatt gatcatatta ggagctctag 70680
tcttcaacag ccttaaaagt ttcatactca taattacttg ccccaaaatt gtaatgcaaa 70740
tgaaataatc aagatttcct ttaaggtaac ttgtctatgt gataataaat tatatcattg 70800
caacattatg catttagaat ataaaatcac ctcattaacc aatccataca ttaaatacaa 70860
attgtcaacc agttatgatg tcgaaaaaaa acaaactcca ctataaggga aaaaatgcct 70920
atcttataac aagaaaggaa tcaatgaatg atattcatgg atgaagggta atcaatttaa 70980
ttttttatct ctatgccacc aatataaaat caaagtagta acatggcaaa acaaaaatca 71040
aaaggaatct atgcatgaaa ctcaatggaa atttaagcct cacattgacc gaacatcaga 71100
gagcatggtg aacctaaaag catgctttct aaatgtttgt tttacaataa gtcattggaa 71160
gtgggataat tagggaagcc agaatttatt tctgatatac tgatcagtga cagtctctat 71220
gcaagactga tttcaaaata agtggtcgca ttatgttgga atgttctaat aaatacattc 71280
ccagtcttta ttagtctgta taaaatatca aggttaccta aagacaaaaa ttgcaaattt 71340
tctatcccaa aatttttaag ttgtttgtgt acttatcaat agtattgtat ttatcaatgg 71400
cattgttttc ttctgaaggt agtttttcaa aaaagagaga cacctatgtt aaaccttacc 71460
ttatgttgag tttcattaca ttagaatcct agagtctccc acccatcttc agggcaataa 71520
tcaacgtgaa ttgggctaac ttttccatta cagtaagatt cagggtgatt ttctggtggt 71580
ttgattcagt ttaatgcctt cttacgttcc tagaaattta catgaatgta cctgtagggg 71640
ctgcgggagt gagaggactg ggcggccgtg gctatttggc atacacaggc ctgggtcgag 71700
gataccaggt caaaggagac aaaagagaag acaaactcta tgacatttta cctgggatgg 71760
agctcacccc aatgaatcct gtcacattaa aaccccaagg aattaaactc gctccccagg 71820
taggtaatgt tattccagaa atagtttctt taagttgtgc caatgagcat cattcacttt 71880
tatcaaatga tttgacttga tccctactca agctatgggt ttttttcttt taatatataa 71940
agcatccaat gaatgtcaca gtctttgaag gaatgctggg catctggtgc cattattcta 72000
ttataggtcc tttctctttt ttaaaaaatc ataaagtcta acaccttgaa caatattcca 72060
ctgaaatgca aagaatctga gagctattaa gaattatcaa cccatacccg aaatgaggca 72120
aagaccccat ctcagaataa atgcctattg tatgtgagcc aggttggctg gcaaatgaag 72180
agtattatgg cagtgccctg aatagaccat ttaggacatc ttttcttgga aatactgtat 72240
ctaagagaaa actccaccat gatatctggg tgaattatta actatgagat gtcatcagtc 72300
ataccaaatt aactcttcct ccatagttat attttggcag tggcattaca gagagttttt 72360
actgtgttca tttaacagtt ctaagtttcc acacttcaac attaacctgt ggtttttatt 72420
attggaaaat taaaagctat aaaagtttca atatggaaac tgactcccgg ggttaaaaat 72480
aaaacaaaac agagtctatg ctaaccctga gactgttccc tgtgggagtg tgataggtgc 72540
tgatctctct gaaatacatt ttggctgaat aatcagagtt acagtttgtg tatcttgaag 72600
gaaacttccc tattcccatg acaaaggtgg gcttatagcc tcacatttat ggaagtagcc 72660
cttataattt caatccagaa gaaaactggt tttctaaaag ctcatcttgg gtaatttttt 72720
aatgggattt ctggctttct tttatgcaca aattagctta tctaaggttt ctgctagccc 72780
cacccaggga attttaaaaa aaatgcctat cagactgcta aacagcaatc atttgttcac 72840
ataagattta gtaaacttct cttatgcacc atgtagtgcg ctaggtgctg gagatgtaga 72900
agtgaatata acaaaatcct tatcatgaaa aattagatgg caatccagtg ggaaaaaact 72960
gacacgtaaa catataatga aatctggaag tgatatgatg aagtttgttc agaaaatata 73020
aaagccactc atccagtttc tcttaggtta aaacccaaaa caaaaaacct gattaaagta 73080
ctggaatact tagaaatatt ttaagaaaat aaaaaataat agtcgcaaat tctgtataat 73140
aatagttccg agagctgcaa tagtatgaaa agagatctct tcattttaca ttaaactcaa 73200
gttagaaatt catcatgtct tttattagta tgtgagtaac aatctctatc aattaataaa 73260
agttctttaa tttgtgtctg accttctaca actatggctt agaaatgaag accatgccac 73320
caccaaccaa cacagatggg gcctaaacaa tcccaaagta gagttgtgaa cttccagcca 73380
gaagcagaga gacaagccct ttcctgcaaa gtcagcagtg agagctggtg ttccttccgc 73440
ccaggtttgc tcacctggca taaacaagca ggcataatat ctaccagcaa aagctccttt 73500
attattgccc aagaactgta gagaatgctc tgaggattac aagagatcct acacaacaag 73560
agtattaaaa agaaaatatc aatagaaaaa acagtaacaa tctacaaatt aataaactgg 73620
aaaatatcat gctattgcag ctgggttagt tagcataaat gaggtaagaa acctcagaga 73680
cacatcctga gacattgttc tgtcttacag agttattttc tcaggcttat gccctgcttt 73740
ccacagtcta ctgaatctgc tgactaacga gagcatcagg acctctggac aaccaaaaat 73800
ggcttcagaa taaagaaact atgaatcttt agaaaatatt cagtttggag taattacaga 73860
agaaaaaaca tgcaggagga tgctaaaaag catattgtca ttaagcaaaa aaacaaacaa 73920
acaaacaaaa aaggcagaaa tagtgtctta ccaaacaaat aaaaacattg caactgtcaa 73980
cacccatcta ggaacactcg ataaatacca agcattaaac tttttaattc tatttttatg 74040
aaattgtgag attaaaaccc tatgacaaat gtcacgaaat aaaaatatat tcttaggcta 74100
tcatctctaa accattataa acacagagat tgagagtaat aatgagtaaa tctatacaaa 74160
tctatacaca cagtgttgga gcaacaattt ttacaaaaac aaatattcca aacaaatcat 74220
aaaattaagc ttttggtaaa aagttacagc taatagacta aactaaaaac atattacagt 74280
aaatggtgtg aaagtgattt tatgaactaa tagacctaac attttaaatg gagttcaaat 74340
tgagttcatc ttaaatttta tgagtcatta aatcatgtgg cattttatgt cttcagatac 74400
tagcttgaac tctgaaaatt agagtttaaa aacctgaaaa cttgggaaat aatgtgaatg 74460
tgtcatttga gggggaaata acttttttta ttcttgtaga tattagaaga gatttgtcag 74520
aaaaataact ggggacagcc agtgtaccag ctgcactctg ctattggaca agaccaaaga 74580
cagctattct tgtacaaaat aactattcct gctctagcca gccagaatcc tgcaatgtgc 74640
gtaacttctc caaattcctt accattttag agcaggatac acttataaat taaatgcatt 74700
tagtcaccat ctaaacaaga tactgaggtc tactacctac tcatttgtca ttcaatgcaa 74760
atattgagat gtgtagttgg gatgtgccag ccatgaaacc agcatataaa ggcccccaaa 74820
tttcatatac acaatgaagg ttgtgtagta tcaccagcca gtggataaca gtcagtagtg 74880
taaaatgtaa tagaaataaa aactatagcc cattcttggc tggatcactt gaggtcggga 74940
gtttgagacc aacctggcca acatggtgaa accccgtctc tactaaaaat acaaaaatta 75000
gccggatgta gtagccggta caggcaggcg cctgtagtca tagttactca gcaggcgcct 75060
gtagtcatag ttactcagca ggctgaggca ggagaatcac ttgaacctga gaggtggagt 75120
ttgcttagat tgtaccactg cactccaacc tgggcaatag agtgagactc catttcaaac 75180
aaacaaagct atagcccatt ctttcatctg tgcagtgttt aggttgaagc atatgaaact 75240
accattttat acataataag acaatggccc atcatttaat tttggaccaa agatatgacc 75300
tctctgttag tggatatcac ctcctgaatt ttaccttgag cctgcatttc tatatatttt 75360
aggaacaatt tgtttcactt gtgctttaga aaagccatgt agtgaattac ttgtatgtcc 75420
caggaatgtc atcaaccact gatgttctag atcaatttgt aaatatttct acatgcaacc 75480
tatatttaga agctttaata gcaaacagaa tgaaaaacac ccactcaaaa taccaccatc 75540
cagtcatctt acaaagctga tagtgcctta agttttcacc tgactcagtt gtaccagttt 75600
aaaaatgcct accctgactg acttgctttc cagccaccct ttcacacctc caaagctgag 75660
tgcctttgtg gatgaagcaa agacgtatgc agccgaatac accctgcaga ccctgggcat 75720
ccccactgat ggaggcgatg gcaccatggc tactgctgct gctgctgcta ctgctttccc 75780
aggtatggga aaattgtgcc agaaatggcg ccctgcagag agtatttggg aaaccctttt 75840
ttggtaccat tgaatcacag aaatgtttgt gtaccctact tacagcaatc tgacttgcac 75900
aaccttggga ccaaaaagag tttcccaaat gagtgactca ttaaaacacg aggcaagaaa 75960
atcaagctgg gcagcagagt gggttctggt ctcggctcag ctttaaactg ctgtgtgatc 76020
ttgaatgagt cagtctctct gagtctggtt tgttttggtt tttactttta gtacgagagt 76080
ttgaaactac ctatagatat atgatgttta ttggagatct tactgtgtgc taggcactca 76140
cttaaatggt caggaagcgt tataatatct tagtaatact catgatacca ccaagagtta 76200
ggttccatca gaaagtctgg tatacaaatg aagagcccat atacagaaag attaagtaat 76260
ttggccactg gcaattagct tttcagcaat cttttctccc tctccagtct tcaatctact 76320
tttattaatt tgatttcaaa aaagattttt taaagtcaaa aattttgtga gagtgagaga 76380
cagacagaga tcctttcaat atgtgaataa tcaggactca actcaattta tttgttctat 76440
aattttggtc tggggcatat gctgattgct taaagcaaag cctatccgtg gatcaacaat 76500
gccttcagag gtcacatttt aaaagatttg tccccatttg ttatgtaccc acaacaaatg 76560
gtaataatta aaactgaatc ctttagagat tgaaggggac caggcaagaa agttgtttag 76620
gaaatttttt ctcagctgaa aattttttat cctttttttt tttagtaaaa gattattttt 76680
attaaagaaa tctgtcattt tttacttctc attgtgtcag cgtgtgccac ataagtccaa 76740
attagagctc taagtagacc tagaaacatg atattcttat tgattaatta attcatatat 76800
tggccatgcg taggtgtgaa aaattttata ttcctcacac ccactgcacc tggggctcct 76860
tctcagtagt gttttttggt tttggggttt tttttctcaa aagttttgaa tatatcctcc 76920
attctggcca gtggggctaa cattaatgat gtttcacatc tgaaagtgac ctcaattctg 76980
gctttgtttc tctgtaagaa catggagatg ctctgtggtg agtccctcgg aggttaccaa 77040
ggtaacagct gacattgcag agggcaaggt ccttcctggg cagtgtgggg ccagcagcca 77100
gtgcttgctt tccacataac agggtgttta catgtccatt tactcaggat gcctgccagg 77160
gcttctcagt tcctagagaa agttgagccc ctgtcttaca gaaagctgca ccccaaagac 77220
acctaacaaa tgtactatta aactaatgag ccactgtcag aattttaaag tttgctttca 77280
cattggaaag gatttgcttt tacccaagaa tgttttatct tattctcact tccactggct 77340
tctgtgagaa gttaaaaata tttagggcat gagtgttgtc ttgggaatgc ctaagaatct 77400
gagagcctct cttataactt tgctgtggag tcaagcaaag aataataggc tccaagggaa 77460
gaatcagttt gaaacccaaa caccctggca cttaacaaat tgaccaagtt gaaaaagaaa 77520
attcaaaatc cctaaaggta aaatctgtgc cacaaacaca tgcatgcatg tgtgcacaca 77580
ctcacacagt tacattactc acttagttta gaaatactgt ttccaaaacc atgaaagtaa 77640
ctgttaacac atgtctccta tccttggaaa atggaccaaa cttcactagt gcattaatca 77700
gcattactga ccaaaatgaa tgcaccaaga gtggattcaa tttttgttca aaataatcca 77760
accagcttcc tgccaccact ttctgagaag ccactagaaa aaaatcaatg tgtctggggt 77820
tgggcaggct tctactgcac ataaactaaa tggggtttaa aacaacaatg aaaaataggt 77880
gcccatttgt acttaagtat acttctctct ttttcttgct atcttttaca atttctggat 77940
aatctcagaa atactcaggt tttaaactaa aacaatacag agaaataatg ctttagatag 78000
tagctaatat gctctcttct tcaaaagtga atgctcatcc actagacaca atgctaacat 78060
gaaagcgcat agattatttt tttaattctc agatactttg gttctctgag gcggagaacc 78120
agcatcaagg cctctgaata caacaagcac aggcttgatg aggggcttgg gaggtaagaa 78180
ggtgcttttg ccattcatag ttacatgtaa atatggacag gttaggcatt tgcttttaag 78240
gtattatgga aaagcacact taacctttac agtatttctc ctactgatct cccagtcttt 78300
acacatcttc ttgggtaaag gcaaatgttt taaatgtttc atttaggcag gtgtggggtt 78360
acaggagaac cagtcccaca gatccccacc tccccacata ccatgcccag ccagcccctc 78420
agtcaccttt tctcatttat aaatttggag accctcaaaa cgctaaaaat cacaagcttt 78480
aatcaactca gtatcctgtt aagtttctct ttcttggacc ctatcccaag catctttaat 78540
tctcttaagt ataaagtgat tctgacacag gtggttgacc ccactttagg gaacattgtc 78600
ctaggactgt ttaaatatca ttgaaaatca ctgagtccac atattgtgtc cttaaggaca 78660
ctttttaaaa catatatatt aacttttagc tttaagcaat atgttaaatg ttcgtatttc 78720
taaaagaaga caaataagcc aaaagggagc aaatgtgaat tcctttcatc aagttttctc 78780
tgcctcttcc tccaggatat gctgtcccta atgcaactgc acccgtgtct gcagcccagc 78840
tcaagcaagc ggtaaccctt ggacaagact tagcagcata tacaacctat gaggtctacc 78900
caacttttgc agtgactgcc cgaggggatg gatatggcac cttctgaaga tgctttttta 78960
aatttaagaa taagacacac aaaactctat taaaaaaaaa aaagaaataa acctctaact 79020
cggtccccaa tgatcataaa taatatgttt cctaaagaaa tgcctttcca gagactgtat 79080
agcttatacc aattatagaa tcatgaagta agaacgttat tctgaaatga aatcaaatgt 79140
taaagagcct tttgtttaac agaaagctgg agagccactg ccccaaaagt tgttcttcca 79200
gtcttcctga gtgtttgggg agtatgttta caaatcctgc cagggtgaag agagatcttg 79260
tagctggcaa gatttgggag ggatggagca gacctgggca gtcagtaata atcaagggaa 79320
gccaagtaaa ctccagagtc ttacctctgg ctcacagctg cttttgtgat acacaaagtc 79380
acaaagagga aaagggaagg gaggaggttg cttttcaaaa tgcattcacc atggctcact 79440
gtgtggggca tgattgcagg cctgagctca tgaaagactg tccaagattt tgtggtttca 79500
acctctcttc agcctgaaaa ttccatccag tcgatttgtc acagatcagg atcttcctgt 79560
cccctgcagc ccatggggac ttcctagaaa tagatatgat atgttgtaga tgtggttaaa 79620
acaaatccag gccccattgt ttattcagct cattagtcca cacctatttt tccctagaac 79680
tcctaccttt tccaataatc atgccagcat gaaatgacct tttctacttt aaaatttttt 79740
gacttgttca tattgcttga ttttcatcat ctcagactca tttttctcct acctaatatc 79800
ataaaaaagt aaatcagata tacagaatat catttatgat acttcttcct ttcagcaaat 79860
tgactgaaaa gtcattttaa agagagaagt gcagatttgc tctcatttct ttgatattgt 79920
tgcagtatcc accccaccat ctagcaatca gagatgctta tattaacttg ggattagctt 79980
tgcattatct aacccattta ttttaaatct gccaggaaat cctctaactt tccttccttt 80040
ttgtttcagt aagtatcagg cagcttcacc atacctgagt ccttttgtct tgaagctgcc 80100
acagaaaaat cttacagcaa tcattgctga ttagaaactg tttcagacaa tcagcatggg 80160
tgttatttac caaattcccc ccagagtcct aggcctcttc tccagaaata tctgatgatg 80220
aagtgagggg agggcaacgg tgctacaaaa cacggaacag aggtaaagag aaggcactac 80280
tttcttgcca tacttgtaaa tgattgcttt gttcaaacat aaataatctt aagtccaaca 80340
ccaaatacct gttactccta catcaatctc attagtggtt taagacacag tactagaatt 80400
ttcatttttt aaaatccctt ggcccttaaa aaaatttaca gaacacaaag gaaaacataa 80460
acacaaagac atggaaaatt ttgtcaactc cttaatggaa ttctgtgatc aaaaagcagg 80520
ccagattcta atcaaaatca ggtaaatttt aatcacaatc agaagtactt gtaacatttc 80580
agttgtccta actccaatga gataacaaag cctccaaggc tacagctgaa actctgaaag 80640
gccctgtgct ttctacttta catttagcgt ctaatatttc ctaggacagt agttcccaaa 80700
gtaggctgta cattagaatc tcctggagag ctttttaaat gctaatgcca ataacatatc 80760
tcataaaatt tacactagaa tttccttgga tgggtgcctg gcatcagtat tttttaatga 80820
tccctaggtg atttcaatgt gcacctaggt ttgggaattg ctatattctt gtatttatac 80880
tctatctctt tatttctttt cctttttatt tcacttttag taaatagaaa aatgcaatta 80940
aaaaatcatc taagttaaga caaatagcca aatcatattt atcccataaa tagtatgaat 81000
ttaaatgtaa cttacgtagg cttcaaacta actctaaaaa tgagaaagta aaacaatctt 81060
gtcctaaaac aattcttaga tccaaattta cactccccta cagatctgct tttattctca 81120
aagacagtga ttacattgac ataacaaatg tccattgggg caggcaaatt tctactgagt 81180
ctaaaaagca ttccaaattc taggagcaaa agttctgatt ttccttaaaa tctttgcaaa 81240
taaacagcaa agggtattct ggatgtcttg tcaatgcaaa ttaggtttga tttagagaag 81300
ttttaaattt aatcgcaatg aaaagattag ttaatacatg aatcttttta tgagaaaaaa 81360
tcattattct ggataaagtc ataattgttt gtttacaata ttaagagcag acacctaaac 81420
atacaataat accaaagtat tgagaaaatt accactggaa caccatctca agttatcaca 81480
ccatttacct ctttagagcc agttttgtat aagtaggtag aagtggtttt ggtttttttg 81540
ctaaaatttt actttgtttt agtaatatct agggaatact ttgaattcca ttaaaatacc 81600
ttcatagaaa gtgttaatgt gtctaccatg ccatatgttt atttttactt tccccaagtt 81660
aggtagatag agcaagtcct gctaccataa gtttaaaatt attaagacaa cgggcttttt 81720
taaattgctg gtagaaccaa aggctaattt tgcataggtt tatattttta gacttaagaa 81780
attagcacct atataatacc ttcatacctt ctgcatcact atcaattttt ctgtaatttc 81840
ttatttgaat gcttcctaat tctttacaga aaaaattaaa atttgtcacc caaccaggtg 81900
ataataacaa aacaataatt taggaacatc cagtaaattt gaattagttc tctaaatttt 81960
ggtaattaat agcttattga taattaaaat cagcctaatg ttgcttaagt aggaggaaat 82020
tgatcagcaa tgggattggg tatctatttt ctttcctata aaagtgctgc ctcttctcaa 82080
attgctttat ttctctccca ctgcattagt atatctagaa cagcaccttc aactgcaaca 82140
aaatataatt ctcctagatg actaggatat cctccaatct ggtatcatgc caaacaacac 82200
tatgtttggg gaacagcacc cgaaatgctg ctaaaaagct acctcatgtc aagaaaatat 82260
ggatttcaaa aaatatctgg cacagtggcc catgcctata accccagtac tttgggaggc 82320
caaggcagga ggattgctgg aggccaggag ttcaagacca gcctgggcaa catggagaga 82380
ctccgcctct acaaaaaaaa aaaaaacaaa tttaatttaa ttggccagtt gtggtggcgt 82440
gggcctgtgg tcccagctac ttgggaagct aaggcaggag gattgctgga ggcctggagg 82500
gcaaggctgc agtgagccat gttcacatcg ctgcactcca gcctgggtga cagagcaaga 82560
ccctgtctcc aaaaaagcaa aaataaatat ctaacaaaaa ggaacctgtt tccaaaccac 82620
agtttcttaa ctttttcatg atggaataga aattaaacta taagtatata ctgataatag 82680
ctgtgcagga aattggtttt tattttactt aaaagtattt tttagaaaaa atgttattct 82740
gattgcatag attagcaaaa tattgcatca atataatgtt ccatttttat taatttttgt 82800
tatattctaa atgaccgttt tataattctg tcttggacaa ctgggccaca gttagaatcc 82860
acatagacag ggaggttctt aggtgtgcca tttgtagaat aaagggcaat caagttaata 82920
ttcggggtaa attttcattg cattctaacc tatgaagttt gataaagtat attattattg 82980
aacaactcta acactaagat ttcctaaaag taacttacaa caaaaaatga actatgtgct 83040
caatattcac ataaagtcat gattattctc ttcttgcatt catataaaag ttcccagggg 83100
gaagaaaata tatctaaaaa ttagactaga aacttggcac tttttatgta ttgtagatac 83160
actttcatat attgtaaata catctgttaa agataaaact aagtttctaa catagcacta 83220
caaggaaact ttggataaat atttttaaaa agaaaatgtt aataggataa cttaagattt 83280
tgtatatact tattggaaga caggaagaaa ctaggcagta aatattccta cctgacgtgc 83340
aaccattgtc aatcaggttt tgttaaactg tcaaatttga ttttgaaatt ttagtttgcc 83400
caaataatat cttgaaaatg ctctgaattt tactagaaca tattcataga aagtgtaatg 83460
tatctaccag gctctatgtt tgtgtttgcc aacattagaa aaacaaagta agttgcgcta 83520
taatgagtga aactaaggaa aatgagattt ttctgactcc cattccctct cttaaaaagt 83580
aaaatattta agcttttttt attaaaggaa aaatgggtac agaatactct attgccctcc 83640
aaatgtccaa catttttaaa gccatgttgt ccaacaatgt ttatacagaa aatagaatgc 83700
ataggtttaa tatagatagc aatgtatatg taggctcatt tgtgggagat tgcaaacttt 83760
atgtgccccc agttctcctt ggttttgtag gaaagctaaa agaaaacctt gtactctcac 83820
taataatgaa attcatagcc aatttagaaa gggaaaataa cctgaaaacc aaaatacctc 83880
attcatctga agatgcctgg aataaaatat ggaattcttc tgtacctacc tcccccttac 83940
agacttttct cctattttga gagagaaatt caagaagaag aatacagctt gttctctttc 84000
cacaaatgat actttgtcta agggaatagg agataccaag aaacagtatc tttaaaaaag 84060
taagctgccc acaggccttc ttggagaatg aagaatatca gccccattca gggtttacca 84120
atgtctctct gaggtgacaa tacattctgg ttttccagga cagtcctggc ttaggtctgc 84180
tgtccttcta taaatattaa caatgatccc tcttatttcc aaacgtgtcc cagtttagac 84240
aacaaattat acagtgtctg cccccaacac acacacacac accccaccat ctttatgggt 84300
tgttgttgtt ttcttgttgt ttttaatttt gtagaattgg ctttgtcttc tccaaagcag 84360
ataacagctt aaactaaaga gcctagctac ttctttctga ctgagcaggg tcatagtaaa 84420
cagagaagaa tggatcactt cctcctctga aatctccatc aatccacttt ctgtccaact 84480
atctctctac ccagcctatt tttggtccta gttttcctct cataacccct gggctgtgag 84540
tcctgagttc tgccttcata tggcagagca agctagtcat tattatgcca ggttaggtgg 84600
tggggcaaga caaaagatag ctcttgggga cacttgcttg gtctgtagag atccacaggg 84660
cactagtagg gtattagagc atttattggt ttctttcttc cttgagttga gttacttcta 84720
tcccaaaaca gacaggtctt acgttaacct tcaccttaaa aaggatattg ccttttttcc 84780
ttctgcttca caaatttgct ccaacactaa ttcccttgca tttgatttca tcattatgat 84840
tgttcatcaa ccattcttca cgaaaaatcc tcacatcacg tcatataaag gttttattat 84900
ttttaatgga aaataacatt gagagattat tttccttttt cataaaattt ccctttttcc 84960
ctccctctat tctcttcact aacattggaa attaaacaag ttttacaggc tctattgtta 85020
ttaaccctca aatctattct tcagagaata tatgatcagc ctgtgtttac tatgcaccta 85080
ctcttatacc agaaactgtg aatacaaata catatatttc ctacttctct ctttaattgg 85140
ggcacacagt cccatggtcc attctgcatt tttcaaaatt gaatataatt gcaacacctg 85200
ataggttttg ccacttagaa ttctgaaaat aaatcaactc tgttctaaac cttaagtttc 85260
cactattatt gccaaactct ggactgatac aataagcctt ttaaaaggtg aatttaacac 85320
ttcacctatt atggttattt aagtaaaatg agttttcaaa tatttccccc aggagaaata 85380
taaaggacta tgcaaaaata gaaggagaaa aaggttagtt agaggtccag aaggagaatt 85440
aaaacatgga attgataaat tcacctactg atttatgatg ttaatgagca ggtacctata 85500
cattttattt acttgaaaac attttggcca ttaactattt ctgttttcta aatacatttg 85560
tgtttataaa attttaaaat ctatatcaca agacttagac atgcctttct ttgcaataaa 85620
gtatatatac ctttttacaa atgtaaattt tattttgaaa cttggcattt tctttataat 85680
tcctaagata tctttgggca cacagactac agataaatct atttaaatca attcatcatt 85740
atcactggtt taaatattta atgtaaccat tggaattttt attcttattc cttcagagaa 85800
ttctcctttt cttctatgtt tctgactgca atacagcccg atattgttat tccctatatc 85860
ttaatgaaaa gcaagctgtc agcaaaatgc atttatagtt tccagatgtt taacaatctc 85920
tttcttcttt tcttttttgt tattattttt atttatgtga agttagttag ctgaggtacc 85980
aaaaaagaga caaagacagt attaaaaagt gtgcataaag cacttatttt tgtactttag 86040
tacaatgttt tatagaactt tgtgatctat ctaaatatat taagtaaaat tacaccattc 86100
acttgttggg aaaataatct ttggtttgga agatattaac ataatgggca tcttagaatc 86160
ataaatcaca tgaaatgaga gacaatgcaa tattgtataa ttcctggatg atgcaattgt 86220
tttaattgaa ttttcaagtg ccattataaa gttttaaaaa ttatcaa 86267
<210> 2
<211> 77253
<212> DNA
<213> 食蟹猴
<400> 2
gctgtagtga cccaattatc tggtcaaagg gctgcatgga tgcaagagac agggtgagtt 60
aaagtttaac tcccaggaat tgtaaaccaa acctaaagcc actgaacctt tggagtttga 120
tatgacgatt agagcataac ccgagtaaca cgttgaattc gccataatca aggaaacctt 180
ttccgggtgg ggatctctga aattactcag gtatgatcca tgtgtttcgc ttttttctat 240
ttcaactctg tggaactgtg cattgtggta tcagtgggaa tgcagtaaaa acagctttca 300
ccttcttcta ttatcgagcc taattctagg aattatctag cttgttttta gacaaatgaa 360
acaagcagaa aacaaaagaa tagattggaa ttattatata atctcaaaat gagacagctg 420
ccaggattta ataaatttct gtagacttac cacggagggt tcaagagtgg agccaatgtt 480
gtgagaagtt tatttagctc taatcagaca gcagggagag ttgtggttga gtgcctgtcc 540
agatcctagg accctgagaa acagaaatgt aattaacaaa agaaacagtt ttaatatcac 600
cggcagattt tcagttctgt gtgtgggtcg taattcctat catactttag acttcgtgta 660
ttcgattatc tcctgagcta ctaccaccat aaaaaagaaa gtcttggtaa actcttgtga 720
tttcccctgc cattatcttg ctaaccaaag gaatgtttaa aatattcact tctgattccg 780
tcccaaaaaa tattatggaa aatgactggt tttcagtgtg ttatatctca atcttggaat 840
ggctaattat tatattgttt ccacaatttg ggcaactgtg ctgaggtgga tgtattttca 900
catttttttc tatactccaa aaacattatt cacaatcaga atataatggt atttaaagaa 960
agaaatcaat ctggacattt accaaaaata tcccgtttct accagaagcc ccctaaactc 1020
tctgactttt tgtcatgatt acctatgtaa gttccaagaa gactggattc caaactaaac 1080
gagtttattt actataggaa ttttcagata tgtattgtaa ttctccaaga cgacgacgaa 1140
catagcatta tttgcacatt gtgcaggatt agtgttttgt agagcatatt ttggtaaatg 1200
cagctctagt tataatttag gatcatcaaa aaatgtgttg gtctgctctg aaactttctt 1260
tataatgtgt gctatggagc atgcaatggg agtataggtc tggaaatgac agtgatatca 1320
ctgatttgtc aaagcagtaa ggttttgccc tgctaaatac agagaaagag acaaatgact 1380
tataaggttc atactttctg gaataacatt gactctgccc attttagaca actcttaaca 1440
ttttactgtt ccgttttact atttatcgat tttaagggaa aaaagaagac agctggcaag 1500
gaaaagaaat attgttgtgg gcaaacatta taaaatgaca taatggatat taaaacgcta 1560
taaatactta gttcttattt tctactgcac taataccaag ttggttttat gtcatttcaa 1620
atatcaacat ttctgacact atattcagtg gatgttaatg aatgtggctc aaaagaaaag 1680
tgactccatt gtcaagtaag ttgaggaaat ggtgttagaa aagttatagc aggtcttgtt 1740
accacatgag tgttttgagt aataatgata gcaagtatct atgaagtact atattatcag 1800
gtctacttct tttttttgtt ttgtttttgt ttgttttttg tttttgtttt tgttttttct 1860
ttttgttttt gttgttgttg ttttgttatt atactttaag ttctagggta catgtgcaca 1920
acgtgcaggt ttgttacata tgtatacatg tgccatgttg gtgtgctgca cccattaact 1980
tgtcatttac attaggtata tctcctaatg ctatccctcc ccgctcccac ctccccacag 2040
taggatctgg tgtgtgatgt tccccttcct gtgtccaagt gggtctactt ctaagttctc 2100
tccatgcatt atctcatgtt attcttagaa caactctatg gtgtagatac tattataaca 2160
gtttataaat gggaaaatgg aggcacagac aagttaccta acaggttcag ctactcagtt 2220
agcaagtggc agagccaggc tcctttgtct ggcggtctca tccagagccc aagcatgtaa 2280
ccattatatc acaccctcaa gcactgggga ctcatgacac atgcaaatat tgtcatttat 2340
cacaattatc taagagagta ggcaatgttt tgcttcctgg gcttaattta caacagaaca 2400
tcttctttca ggaatatcta tcaatatctc tcaaaattag tatttctcag aatacaggag 2460
aagaaagaac aaattgcttt tatagcccat gtccagcatt cataacaatg agaatcaatt 2520
gaaatcatca caattgaaac atctaaagga ctttagagtc tagtcttctt ccaccaaata 2580
ggactacgcc tatctgagaa acttttaaaa ttaattacag aaagaacact aggctttttg 2640
cctcgacaca gctaagtgga aacgcctatt gcaaaactcc ctaggtttgt gaccttgggc 2700
atattgtttg actcctctga atctcagatt cctcaaatgt gaaatggggg taagatctga 2760
cccacagtat tttgtgaagg ttaaattaga tgataaagcg aaggagagaa atgtggtccc 2820
gggtgcttaa gaattcagca aaaatcccac ttcccttttc actttcctat ttgtaataac 2880
ctccagaaaa attttctaaa attgcccaag tatacctatt aggccttgtt tgtcaaaaca 2940
atactaataa agttgaaatc ataaactgta cataaaaaat ttttgatgaa tcacaaatag 3000
tagcagtatt ccatttattc agagaaagtc agtcggtaat ttttttcagt atcaaagcac 3060
acacacagag tatattttta ttttagagat tattgctgaa gaaaactctt agttataaaa 3120
ccccaacacc ttttcaccca aacccgtggg acaccctgac acggggcatg cttatttcat 3180
catggaggca gttgctgtta aaaatctgtt tcagtaactg tcttttaaaa tattgtcatc 3240
ccttagaaag ctgagtagta ctgtgggtac tattgcacaa tggttttcat tgccttatgt 3300
gtctctaaaa tgactcaata agttcaaaca agacagtatt gatcgacaga ggataaacac 3360
tattttatct tattcacaga aacagtaacc aggctcctgc aaagtgcagc tctcacaatc 3420
caactgcccc caggaaaagc atctggaaaa ggagcagcac ccttgcggtg acattccata 3480
ttagaaatct gtatcccatc tgctccttgg cctgatcctg taaaatccag agagttatta 3540
acaaatgttt gctgctgatt caaccaggaa agctacttca ttgttttatt tcatcaaatc 3600
tactctgatg aaataaaacc tagtttatcc gttttttgtt gttgttgttt gtttgagatg 3660
gaatatcatt ctgttgccta ggctggagtg cagtggtgca atctcagctc atcagaacct 3720
ccgcctcctg ggttcaagtg attctcctgc ctcagcctcc cgagtagctg ggattacagg 3780
tgcacaccac catgcccaac taatttttgt atttttagta gagacgaggt ttcattatgt 3840
tggccagact ggtctcgaac tcctgacctc gtgatctact tgcctcggcc tcccaaagtg 3900
ctgggattac agatgtgagc caccacgcgc agcctaggtt atcagtttta ataaccactt 3960
agaattttta atttaataaa ctaaaatttt gtattgaata ttttttattg atgcaatcca 4020
aaaattaaaa catgtccttt tgtaaaaaaa ttattgtctt gactaaaaca tgctggtatc 4080
ttgagagctc taatttgatt tcttttaaac atatgtaagc taagatattt ttcctatata 4140
gatttatatg gggagtttta tgcatatatg tattaatcac atgaagaaca ttttccaagt 4200
ttgtttattc aataagaatt ggtccctggt aatattaaga gggaaatatt aataaggatg 4260
taagataaat ccctctgatt tgcacagtta ggtgcaatgc tctgctccag acataatatg 4320
actgaagaga attagctcat gacaatttag gcagacagaa tgtctaagtg agcagatcgg 4380
tttgtaattc tataaaatct cacttgcaat gatgtagtga tgccttccct tcctccagca 4440
attaaaaaat aatcattgct ttaggatgcc caattgattt aaaaatcact aggttgaagt 4500
aatagaacta actacaacaa taccttattt ctataggata ttctagttta taaagctttt 4560
catatagtac ttatatagat ttttaacgac aaatttcttc atagttgatg tcaattcagt 4620
atgcctagtt tcttcaaggt aactgtgtca atgttcacca ttccaattgt acaaatctga 4680
ttaactgaaa gatgctccca cctaacgttt ataagcccga ctctgtttat gtagcacaat 4740
gatgattagg tagtgggcct ttaacatctt cactggatat taatgtgcct atcaattaag 4800
aggttagatg aggacaggcg cagtggctca tgcctgtaat tccagcactt tgggaggccg 4860
aggtcggcag atcacctgag gtcaggagtt caagaccagc ctggctaata tggtgaaacc 4920
ctgtctctag aaaaatacaa aaattagcca ggcctggtgg tgggtgccta taatcccagc 4980
tacctgggag gctaaggcag gagaatcgct tgaacccggt aggcagaggt tgcagtgaac 5040
ctagatcatg ccattgcact ccagcctggg caacagagtg agactcaatc tcaaacaaaa 5100
aaaaaaaaga aaagaaagaa agaaaaagag gtaaatgaaa acagtgaaga gcggacatat 5160
gggttcatgt ggaaggtgag agaagaacca ctcccatata ggacctagaa gaaaatagcc 5220
ctaaaaagat gtaattataa ctcagtccag atgctgtaac taacacagtg aaagatataa 5280
aggaacagag atttataaaa tctcctacct gcctggcagg ggactggcaa agcattgtgt 5340
acaaatgaaa ttttttattt ctattgattt tagtattctt ctatccacct cttctattgg 5400
gattctgctt agtgcttatc tttccagctg gggccttcag catgaactaa atagtacttt 5460
aaattattag gtgtaattaa accctaatgc ctctgacttt ttgcaatgga agtcagaaat 5520
caaaatctgg ttccataggg ggaaaattgt gttgatacat atagatgttc atctcaggaa 5580
tcctctttct aaccttcttt tctgaagatc cctaacaact ccttgccatt catgtactta 5640
ttaccaacta attataattg gcactctatg atgatgataa cgatgatgtt aataaaagcc 5700
cttacatcct gttacatcct gccacatgcc aggcacatag gttaactcat ttaatcctcc 5760
atctctctat ggaatgggta ctattgctac gccatttttc ccataaagca actacggctt 5820
agggacacag agaaacttgc cccaggtcac accactagta agtggtgcag gagggggtcc 5880
aggcagtctg gcacaggcca ccctgtgaac aaaggacaaa tggaacactg ggaagcatcg 5940
aggcttagaa ctagaagaaa acttttgaga tcttttattt gacagagaaa agcaagttgg 6000
cttccccaag ttaggttttt gttagaatga aaacccaagg gcagaaccca aaccctcagg 6060
ggggcttttc cattgtacca cttcccactg tatagcatgt ctaattcaag ccgattctct 6120
atgaaaattc tgagagatga attactagaa cccctgtgat tacagaggaa tactccattc 6180
actccaagtc tcaccttctt ttctgtgccc agactcatgg actgacgtag ccagagactc 6240
agttaaagga gacccattct gtgacttgga gagactgaca ggcccacatc acagaggaaa 6300
tacatgcaga cataggcatg gatatggttt agcttttcgt ccccacccaa atctcatctt 6360
gaactgtaat ccttagacct gtaggaaaga acctggtggg aagtgatagg attatggggt 6420
ggtttcccca gctgttttca tgataatgag tgaattctca tgagatctgg tggttttgta 6480
agtgtttgac ttccctcctg cacatgctac ttctttctcc tgctgtcatg taagaaggcc 6540
caagcttgct acccctttgc cttccgccat aattgtgagt ttcctgaggc ctccccagcc 6600
atgcagaatt gtgagtcaat taaacctctt ttcttgataa attacccagt ctcaggtatt 6660
ctttatagtg atgtgagaac aggctaatac aggcaccatg accatagtga caggataaac 6720
catggagaca ttactgaaaa tacaaagtaa ttgtcgtaaa tgacttggtt gccttacact 6780
caaattctgt tagtgtctga agaggacata gcacctccta cctggaggac ataccgtttt 6840
ccccatggaa aaaataattg ggctgccagg tctgtatctg ctaagggagt cccatattta 6900
aactgaccta atttagaact ttaaattgag actcagatgc ccccaaatag cagctccacc 6960
aacctgaata gagttattca tttagaataa gagtttgttt ccacaagttt tgttaaaata 7020
caaattagtt gggatgtggg gtgtgagcga tagagactaa aatcgcttaa cagattaact 7080
agcctggcaa agccttgtgg gaagcaagtt ttgatgatgg ggaagagaag atgtcaagag 7140
cagatggtcc agggaggaag tgtcaccagt aacttagggg tgatataagg gacatgagta 7200
gcagctattt gtccgatctt taagaaataa ttaacttatt agagaatttt gtcagtaaag 7260
tcatttgagt atcacacttg caagatacta attcatccat gtcaagtttt ctcattattt 7320
cacagatatt aaacaggtgc attgacttga attgacatca tgcaggaaat gccattatat 7380
gaacccttaa gatattttaa gagaaaaacc tataatgcct ggaaactctt agttttctct 7440
gacatttaaa agcagctgta aagttaaatc ctttctataa taatttagta aatcagaatt 7500
gcaaagcatt tcctaaagcc caaggatcca aagctctgac ctgtggtgtt ggcatagcag 7560
agtgagagac aaattacatg ttaaagcaga aggctctgga cctggaatgc ttggatacaa 7620
attctggctc caccacttgc taccgtttaa ctctaggcaa attactgaac tctgtgacta 7680
tttcctcttc tgtaaagtca gggttgtttt aataattaga tcagaaatta taaagtgctt 7740
agagtaatac caagcaagtg tgcataaact ttagccattt agctataact ctcatcatat 7800
ttctgtgttg attacaaaat gctttactag aggaaaatag atgagaaaga ggccatgagg 7860
taaaaatgta gagtgctttt tagagtagaa tgagcttaga aattaactct atccccatca 7920
ctggcttgca gtggaaattt gaaacagtct ctccataatt ttcttgtagt gttttttttt 7980
cttttttttt tttttaagaa tctcagtcca tctcccaggc tggagtgcag tggtgcaatc 8040
tcggctcact gcaacctccg cttccccagt tcaagcaatt ctcctgcctc agcctcctga 8100
gtagttggga ctacaagcgt gtgccatcac gcctggctaa ttttttgtat ttttagtaga 8160
gacagagttt cactgtgtta gccagaactc ctgacctcat gatcctcctg cctgagcctc 8220
ccaaagtgct gggattacag gcatgagcca ctgcacctgg ccctctttca gatttttttc 8280
taagacagag acactcccta tcacagacag ggtcttctaa attagtacag aatgatttga 8340
aggaacctgg gtaattatca gaggaagcaa aagagaaata cagatcctcc catcagaaag 8400
caaatctcta agactttatc attttcatcg ttatgaaaga aaagatcagt actcaaagcc 8460
acttatgatg atgcacgtaa attagtataa aatcagaaca aatacaatat ggctttaaaa 8520
tagaaacata aggctatctt tccttacaag tgtcagattg cttctgtgcc actgtaacac 8580
agagctttag atggattttt ttaagcttca atcagagatc aaatatattc cattagtcag 8640
tgattgacag acttggtgaa aattgagttt tcaacttaaa cttctccaaa ttgtctgaga 8700
aaatcagatg cagcaactaa gttcagaagg tcagagtctc aggctaaaaa gagagggaga 8760
aacctaacac tagaagaaga atgaatgaaa tagagcacac acagctcatt aggtctctat 8820
aatataccac gcaaatcatt ggtaccagga ctatcgaata atcaaacgct tttaagctga 8880
agaatatcta cattatatgc catgattact gctttaccga ttcataagac aacttaaaaa 8940
ttaaacatgt atacaaagac attctacttt tctcattagt ccatgccatt atataatttc 9000
taaattctgc caactctctt tcctaggaat cttctagaag tcaggcattt tgggaatagc 9060
tgagtatcat aactgaataa agacaccaca acagtcacct gtagtagtca gatcttacag 9120
gtactagaac aataacagca caaagaccga gttatgtgta tgtattagtc agcattctct 9180
ggaaaaaatg taatatatgt atatataggc aataaattta taaatgcata aaacatataa 9240
aaatataaat ttatgtaaat aggcatataa atatgtaata ctacacatat aaatacaaat 9300
aaagagattt attctatggg attggctcat gcagttatag aagcagaagt cccaagattt 9360
gcagtaagca agctggagat tcaggggagc ccatgcatag ttccagccca agtccaaagg 9420
tttgaaaccc agaaaagtca atgatataag ttccagtcca gaagccatca ggttacagat 9480
gcaagaagag ccaatatttc aagtccgaag atcaggaaag gccaatgtca ctgctctgtc 9540
atgcaggccg agctccctct tactcagctt ttatgtttta ttcaggtctt cggttgactg 9600
gatgaggccc actaacattg catctgctgt taaaattttt caagatcttt ttggggtgaa 9660
aaaaacctat cattcatctt tcaatcttca gtgttgacaa ggacaggaca tttatgagta 9720
ttcctgtttc tgagtttctg ataagcttgt ccaagttgag cacaggctgg aaaatttata 9780
agagtattgg aggcagagca gttacaaaag gaaaggggca tatacaaagg tctcttgtgt 9840
gatgttgtgc tgcaaacact gacctttcag agtttattca cccctgtgta tatatacata 9900
ttcatgtctg cacatgtgtg ctagtaccta tatacatcta tacacacaca caatcacata 9960
tacctgagac ctaatggaat agacatgaat ttggcttagc cagggaaatt atagaaagaa 10020
taatgggaaa caaggacaaa ggcacctaga taaaataaaa agcaactggt gtgcctagga 10080
gacctgatgg acttgagcgt ggaatagctc cagacttgca ttgaaagaaa atcaggaaag 10140
tcaagttagg accaggtcat ggcaggcact gaatgtcagg ttaaggggct gaactgtttc 10200
tttctagtta gtgatgggtc cagtgaagga tttagggcag gagaatacta gagggaatat 10260
tttagggaga ttgatcttcc agtggtgtgc agaacagata tgccatgcct acagggtagt 10320
aagcagtgac gtttctttca ctctacactt tagccgagct ctggttaagt ccaataatgg 10380
aagatggggt gggaaataga gctaggagtg tagagggggc aacaggtaag gatacgtatg 10440
taccgaaagc agaaaacaag ttaagatcca ggcttcatga gatgcctata ttgaaaattg 10500
ctctggataa agagactgtt aggacttcag agttagaatt catagcaatt cacagaactg 10560
ctcaggctct tcattattca cttgactcaa cgttcctaca tcggctcctt tctcataaga 10620
gctttccttg ctctctgtcc tttttctacc ccacagcttt tgcttccttt ccatacatag 10680
aaccacacaa caaatacttg ttgtatgcat gcagtggtca tataaatatc ttattgtcta 10740
gtcctcatca aaactaagtt gaaacaaatc atttgagcca gaatctacta agagtcagat 10800
tttttaaggt agttcaaggt ttttatttat aaatactaac aactaggaga acatttactc 10860
attcgaaatt atgaaaacat agacaaaaca attattagag aaaattttga attattcttt 10920
tctcctgcta tctaatttct acctttctca tgtagtcttt ttctttttaa ttagattttt 10980
tatgtgagta taaggcccat ttatttggca ggtggaataa attcaattac tctcaattgt 11040
tttgtttgac ctgtaacatg tataagttag agcttaagtc agctgttcta gatgcaactg 11100
catattgtta tcacctgaga agctttaaaa tctatcattt cctgggcccc attccaaacc 11160
agctgaatca gaatccttcc ggggtgggga agatgatgcc taagcacagg tgattctacc 11220
atgagtccag gcagggagcc tggtttttgt gcacagctcc cgtatgtcat agctatcggc 11280
acctggctct gctctagctg ttcttaagta atcttttaat gccaattggg agtatgtttt 11340
aatagtggta caatatttta agaataaggg tttaaagcaa gttattgcaa gtaacagtta 11400
agggatttac tcaaactgga cacaacctct gttggagcag attacagtga agttttgagg 11460
gcacgggata aaaaagagga aggagagatt taatggaatg aacattattt gctaaaattt 11520
aagaacgctt gcagttaaat ctcgtgctat tttgacaaga tgtgcacagg tgcataggtg 11580
aatgcttcct cttctggtat ttccttgtgt aatttatagt tcaaactaaa tcctagggat 11640
ttaaagtgct tctcattgat atttaaaggg cattttaaac cagtgggaaa atgtctttcg 11700
aaacagataa aatgtacctt tataaaatcc acttaatgag aatatgctaa aaagcaagat 11760
gtgtttctat tggatcataa attatataat tttaaacgag tttttaaatg aaagtaaatt 11820
gttccaacta tttgaaatta ctttttcctc aaacaaaaca aaaaaaattt ctagatgtca 11880
ggattgtttt acaaaaatga tgatctgatg atctgttggc cagattaata tgcttaactt 11940
tcctaagagt taaggtaaca ttattccttt aatgagcttg tatattattt ctgatttgat 12000
gtagtttttt aaaaattggg aaaacatgcc ttctctaccc cttgcatgtt ttaatgccct 12060
gatttaatac cggtgtgtgt gtgtgtatgt gcatatacac agatatacac atatatacac 12120
aaacacatat taaaattata ataaaataat catttgttca ttatatattt gcttgttctt 12180
tttctctgat aaactctaag acagtggttc ctatggtatt ttttttctct gacatagttt 12240
ttcttttctc tatagatatt ttcactacag tgcaattttt ccagtatctt aggttttgct 12300
atcttaagtt actctactta ggacttagaa tgattccaaa tagggtggta tatagatttt 12360
aaaccttaac aaacagtaat caaacatcag ctagccctat acatccttgc aaaaataaca 12420
atttatttag aaattgtatc agcattactc cttcacaaca tttaatatct tgccttgcaa 12480
gttcattata cgtgtcagat ggattcagaa acttctttag ccatagatat caccaaaaga 12540
gcaggaaaga taacaaaaaa attaaagaat aaaacagaaa aagagataga agaaggaaaa 12600
atgaattaca tggacatttg agaatggaga gagggaagac cctactcatt ccctgcgtgt 12660
agctgtatgt aacacaacta cacaaagtag ttgtgttggg tgtcttgaga agcacttggg 12720
gctgtgatta cctccactac aacctcatga gatatttggt ctatagataa tttcttcctc 12780
tcttgctatc tacaatcctg aagaactaaa aatcagtgga aagaagaatc aacatcttaa 12840
ataatttaaa tggctgggca cagtggctca cacctgtaat cccagcattt tgggaggctg 12900
aggcgggtgg atcactagag gtcaggagtt caagaccagc ctggtcaaca cggcaaaacc 12960
ccgtctctac taaaaataca aaaattagcc aagcatagtg gcatgcatct gtaatcccag 13020
ctaccccgga ggctgaggca ggagaatttc ttgaacccag gaggaggagt ttgcagtgag 13080
ctgagatcac cccaccacac tccagcctgg gtgatagagc gagattctgt ctttaaaaaa 13140
agcaaaagaa tttaaatata agaataaaag taagcatgaa agctgagcca gatcttgcca 13200
aatgatacat cacttggtaa accacgaagg tgccacactt gccaaggagt aatatttcaa 13260
tgagatgtga ctcagtgcat agcagacagc tgagtccatt tggaccatat ccacaggggg 13320
tcaatccttg atgtgtccga gtgaagcatc agacaaacca cccacaacac tcctcaaagg 13380
agctattacc atagctcact ttcattccgg caaagaggct aagttaccat agtgcttcag 13440
atgctccaga ccgtgtgtcc ctatggaaga gaatgtggac cacagcatca ccctcatcag 13500
ctcattacgg tgtcctgtgt tcttcacagc aacactttaa ggaaggcagg gtagctataa 13560
tctccacacc tcctgtctaa ctttttttaa catgaggaaa ctggaaagaa gtaaaattag 13620
taattaggaa cacaatctta gcctccaggc tacttaaatt cagatcatct gtctgccact 13680
cattaccagt gtaaacttaa gcactttaag ctctctattc cttgatttat tacccgtatc 13740
ataggaataa taatagctac accactgagc ttttatgagg attaaatgaa ttatgtttaa 13800
aattttcaga acatagcatt tgtgttcagt aaatgttagc tatgtttatt attcttactt 13860
aaaatatttt taaatattgc cacataatag gcaaaaaaat gttatcttgg ttttttgttt 13920
taatttgcct tttcctgatc actaaagatt accattttta aatcataagt ttataagcta 13980
ttctgatttc ttttctttaa attgactgtt catttccttt gctcatttgt ccattgattt 14040
gtgtctatta tttatttaaa agtaatctgt atattacaga taatatttct ctatctacta 14100
tataaataac aattattctc ttccagtctg tgggctttta aattttcatt tattttgcca 14160
ttacagaagt ttgtaatatt tttgtaatca aatctgctag tcttttcatt tatggttctt 14220
aatatgcttg gttcagaaga ccttctgtac catgagatta taaaaacacg cctacatttt 14280
cttctggagg ttacacaatg tttttaaagg ttatttcttt attctattta gaatgctggc 14340
atgtaatgag gtgatatgcc cgctttattt tttttctcaa attgtttatg atccccctat 14400
gaatttgaaa tagcacctat tggtgaattc cagtacaaac aaaactatgg gtccagagtt 14460
tttattttac tccattcatc tggttgtcta cttctatgct tgttgtaatc ttaactgtta 14520
attagggtgg ttccaaatca ttataaactg tcaatatatg ttgtggcatt tattgcacat 14580
tgttcctgcc aggtgaactt tgaaatcaat ttgtcaaatt tcagaataat ttcattggac 14640
tttaaattag aattgcatta aagtaataat ttgggaaaaa ctgatctttt tacatcaata 14700
aggcttccat ttattaaggc ctttagatct ttcagtcaaa ttttataatt tttatatagg 14760
gtttaaacat ttcttattaa gtttattcat attttatgtt tttattctat tgtttagacc 14820
ttattatact tcacttgcta tttctgttaa atacagaaca tttattttat aagtttcttt 14880
gtagtagtct ttcattagtt tcaattgtat tatatagttg atttacttgt ttttaatgag 14940
aataaatgat tgtggtgttt cattactaag tctaatgttt gtttcatgtt tctgagagac 15000
gctttttatc aatttaaaga tgttttgttc tactgctaac ttatgaagat gttttcttaa 15060
accaatagtg ggtattaact ttcattaagt gccacttgta gatttactgt gatgatcgcg 15120
tgttttctct ttatcaatga aatgaattca aacttccaga atccccaatg ttcaataaac 15180
tttatatttt tgtactgctc tcatcttgct cattgtatat tattattttg tatgcttttt 15240
catatatagt tcatatctat actcctatat ttgtctagtg ttctactttg tagtaaattt 15300
ttctctatca tatatgatga gcttgtagat aatttcagaa gttttctatt agtttctact 15360
ctccaaaagg ctttatatag caaaggaata atttgcttct aaagtgattt ataaaacttg 15420
cctaataaaa caatctggac ctggtgttat ttgggaggaa aacattgaat gttttcaatg 15480
tagattatga ttactagttt attcaaattt taaacttatc cttgagataa ttttaaaaat 15540
tcacactttt ctaaggtttt gtccactgta tgtatatttt tcaaattatt ggtaaaagta 15600
ttctcttttg taaaagtcta tgactctttg gttatatcca atttttctct tgttttgaaa 15660
atttatttac tcctttttac cttgtcagga ttgctagctg gatgctaatt tactactaca 15720
atcagctgtt acatacattt atcaagtata cagatttgtt ttattaattc tacttttatc 15780
tttgattcct tctaatttct ttttgtccat ttcactctta tcctagcttc tttagttgaa 15840
tgcttatttt cagcgtttat tgtcttgtaa ttaataataa acagactata gtttacaaaa 15900
atctactgta catttcaaaa tagctagaga gaatgatgtg aatgttttca gcataaagaa 15960
gagacaaatg tttaaagtga tagatatccc aattatactg ttttaagctt tacaaacaat 16020
ataaaaggat taaattatca catgtaccct caaaatatgt acacctatta ggtattaatt 16080
taaaaagaaa agcaagaata gaaacttgac cacatcttaa tgaaaagcat gacattttca 16140
ttaacattca tttattaaca taattttaac ttttatattt tgtattatga gcaagagcta 16200
tatatcatag aaagctaaaa atagtcaaat aagcaagaat gaagaaaaca aaaataattt 16260
gttaattcac tcacccagag ataaccaatt agccttgtgt aatcaaagta tttttgaata 16320
taaaaattaa tacaaatgaa atcagaccat acattcggtt ttgtaacctg ccttttccac 16380
tttactatat ttcacaaata tctctctaaa ttattatata ttcttctaga acattgattt 16440
gattagctat actgtatcac tgcttatcca aatatttctt tatcattaga tatttcagtt 16500
gtgcctacct ttcataacaa tactaatata ttctatgaga ggtgacaagc atgaacaatc 16560
ttaggacctt aacgactttt ctactaggca gcaaaaacaa agataaatga aataactgga 16620
tccattatta aggcaacata aaagagctca agataatgca tttgaagttg aatttttctc 16680
tgcattggag aaacaggagg agaataacca aagagaaaat cacagatcat ggctaagatg 16740
agttaaacaa agcagcaaat aaagaataag aatggaatat ttctatagca ccttctacat 16800
gccaggtact atgttaggca ctctcacatt cattacttta tttatttcat gcttaaaaaa 16860
atcttcaagt taggtatcag tattcttatc cttttttaga ctagaaaacc agacctcaga 16920
aaagttaaaa tcatggtggc agaactaatt tttttttaac ttttttttaa gttcaggggt 16980
acaagtgcag atttattaca taggtaaact tgtgtcatgg gggtttgttg tgcagattat 17040
ttcatcaccc aggtgttaag cctagtaccc attagttatt tttcctgttc ctctcctttc 17100
tcccaccctc catcctccaa aaggcaccag tgtgtgttgt ccccctctat gtgtccatgt 17160
gttcccatca cttagctccc acttataagt gagaacatat ggtatttggt tttctgttac 17220
cctcctctgc agcaggttcc acaagtttaa agatgcttac atttacattt cagttctgtg 17280
actgtgtaag tttgctacag ataatgcagg aacagaactg aaatttcagt gtaagcttgt 17340
ccttctttaa aaatgtggaa acctactaca gaagaaaatt tttgtcaata cttataagta 17400
aaattaacat gtccactatg aacaactttt acatttcttt tctttcttta atttaagcct 17460
tgtcttggcc caaattgaca agttccaaat taatatatga tttattacta atgccttaat 17520
aacatagagg aggttctggt taatattttt ttctagtatt gttttaaaaa actaagatgt 17580
tgcatattgg gactttgtgt gatgtcttca tggctacatt tggaaatctt atgtatacgt 17640
attctctatt aattttgcta cagctcatga tgcatgacca aaatgcatgc taccacatga 17700
attaatttcc aaaatagact taagatcaat tgtaaatatt tttccaatgt ggatattaga 17760
gctttatatc aagcaatgca aagtaatatt tacttagcat catcaggcaa attagacttc 17820
agtcataaat ccttcaccaa ccatttcagt actatctaga atttctttca tgtaaaattc 17880
ccaggagata ctcaagggct gaaattcatg ctaaaaccac ttgtacaact cgcatgttac 17940
agaaaagtta tgtcaaggca caattaaacg ttgaggaaag actggattca gtttggagag 18000
gtcccagtgg caagtgaagc catcatggat ttgaaatgca catggagcac atcactgtac 18060
aggccccagt ggcttctcac tcaattacaa aagaacactt ctctgcttac caagtcagaa 18120
atagtctttg tccccattca gttttcttat ccaatttctt ctgaaaaatc aaatcaagat 18180
ggtaaacata ctattaagag aatgcctcta tttcctaact ctaaattgtt taccacggtg 18240
cagatattaa attaatattt gctgaccatt ttgttaaagt caaggataat tactttaatt 18300
tttaaccaag aaaccatcta actttaattc tgtatttatc ttttgtctcc tttctgttct 18360
tctctgcctg tcattcacac tgaccatttc ttttgtttgt ataaactttt ggggtgcaag 18420
tgtaattttg ttatatgcct agattgcaga gtggttaaga cttttagggt atccatcacc 18480
caaataatct acattgtaac catgaaggaa tccctcatca tccaccacct tctcacctca 18540
tgacctttcc agatctccat tgtctatcat ttcactctct acctccatgt gtacacatta 18600
tgtaactccc atttatgaat gagaacagat ttgtttttct gtgcctgact tgtttcactt 18660
aagaaaatag cctccagttc cacctaggtt gctgcaaaag ataaaataaa atgaaataat 18720
ttcgtgattt tttatggctg aataaaattc tactatatat tatatatata atacattaat 18780
acataatata tatactatat atatataatt ttctttatcc aattgttgat ggatacttat 18840
gttgattcca tatctttgcc attatgaata ttactgctat aaacatatga gtgcaggtat 18900
gtttctgata tattgatttc ttttcctttg gatagatacc cagtagtgcc caactaccat 18960
ttctagttct gtttttgcca agctatgctt tcatgactct ttaaatgtgt ttttctagta 19020
tgtactcctc ttacctttgt cttgtatctt tcccacttta ccatttgaaa gactttaaga 19080
aaaaaaaaaa acaggccagg catgttggat cacgcctgta atcccagcac tctaggaggc 19140
cgagatggga agactgcttg agcccaggag ttcgagacca acctgggcaa catagatagc 19200
cccgtctgta ttttctttta aaaaaattta tacatatata ataaaatact cattttccct 19260
ctttctctgt ttccctagct gccaacttaa tggtacacta gggcagtaag accttctacc 19320
attctcataa cttcaggcaa atctagataa caaatctcac ccaaaatcct cgcttagttt 19380
tctttccatg acttggttct tcatgtggga tcagtttttt aggtacaaga taaaagtgtt 19440
tcctctttct agctcagggt tataatcaaa gagcaggaca tactatccag ctaacaggtt 19500
tagatttaga aaagtcagaa tgtactaccc tgcctgtgtc tctcttccaa cttccttctc 19560
atctgtttcc ctgccaactt ccctgaaact ggacccactg gcacctgagg ccaacagggt 19620
caggaactgc agctccaact ttgcccaatt tccattgagt agttgcagcc aagtgacaag 19680
gtgagctatt cattccaacc cctctctgcc tttcaggaag gcagaagtct tgagccccca 19740
ataatttctg gatctttgtt ttcttggtca aatagtcact gatgttgcaa atataaaacc 19800
agaaagagat agaaaagtgt gtacaaatat caattttata ttttaatcac tctgcactct 19860
gaattttttt acttttcttg tctctctcac aagtatgatg acatattcat aaacgcggag 19920
aaaccacaaa gatcaatttc ttatataaaa caaatccatt ccaggacaga actttcagga 19980
agtaactgga aaaagagaaa taataagtat caggactttc aattcagatt aattttactt 20040
ctgattgact gcaagtcact gtaatttata aaattgctga tccaaagttt tgcatttctt 20100
ctataagtat ctattaagca cttagcataa tgtcaagctg agccttctgg gcaaacaaag 20160
atgaagtaca agatagtccc tgtgctcaga aagctcacag tttagtgaga atgttagaca 20220
tggaagccga caaatacagt catgtgtgaa acaataaaag gacatacagg ttttctttga 20280
gagcactgag gagctgacac ttaaaggtta cctacagagg ttgtcaaaga aagagagcat 20340
cacagagcaa agaagatgtt aatcaagtct agaagaatca gtaaggccaa tgtggtgaag 20400
ttaggaggca tgggaaggaa aaggcattcc aagcagggaa actggaggtg taagaaagca 20460
tgggaaggcc cagtggcagg gcatgtgaat gacaccgaaa ggggagtcta ggatctagtc 20520
ctgaagggac aacgtgtcat gctaagaacc tgggacttta tccttctcac agttggtttt 20580
gaaattctgc ctcttagatt tagagattga taattataat aattaaaatg atataatagc 20640
tactttttat tggatattta ttaaatgcca gaaaccattt taagtgtttt aaatgtatat 20700
tcattattta gctcccaata ttaatattga ctcctcaaag aacattatga tggatgtatt 20760
attatcctaa ttgtattaat ttagtattag gagtagtatt ttgagacagg atctcattct 20820
gtcacccagg ctgaagtgca gtgcagctca ttgtaggctc aacctcccag gctcaagtga 20880
ttcacagccc aggtagcatg actacaggtg catgccacta cacctggcta attttttgta 20940
ttttttgtag aggtgagctt ttgccaggtt acccgggctg gtctggaact cctggacctc 21000
ccaaaatgct gggattacag gcatgagcca ccacatccgg ccccctccta attttatgtg 21060
taaagaaaca ggctcagata gcttcctcta ggacgaaagt ggaagaagaa aagatgggac 21120
ccgccgggag gattggccag gctcagtggc tcacgcccat aatcccagca ctttcggagg 21180
ctgaggcggg cagatcacct gagggcagga gttcgagacc agcctgacca acatggagaa 21240
accccatctc tactacaaat acaacattag ccaggcgtgg tggcgcatgc ctgtaatccc 21300
agcttctcag gaagctgggg caggagaatt gcttgaaccc gggaggcgga ggttgcggtg 21360
agccaaaatc atgccattgc tcttcagtct gggcaacaag agcaaaactc catctccaaa 21420
aaaaaaaaag aaagaaagaa agaaagaaaa gaggtgacca tttttacata gcaggtttgg 21480
tggtgaggat acatttgaac caagtgttcc attgctaata aaaacatact gtctgagagg 21540
acaaggagac actgatcgcc agttaatgga agctgtaaga actagaggaa gccctggctt 21600
tcaatacttt gtgtcttttc cttatcccat tgttagaagg gatataaaga agaagggaaa 21660
ggggaggaaa ttatacaagt aggagttgac atttcatcag gccctttctg gagttctttt 21720
gctgttcctc tactctgctt ctcctccaac atgagctatt agcaaaccta gggcaattct 21780
tcacaggtgt tttctcattt catcttcaca acaatatgat gcacagcctg ctcatcactc 21840
caattcacaa atgaggaaat tgatgcttag agacagtatg tgaatatatg attctttcct 21900
gtaatattga ctgtagcctt cccctccatc caatctccat cttttttgac cctttctgct 21960
ctcagccatc ctcaactaga taacagtgct gtgccacaaa cctgcggatt ttctccacag 22020
aaattatata agtacactat attttactta gtctgtattg atatatattg gttgtacata 22080
ttttgagggt acatgtgata ttatgatacc tctatacaat gtataatgat caaatcaggg 22140
taattagaat atcacatcaa acatttattt tctctttatg tttgcaacat tatgaatctt 22200
ctagttattt taaaatatat aatgaattat tgttaactat aatttcccta ctatactatc 22260
aaatatagaa cttctgtctt gctgtacctt gtacccctta accaacttct attcatctcc 22320
ttctccccat tacctttctc agcctctggt aaccaccttt atacttttaa cctccatgag 22380
atccactttt tgtattctag ttattgatct tatttattat ctctctcacc ccctataaaa 22440
ctccatgata ttttggggga tgagaggttt ggtttttttt ctcatctcca tctctatgtc 22500
ttgaaaattc ttagaagaca gtagatattc aataaataat ttcagaatta ataggtgata 22560
aatactcatg aatgcttttc tctatctttc caaaatctta atgcctgccc tgtttgtttt 22620
aaattctatt gcttcaataa gatagtttga gaactatcct ttcataattc tgatctgaag 22680
aacttacaag gtgctaaatt agaagatgta ttgcaaagcc tttatttcaa attggccaat 22740
atgtttaata aaagtttgac ttgcttaaaa gaaatattta tctgggattc aagttcactc 22800
cttagaatag gtcaacactt tgaggggggt tgtttttgca aaataaaaat taaaggttaa 22860
gtgtttcttg tggcaaattt tgaattttat ttccatgccc tgattcccaa tgacatgaca 22920
ctatagttga gatattatac cgattttctc aataacttca gaatgaattt atatgtgatc 22980
aaaagacctt tctgatttca agataccttt aataaccttt actaattatt aaccaaaact 23040
aaaggcagat tttgcaaata caaacttgtc atttccccat gactgttatc tttttgatgg 23100
aaaagatgaa gttcagcaaa gaacaaatct acaacttggc cagaagacgg tagactttgc 23160
cttcaaagag ctgtaatacg tacataaata atctcatcag accccatcct tgctcttgca 23220
ggttaattaa gcacagtggg agggtttgag agtatcctca tgaaaagata attttagtaa 23280
catttgggaa aagagcaagg gttaaatttt atctgaaaga ctagtttcct ttgtaagtct 23340
tcaaaatgtt ttgccttttg caaagtacag acgctgaagc tggcatatta acttactaag 23400
ttagcagatt ccccctaaaa cacaatgccc taaagccagg cagagggtag aactggcaaa 23460
cagagagcat taactgtatg cttcttgaaa caatcagtga atgcaaactg aattgccctg 23520
ggtcagcagc aagcaagaac aatcagaaag gtgaaggcaa gaatgtccat gtttatataa 23580
agaggatgac attgttctgc cctaaaaaga gctaactctg tataatctca tgttttcctt 23640
tgatattcta aattatactg aaaatatact tccttttttt ttgagacaga gtctcactct 23700
gttgcccagg ctgcagtgca atggcatgat ctcagcttac tgcaaccttc acctcccagg 23760
ttcaagcaat tctcatgctt cagcttccca agtacttggg attacaggca tgcaccacca 23820
ctcctggcta atttttacat ttttgataga gatggggttt caccatgtag gccaggctga 23880
tctcagactc ctgacttcag gtgatctacc tgccttggcc tcccaaagtg ctgagattac 23940
agggatgagc caccgcgcct ggcaaaaata ttactttcta aatgatactt atctgttagc 24000
ttggggacat ttatttaatt atactacttc agtagtagaa tacctatttc tattactaat 24060
agtagtacta tagtaatact aatcataatg atagtagtaa tagtaataac tagtaattat 24120
aatactctaa tgatagtagc aatagtaata ttaatagtat tagtaatact actattagta 24180
ttgctattgc tactaatatt gctattgcta ctactattac tatattggta ttattactac 24240
tattagtaat actagcactg tcattactaa tagtgctaca attagcaata ctagtgctac 24300
tagtaatatt agcactaata ttagtgttat tagtaatggt tgtactatta atactaatat 24360
tagtaggtag tcctaataat attgttattg ttactaatag taatactcta ttactattct 24420
gtcattcaag taatagcaat tttagtaata gaatacctta aagctgcatt tttcagaaat 24480
gatcacttca gcttcacttt tttctttcac ccaatttttc acccagtttc ttatattata 24540
aatgatgtct tcattctgag cctttaaagg acaatgtgaa gcagtacatg catatgacag 24600
aaaattttca aaagtaccta tattcaaata cattcaggtt gcatttgatt cagatcattg 24660
taaaacatat ttcctctgtc ctggttggca gagcacattc agcagggtga aaacccagca 24720
tagaaccttc cccgagccac tgataactgc aacccagtgt ggcagccttc acctctgtgt 24780
atgtgggaaa ctccagggcc tcacactccc acagcttaga accttcaaaa tggacattat 24840
cttgttctgg gaacctgtgg atatgagcaa ccatcacatt tggaatgtga ttcaaatctt 24900
gttcccaaaa tagaaaatat agacaaggaa atgctgaaat tatatattta tatctgtata 24960
cacaaacatg aacatatgta aactttcaac accttttaga atttacagaa gtttcattgt 25020
actctactga acacgtctgt ggtatgtgat ctggatgtta gcaaaccctt ccacgtcaac 25080
tcaaaagcat ccattgttct tgctttgtta aaattaatgt cacattttta ttacatagag 25140
tactttgcat gatgacttct gtgtatatga tactggcaca ttttgttcta aacgtttgtc 25200
tttggagaat aagtagataa ctatattagt ggacatatag actaaagatc aatctctgag 25260
aattctgatg ccttatctta gtcgttagaa ttagcgacag tgccctcttc ctgcatctgt 25320
aaggaacatc cttcatatta ttttaataga tgtgagttga tctgttttgg agtatttggt 25380
gacatactga gataagtgga ttcagaattg ctaatctgca ttataattgg agaatgggta 25440
ttgttcattt tttttttgtt tctaaatttc aactaatatt gtgcattttt aaaagttttt 25500
tttagagtac atttacagag ccttgtttgt atgctactct tagttgctct aactttaatg 25560
actcatttgc agagaatatt tcctaaagat gtccttcata aaaaggagaa gtttggactt 25620
gacaacagta atttacttaa tttatcttaa atttggtttc agtgagcaac cctaattaac 25680
ctgatttttt gctgataatc actctcaatg gaatcaaatc acaaatccgg ggatggattg 25740
agcggcaccc agaaggaagc agccctccgc gcactggtcc agcgcacagg atatagcttg 25800
gtccaggtag gaacttcttg tgaaatctgc tgagactcac cactgaatgt gcacagtggt 25860
gggaatatta gtggtcctaa gatgcaaaat gggaatggtc agttacatag ctctttaaag 25920
aaatgtccct ttctaaaaga gaaggaaatt gcaacatttc tgttttgtag atgaccctga 25980
attcatagga tgtaaccttc tgaatgtaac cttctttcta ctctaagtta tcagttcaac 26040
cttaacttgt cgcagaatca gtgtccacag ttatagagac tatcacaaaa aggcagctag 26100
aatttgccac ccaacactgt gaagtagcac cacattggtg tttcaggaat cagcagaaaa 26160
taaactacag caggaaccag gcttggcttc cagagagatc actgcacaca taagacttct 26220
acatgtggga tccaaggaat gaacgctttg tgtctagctg ctgaagttta ttttctcaga 26280
acacttgctc atccagtcta ggatatgtaa tactaacttc tctccatgtt cagcattttg 26340
taaaaggaaa aaataaaaca ccacaatctt aaaactgtct atttgtagac actgtctttt 26400
agaaattatc tgtgtgtata tatatatatc tttatgatat cttcttttag agaactaaaa 26460
tgcattaaaa aatgtagtgt tagatacata tattatctta tttaaagaga aaaatggtgc 26520
ttttctacag taggacaaaa tattttaatt tctcagctat tttctttcac tcacatattt 26580
tcccaactta accaaatcta gatactacta tgaattcaaa tgtcatgtgt gattagcaat 26640
aaaatataca atagtgtcct ttcattagat gctcctttgt caggtgcaaa ttttacattt 26700
attttattta tttacttatt tatttattta tttttgagat ggagtctcgc tctgtcaccc 26760
aggttggagt gcagtggcac aatcttggct cactgcaagc tccgcctccc aggttcacac 26820
cattctcctg cctcagcctc tggagtaact gggactacag gcgcccgcca ccacgtctga 26880
ctaatttttg tgtgtgtgtg tatatgtgta tatatatata tatatatata tatttttttt 26940
ttagtagaga cggggtttca ctgtgttagc caggatggtc tcgatctcct gacctcgtga 27000
tccatccacc ttagcttccc aaagtgctgg gattataggc gtgagccacc gctcccagcc 27060
aaaatgtaca tttattttta attaattttt ataaatcata gcatgctttg ttagacataa 27120
tataataata aagttatttt cttcatccta attaagagtg ttagtctttt ttaagatttc 27180
aaaaagtttc tattatttca taggtgactt tttgaagttt catttaagtc aatggagata 27240
ctgacatatt agttttttta atacttaaaa gtcaaattac ttcaggctca ttaataaact 27300
tttgaaaaga gcgttttctt tctttttgca atcaacactt tcataaatgt tataaaaaca 27360
agaatgtttt tgaatctttt taaaattttg aacttcttga tattagaaac atttgtgcaa 27420
agacaatgga aatagaaaac atttcaaccc tttcaaacag caatctgtta atatttatat 27480
ataagagtgt tccctttctg gaactgtatt tctaatgacc cataatataa gatagaaata 27540
tgtataaatc tgtctagggt gagattagct gtaatgcata tcacaaactt aaatgtataa 27600
atataagaaa attattaagt gaactatgaa tgtgtaatta ttatactcaa caagcagaat 27660
ttatgaaaaa taatcctaaa acaatataca ttgtcaatta cattaaattc aattctggat 27720
actggttctt ccttttcccc cagatgaaat tcaggttaag tctcataact tttctggtaa 27780
cgtccaggta ataaaagatc cttcattaaa aaaattgata ttttttcata ttgatgttat 27840
tccaaactag atcgtttgga ataatagtaa agacataaaa tcattcaaag ttacagttat 27900
ttccctttcc caagtatgtc agagtggagg ataatttctt ttctgttttt ctgcactgtg 27960
ttttcctctt tcaacaccag tttggtaact acaatttctg actcctgatg gaagcagaag 28020
ggagaaataa aagcaaagga aatgatgaag ggaagctttt actgagctac cttcattggg 28080
ttcttgggcc taacaggtta tcgaagcttg tgagattctt tgtaggatcc tcagacacct 28140
agccttctgc tgggttctct ttgatatttg aagcagccct catggagagg atggaagata 28200
atcattaatt cctacatgtg gccaaactct ggtcccctgg aaacacgcat tccctggaat 28260
gtggaaacac ctagcaaaat ctggaaacac ccctggaaac acccagcaaa atctggaagt 28320
tgaggtgaca caaagcaacc acctctcctt gccaacaaca aagctgcagg ccaacccatt 28380
gttcacagtg agagatttca gaactgagtt agacccacca gcttagtgtg ttccccaaac 28440
acaaaggcag ggaatacaca tcaagctgtc taagtggttt ctcctgcttt aggcaaaatg 28500
ataggcgcct ctcagtccct cccacttagg gggaactaag actcacaaca caacagcagt 28560
tgtctccaaa tatctttctg taaattctaa aactcctctc aaactctcca atctcttttc 28620
taagcttagg gtgtaaggtg acagttaaca atagaaaaat agtttcctgc taccttctca 28680
tcctgcttgg cgctctagtc acttggtttc atacctaaac cagaggccag agttaatgat 28740
aatttattac atatttcaaa atagctagaa gagaagattt gaaatgttcc taacacaaat 28800
aaatgtttga ggtgaaggat atcctatacc ctgatttgat ccttacctga tttgatcatt 28860
acatattgta tgcatatatt aaaatatcac acatggactc cttaaatgtg tacaatcatt 28920
atgcatccat tttaaaagtc caattccatc ttaaaatctt gttacagatg aaatagtatt 28980
cagttactaa cagtaatcat ataaaaaatt ctgaagggca attgtaacac attactgtta 29040
cagctatgaa gaaagcttgc aaataatttt tttgaaaaga gacccaaata acaatggaga 29100
taatcttact ccattaaaaa attttactcc attgtaaggt caaatgttat gatttaagga 29160
catttatctg atacagaaaa taatgatatg tataatttaa aatatttaca tataaaatac 29220
tcctaaaata tatggccaat ctttatttta cgttgatctt atctattcaa taatattcag 29280
aaaatgttta taataacgac ttagaccaca agttattgta ataataataa taataacaaa 29340
aaatattcta actgctttgt gtatactaac tcatctagtc cttacaatac actgtatggt 29400
agctactatg tttatcccca atttcctgat gaagaaaaca aggcacaaac aatttaggta 29460
acttgtgaga tgaagattct gttgttattg gccaaaattt ttggttagac tcagaaaact 29520
aagagttgtt ataatgttgt tgcaatgtga cttttaagat tgcaatttta gagatcagca 29580
tgctacagca tatgaaaaac atttttttgg aacctaaact ttgtaacatg attcacttta 29640
agtaatattc attagcagcg tgactgttga atcagaagtg cttcaataat gtagaagcct 29700
aatgttccaa aagctagtta tctataccta agtcctctaa tcaaaaatgt aaatacctat 29760
ataattcaat cattttgaat gaattgaaga atgcctcctg attttggcta cagagtgtgg 29820
aaaattatcc aagactttaa atcagaaggc ctataatcta atctagtccc taccacatat 29880
gagttgtacg atcttgaata aatcccttaa catctccagg ccataatctc ctggaagatc 29940
agctaggcaa tacccaacta tttgtccatg atttttgtga ttctagtatc ttctgaatct 30000
actcactggt tagcacactg gactattcgg tcaaaagggt agcctaaata tgtagaaaca 30060
caacttcaaa ctctttgtaa cttaaggaaa atcctttagt cttactaata cttcagcctt 30120
cctactctgg attatacaaa agattaatac gattatccaa aaagaaagaa agaaaggcaa 30180
cattaagaac atcaagttta cttttttaaa aaagtttttg tacaaaaatt aagataaaga 30240
aacatcctaa tacaatccaa gaagcatacc cataaaatga tagtttagaa ttatataaat 30300
tagggtttga aggatttact tttgctgtat ctttgcagtc tctgatattg aatgttgaat 30360
atttgcagaa caagaattca aaaaacagag ggtgatgaat ttgtgctctc ttatcactag 30420
caggacaaat acagctatca aaaatagaat tttgtgagtt acttaataac gtgacccagg 30480
cttttatgta gcaactgatg caataatgcc tgcttctaag ggtttggaaa tatgctttgt 30540
gatctctttt taaaataatt aaatatcttt ggatattgat ggctgaagtt tttatcaaag 30600
tactttagag aataaaagag acgtaatgca gtaccccgca tatagtaagt attcaataca 30660
tactcttgat gaaaactgtg taatgttact aagttaaact ttaagcttca taattgtatt 30720
atgccttgta aaaatatttt taaagaaagt atgctacagt attaacatgt gaatagtctt 30780
tgtctctggg taatggaatt atgtatggga attcttttct ctactttttt attcttaact 30840
gtacctacaa atttcaaaag ctagtatata cttctctgat agctaaagac aaaaaaaaaa 30900
aatcacatta tgatgagcct ttcctcaaga atgcgttaat gatgtgggtc ataaactatg 30960
atatgtgatg ctcctcccac atgaaatttt ctccttagaa ctagaaaaat acattctcat 31020
aggtgagcat attcagaaac atatacactt ccacccaatg tggtgtctgt tgacatcaag 31080
tttaattcta ctgcaactaa acctaaatgt atatttaata aaaatcaccc tcaagtagtc 31140
tgaatatttt taaaaataga ctcattatat ctaatatata taaaatttaa aatgtggtat 31200
gtattagctt tgtttaccca gctatcctat tggtaatcta ttttctaaaa atcgttacag 31260
cacaattttt atgaggtatg atagtcccct tgctttcgta aaccagtgat catcctacat 31320
aaacatcaag attttttgtt ttgttttgtt cttctctttt gcttccttag tccctattat 31380
tgagaaaaat gtattagtgc caggtcttgg gattatagaa tataaaaatg cagtgcctga 31440
cctaaagttc atataaagtg ggtgaaatga aaaagaatgc atccaaaatt tacaacaaca 31500
acataaggca gcctcaaatg agcagtccag ctgtgagtac caaaaagatc agcattttct 31560
gtatagagcc ttaaaagtga caatgctctt tgacctgagg aatgaggaca aacatttagg 31620
cataacaatg ttcatcatgc tgaaatttat aattttttag aaatttaaac ttaaacatat 31680
cctaaatatc caatataata ttactggtca aataaactat gatcattctt atattttcaa 31740
attatatagt aatataaaat tatgatttca aataattttc aaagacatgg agaagtattc 31800
aaattttaac atttagttaa aaatctgaaa gctacatata aatttgtgaa gaatatttta 31860
agaaattatt cacatataat aaagaatatt ataaaataaa gtataatctc ttagtttttc 31920
ttgcctgatg ctcttcttca ttttctaaat tttctataat aaatgcagat cgtttttatt 31980
acaaggaaaa aatctcatga ggcagaaaat atttctaagg gtcatttggt caggagtaaa 32040
aagaaaaaaa agaaaaaaat catggaaaaa aacttcatga ttaaatttgg gtgataagtc 32100
cctaggttca ctagactatt ctttctaatt ctacatatac atgaaatttg tttaatattg 32160
atatagtcca atccttttgt tttgcagtta gaaaataagc cccagaggta cacaattata 32220
aattaggggc caacaaacta tgccccatga accaaatgtg gctacagctt gtttatgtag 32280
taattgcagg ctatgaattt tgttttttta cattttaagg atttttttaa aacagcctaa 32340
aatatacaac tatttggcct tttacaaaaa aaaaaaaaaa aaaattgctg actccaacct 32400
gattccttaa cgtagcactc tatattagaa gtgagtctag gttttaaaga aaattattta 32460
atttagtatt taatcttctg taaaagaagt aggtgcatcc cttcttgtgc tgcctattca 32520
caccaactca agcactgggc cctcactcat tcatttatta attcatttgt tgattccacc 32580
acaaagagag acacgtttct acctttatga agattagtct catagaaaag atagaaaata 32640
aacagataaa gaaacaagca aagtaattac agatcatggt aagtgccaag aatgtgataa 32700
accaggttgt ataaaacaga aagccaggtg accttcttta ggaaaaatga cagtggaagc 32760
taagacttat aagatgagag caaatgtact ttgcaaggag ccaagtatcc ctggaagatg 32820
gaacacacaa gcagtactcc ttaaagaaaa tatttataaa atacagaaca cttttgggta 32880
gtgaagacat taatgtgtct taatctcaaa gatctagtgg gattacagca gataagtagg 32940
tggctttcat ctttcccttc ctctattaat cagccatgga cctggtgtcc tgggaacaat 33000
ctcctcaacc taggaacaaa gtacaatttt caattcccac ccctcacact ttcctttcta 33060
tgtatactct cttgtatgga aattcaatga aatcacttgt tttgattcta atttgttcaa 33120
ttcttcagca aatacaagcc atcaggtaca aaggatggcg ctagatcaag tctaactaga 33180
ataccgttcc tcttctaaga gtgccccaaa ttaagttaac tctccatctt tccggtttga 33240
gataatgtat ttaggtaatt ttaattgaat gtttctcaaa tggcattttt ttcctataaa 33300
taatacaata aaaataacct gagggcctcg ggtttactaa ttggcttcat ctagaatggc 33360
tccaagagga gcagatggaa aaacactgtg gcattgacat tctttttcaa ccactgcaca 33420
aaaaatccta gggacagaaa taggaatttg acttcatggc aaaatatagc tcctgggtcc 33480
tactttttcc tctattgcct gttctcgcca cctgctcaca tccctgctat ccaaggactt 33540
aggtcattca ccaagtgcat ggataccaac tctttaaata ggtagcaata agcatcagaa 33600
caggatggga ccagtagatc atcacagggt catgcttccc taagcttatc accccagcca 33660
cccagaggcc aactttattt taaagctcag aagcaatctt tcttctacta gccagagatg 33720
ccatagcacg gtgcaaaaga ctccaaatga aggagcagtt ctgcgaatcc ccttgtggag 33780
ggggtgtgtg cccaacattt gtggaaagtt cattacccca aggaacacag atatgttcca 33840
gaagctatta tttccaaata gcaatgaatt tctcctcaaa tagcctcata gggtattggc 33900
tatacatgaa gtctttgata taagattcaa aatcttcata aactacacaa ggtagtgttt 33960
tcccttaagc tagaagcaca gagtttttct attttatcgg cttaaaaatt ggtgtgaacc 34020
tcatgaccca aacatgcaga agcatgacca ggtcttgtga actttggact gtgcgtgctg 34080
acaaattcac aattttttaa aagtgctatt catttgttag tactgattgg caaataaaat 34140
taagtgactc ttcaacgtca gaacctgaaa gcttaccatt atgagatgca aagacagctt 34200
tcaaacaagc taggcaaaga agaaattatt gagatcacag ccttgcagtc atgaatttgt 34260
ataggatttc agcagctgtg atcctttata acattgttaa agaggtgccg agcagggaac 34320
caagatgaca ttaaatggta cattgtccac atcattaaat aacatccaat cccatataga 34380
gagaattatt ccactttcag ttctctttca ggctttcagg tgaggaaagt tagttgttgg 34440
aggtatgatt taaacacctc tccaggccct actaacgttt ttaagtcccg agagcaggac 34500
tagagtacag agcttttagt agacgacagt gtctaggtag aagttgatca tgatttccct 34560
tgtttgcaat tgtttttata attaccgtcc atttgtggga aatgatactg atattccact 34620
tataagaaca atatatattt tctttttggt ataagtttat ttaagtaaca aagtgaatcc 34680
acacataaag tcattaggta attaacagaa taggtgtcaa ttggacatgg aattggagat 34740
acactgattt ttaaaattac aacaacatcc tcttaagact ccaattgact aactcacaaa 34800
acatcctatg aacattttcc tccattaaac atgatatcaa attcagcctt cctttcacaa 34860
gcaccctcac actcccacag gactactgca atcacctagt caaccctcct actccttcat 34920
aaatgaaata aagtcagaaa agatttagtg ccttgccgag tccctcagct tgtcagaaat 34980
taaaattcac aagggtgttg taaggagaag aatgattgta taaaattcct tacatgcctc 35040
aaacccggtg cattagatgg gattatgctt ggcatatgtt gaactaggaa aagacagaag 35100
agcaattaac caaaccaaat gttctttatt atgtctttat ctgcacatgg gaagtttcgc 35160
ataacttaat cagatctaga gacaataata ataattaatt ccgaaaggca aattgtatct 35220
gtaagtaaac aaaatgttat tgggcctatt gaataaatta cacattctgt aaggataaaa 35280
gccccaaacg gattaaggaa tgactaaagt tgtcatctaa ttacttcttg gaaggaattt 35340
agaggttcct atagatggaa gcagtgtgtc tgggcacgtg cccagagcca gaagtgagca 35400
tgagcacagc catttctgac ctcaaaaaaa aggaaataat gctttgcagt ccatcgttat 35460
gcaaactttg ctggaaaagg taagcagagg gtcgtagaag tgacttggca ttttacagat 35520
tctcttttat agaaaaacac acacacaaat gctttttgtt ttctaatttt gaaaaacact 35580
caaaaaaatt ttctgttttg taattttgaa agaaaaagtg ttttgttttc taattttgtc 35640
tattttcaaa ttcaatattc ttatgaatga ccaaaatctt acattataag aagttttgca 35700
aaacacaaca ttttaaaaag cctatttgct tttgaatgct tcaaatgttg atactgaata 35760
atcctcaaac ataaagggaa attattaaaa tacgttatta aatgcatcaa tttgataaca 35820
taaattgctt ctgcttccat aagatagtta acaacttcaa gtgaaattag gattaatttc 35880
cttggaaata gacttttaat agtcaacctt ccaaagtgaa acaggaaggt gactcataat 35940
ttactaatag ttgtttcctc agaagaacca tatcatacat tttttaaaga taaaatgtca 36000
gggctttgta aaaagtgaaa ccaataaatg aattttcaag agccaagagc catttgcatc 36060
tttcttcatg atttttgcca tagatacatg ccaccaatat tatttattta gaattcattc 36120
aatcaactca ctatttttag tcatttattt taaaagtaaa ctttttttca cttatgtaag 36180
aaacccacgg gttttgtgtg ctaattatgc tttttctaat gtacattaaa ataaatgcat 36240
aattattaaa ataagaaata ttgacctata aactacctaa tatcatcctc atatattttg 36300
gaaactctag gctgtatgat gataaagcta aattaatatt tgaatattat gttcatatcc 36360
tagcttttcc tgtcattgtt tctaattcta catctctaca aaatttccac aactcattta 36420
gtctttatat cacaattttt attactcttc atactttagg aatattatat ctggcattca 36480
tgttgcatat accttgtaaa aattgtagaa aataactaat agaaataatg ccaacttcta 36540
cagtatatta agccaaataa attctgcttt ctaaattcca gtctaaaagc agattttacc 36600
aacatgaaat cactgatttt aacaagatgt gaaggtgaac aaactataca aaatagataa 36660
ttattttatg tacaatttaa aaatgaatat tccctacatc actgtttgtt gtcctcaggc 36720
aataaaaact ttggaagaga ctaaaggcaa aatcacattg aagagggtcc tgttggtaca 36780
ttttacggcc ccctagactt tccttaaact acctatcaca taatgaagga tctagtatat 36840
aggtggaata caatagaaat aatgtctaat aaatactttt attaaatttc acaaatcaat 36900
aactaggaaa atgcagtata gactcatgaa acacaagtga catagttaag agagatgacc 36960
tccatgcctt gttgtcaact ttaagaacca tacacaggag tttggtcaca gaaccactgt 37020
tctgggcatg gtcctggtga ctggcaagct ggtaaaggct tgaagtgcta ctaagcaagc 37080
gtagattggc caggacccaa gggaacagga gcaagaataa atacaaacct ggtcaattgg 37140
aaaatgcata ggaaaacatc tgaaacaagt ttagttatga aaaatacaca gtttcttccc 37200
tcttacggag aggggaaaaa agaaacaaag aaccaaagag aaccacaaag atgattacaa 37260
acttgaaata tgaactttcc aaagagccat taaagagact gaaattacta ctcaggaaaa 37320
aacaggctga atgagggttc attaattaat gtccttccag ttatgaatga gcttgtttat 37380
gggaaacagt aaacatctgg tgtccatgat tggtgaagtt gagcaggaaa ataaatgtaa 37440
cacacaacat gaggatttaa gaggctggta agcctgagaa gaataatcat cacaattttt 37500
gaatactata taggccataa agttcaccaa attgagaact gcaaggaagc ctggaaaaat 37560
caatgatagg acctttattc tagtgttttc tacaataaat taaaccagtg tgatattaga 37620
caagttatgt acctctggcc ttagtttcct cctctataaa attagtatat tgtgttaatg 37680
taaaaatgaa agagagataa tgtaactaca agtgtcttca tattttgtct cttctgttta 37740
ctgcttgtat gaatttggac atattttatg ccttggattc ctggcctata aaatgaaaat 37800
aatagtagta gcatcctcat agatttgttg agaagattaa atgaatgtaa aacactcagc 37860
aaaataccta attcaattgg agatagttgt ttttgctgcc attactatca tgtgcaacta 37920
acagaagcta actctaactg gctaagtagg aaagagttta ttgaaaggat actggttcac 37980
agaaacttta gatgtggaga atccgattca agggtaagct tttaacaaca aaacccaaaa 38040
ccacatcaca tatttgtcac gataagaaaa tgttatctac catcacagaa tgctcaaaat 38100
taaagtttgc atcatttgtg acttttgcat cagaactcaa ttttagtaaa ggaaaccatg 38160
attgtccatg gtttagtaaa ggaaaccatg gttttccaat aaccatgatg gccccagctg 38220
caaggaaggc tggaaaaatc aagtgtctgt catttttaag ttctatagga gaaggcaatt 38280
tttgcccaga ttccccaggt atataacaag ttcaaatgct cagtggccaa aattaactca 38340
gttcattcaa cctccatgct aagacttatg gcttagaatg atttattgag gaaggttttg 38400
tgggttttat ccaaggtcaa gaagatgata gacataatct cttgaagact caatggctcc 38460
attatgaagg acttgaaata tctgtgatag gaggaaattt ccaagtaatc ttgacatata 38520
aactgagtaa ctgggtaggg gctcagcatc caatatttaa attaaagcca ctagatttat 38580
agttagaaat tgtgtcctca attgttaatt tacataggtg aagactttcc acctatttgt 38640
atatgactct agagagacaa aggtttctaa gtctttgatt ggaaaaataa aagttttcag 38700
agtttaataa acattctctc atgaaaagca aaaatctata ttcttttagt ctgaactatt 38760
aatacatttg tgctgctggg gagaatgctt cccttgagga agacatcagc taggagggaa 38820
aagaccagtt ataactgggc tttatctatt ttaaactcct caactgagaa aatagtgcct 38880
gacatattag caacccagaa cccaactgtc ctttctgagt aatggacagc tattctaacc 38940
ccatgactaa tgcccagtgc ctgtcttaaa ttgatctgaa cttccattac tggtacattc 39000
caagaccagt gggtggctca cagagcaaat ctcccccact gagtgaactg cagggcattc 39060
ctgaactggt cagactcttt acagtctcaa aaaatattct ttagattttt ttcatgtgtt 39120
tatgaaaaac aaagacaatt aatattcttt cttgcccagt tatttcagat tataagcagg 39180
taaatcctgc tctacacgtc ttacgtataa atagttggca ttttcagcaa ttatagcaat 39240
caagcaagtt gaagatacat tttaaaaggt caatctgagg gttgtctatt tattttcaaa 39300
ctaccaaagc ttttcaaagc ataatttctg gaattaccac tttactacta tggaatgaaa 39360
gttgggtttc ctcaacttga agggtaaaaa taccaccgaa tgtatagtaa atttattcct 39420
ataatctgtt gaatgttata cacatcaaag atatacaaaa attggctcag aggaatcatt 39480
gtcacccaaa tggagtttgt ccagggagga ggatggtaat ttggcaattc aggttgagta 39540
tcttttagcc aaaatgctta ggaccagaag tattttggat ttcagatttt ttttaatttt 39600
agaatttttg catatgcata ataaagatat cttggggatg ggacctaaag tataaacaca 39660
aaattcattt atgtttcata tgcaccctac acacatagct tgaaggtgat tttatacaat 39720
gcttttaata attttgttac ccctcacatg aggccaagtg tggaattttc tacttgtggc 39780
atgatgttga cactgaaaaa ttttgaattt tggattttgg ggttagaaat atgagataca 39840
tttttctaaa tattttatgt aataaaatga ttggaaatta aaatgatttg aaattgtagt 39900
agggaattta ctatttaatg gcatgatata ttttttcata aataaggagt tttgtttgtt 39960
tgttttgaga cagagtctcg ccctgtcgcc caggctggag tgcagtggcg cgatcttggc 40020
tcactgcaag ctccgcctcc caggttcaga acattctcct gcctcagcct cctgagtagc 40080
tgggaccaca ggtgcccgcc actacgcccg gctaattttg tgtattttta gtagagacgg 40140
cgttttaccg tgttagccag gatggtctcg atctcctgac ctagtgatcc gccgacctcg 40200
gcctcccaac atgctgggat tacaggcatg agccactgtg cccagccctt tctttctttc 40260
tttcttttct tttttctttt tctctttttt tttttttttt tttttttttg agacagagtc 40320
ttgctctgtc acccaggctg gagtgcagtg acaccatctc agctcactac aacgtctact 40380
tcccgggttc aagtgattct catgcctcag actcccaagt aactgggatt acaggcatgt 40440
gccaccattt ccaactaatg tttgtatttt tagtagagac agggtttcac catgttggcc 40500
aggatggtct caaactccta ggctcaagcc gtccacccaa ctcggcctcc caaagtcctg 40560
ggattatagg cgtgagccac catgccacac caatagggaa tattttaatg tatgtatctg 40620
ttgtaagtgg cttccataca tcaaaggagc aaaacggaga aattaagctg atgcctgact 40680
gcctgggttc aaattctggc ttctccactt ccccaccatg tgactttgac aaattactta 40740
atttatctgg gctttggtac cttatgtaaa tgggataata acagtcctta atccatgaca 40800
ttaagtaatg atagagcaat atctgacata tattaagtgt tacataggta tttgtttgaa 40860
aataagtaaa taaatgtgtc tgaaaatatc gattgcacat atttaaggta attattggtt 40920
gagatataaa ccactaaatt accaaggttt ggggtttttt ctataagcat aaagacttcc 40980
atttctcagg tttctctgtg atatcaaagt tttactactg gacaagaata ttagggtaag 41040
aaaaaaatac aagaactctc taggcaaaaa tttaaatatt cagttagatt aaaaacatac 41100
tcagttgttt aaaacaaaca aaaaaaaagg aatccaggta aagtagaaga ctcatatgac 41160
attttttaaa ttactatttt taaaaacgtt gtaggaatta ttataaataa aaaagtgatc 41220
atgaccacag acaccacaga catcaattaa ataatgtgat ccaaagaacc tttgtgctaa 41280
cacttacaaa ataattgaga aagactcaag ttagtgtata tgaagattta acagggacac 41340
cacaagctgc tttacttcaa ttttaaacaa caaacaactg tcatacaaaa cagtgtcttt 41400
aaacaactaa cgtatgtctt ttaaaaatct acatagaaaa atatttgaaa aggcctatga 41460
aattttaaac agtaactact tctaaggatg agtagagtca tacattggat aatttttctt 41520
tttactttac atgtcaccat gttttttcca caacatgtat tatgttatag cataaaactt 41580
cttaaaatat tagttgtaga agttagtaat gaactcctgg gctcaaagca tccttccgcc 41640
tcagccagag taagttctag tgttctatag cactgcagga tgactacagt taacaataat 41700
atattctcaa tatgtagttg taaatagcta gaagaaggct attccttgca ttcccaacac 41760
aaagaaatga taaatgtttg agaggatgga tatactaatt accctgatct gttcactctt 41820
tgatgtggta agaagataga tctcttaagt attcttactt aatgaaatta aaaaagaaaa 41880
aaaaaaattg gcctagcagt ttacaagttt tcacaatgtt tatctcaagc aagctgctga 41940
agcacagagt gtggtattat aatccacata aaaagcttta ttttttctcc tttaaccagt 42000
ccactattat tatttgtcaa tgataaatac attccttatt gtgaaatgat tttgaaaaat 42060
actcaaggaa actgaattaa agacttgatc attttcttct gtccttcaca cctgccctgg 42120
atttgcagga aaatggacaa agaaaatatg gtggccctcc acctggctgg gatgctgcac 42180
cccctgaaag aggctgtgaa atttttattg gaaaacttcc ccgagacctt tttgaggatg 42240
agcttatacc attatgtgaa aaagtgagtc caagtttaac atttaatttt tcttatcttt 42300
caagggaaaa atactattct cttcactttg ctttcattct cagccttttt ggtcaatgat 42360
tgtttctgtt caaattacca ttcgtcaatt atggacaaag tttctagtga ttgtcccttt 42420
ataatcactg ccttgaccta gctcttgtcc tgttactgac agcttgaatt gctactattt 42480
ctaatgactt tcaaatctat atcttgttcc ccaatctttc cactgtcatg ccatctaact 42540
acaaactatc catctacaat aatcctacaa caacctgtct acaattagat attgctccaa 42600
cttgacattt taatatgatt ttataaagta cattttcatt ttaaaagaat gcatacgttt 42660
gacatggctc aatatgtacc tataatccag aatgaaatct tctccaagtc tgaatttttc 42720
atctacctaa atgcatcaag aagattaaga atatggcttt tcaattaaag gaagaatatg 42780
aaattcaatt tcatttttaa taatttaccg agcagttttt agcaacaagc aattcctgaa 42840
aaatttagta aatatgataa ttcagctctc tgtctaaatg ccaaaatcaa attgtgtgtg 42900
tgtgtatgtt aacagcctca tattcagaac tgcacctaat tttacacata caatccctgt 42960
tggcacaagg acaaatgatg aggacttaat tctgtaagaa tcttatacat tgaatctgaa 43020
aatgaacatc gagaaacacc tgaaacatag agatgaaacg tgctcaaact ctttcctaat 43080
gagcccagaa gaaataggtg ttcattactg aatacatggg ggtggggtag ggtaaggctg 43140
agctgagaag tgaccaacca caaaggtaat ggcatgtgct taatggcact tctctccaga 43200
catgccccaa catatttatc tgggcaaccc ttcctacagc agccagcaat agtaaattgc 43260
tcagtctaga ctgctgcagg acagttgtgg gggtagaagg gagtattata tgggcaagta 43320
gagtcactat agccagggga atagagtgct ctcctgctct ggaggccctg gccctgagtt 43380
agtagcattt aggctagcat ttatattcag ccagcagact aagaaaatga caagcctccc 43440
agatcatacc ctgaaacaca cctgtgttca ttttgatgtc atggctgagg aaaaagacag 43500
ctaagaagtt agtttggcga atgagcattc ttgtattttg ttttaaagat caatgataga 43560
ataggaccaa ctggaaataa aactatggag atttcagagg acaatttaga gggaatggac 43620
agatacatca aaaaagtgct tttttttttt tttttttttt ttttgagaca gtgtcttgct 43680
ctgttttcca ggctggagtg cagtggcaca attatggctc attacagcct cgatcgcctg 43740
ggctcaagca attctcccac ttctgccttc caagtagctg ggactacaag cacgtgccac 43800
catgctcagc taatttttgt gttttttgta gactcagggt gtcaccatct tgcccaaact 43860
ggtttcaaat tcccagggtc aagcaatcca cctgccctgg cctcccaaaa tgctggaatt 43920
acaggtgtaa gaaactatac ttatgataaa atgtgttttc atgtctctaa gatgttccag 43980
ataattatgt gatgaaaggt aatttgctct actaaaaaca cattctgtta actcaggctg 44040
aaatgtcact tggacacatt ttatttaact taagttctct cacgaatcag ataactgatc 44100
tgaacccaca tgaaaatatg caaaccattc cacatgggat gcaaatgcca aatagtactg 44160
gcaggaggca aacttcagaa aacattgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt 44220
gtgtgtgtat cagcacatgc acacatacat tcagaagtac aaacatataa attttctatt 44280
tctattactt gcagatcggt aaaatttatg aaatgagaat gatgatggat tttaatggca 44340
acaatagagg atatgcattt gtaacattct caaataaact ggaagccaag aatgcaatca 44400
agcaacttaa taattatgaa attaggtaag ctctgcctct tctagattaa aagtgaaaca 44460
gacaatgcac ctgtatctgt ttttctatca agtttatcta atatggtata tgccaaaaaa 44520
aagccaagcc agaaatgaaa cagattaata gttttccttg gcaaaaataa atttgattaa 44580
atatttgttt aatatcaata ctatatgaag taccaaacta agttctatga gtgttcaaag 44640
aaacaaaact taataatttg cctgtttcat aaatatattt tgggcagtgt tcaaaatatt 44700
gggaatatat caaggtataa tttcctactc gcacagcaaa tatataagat cactcaaaat 44760
agtatgaaaa aaatcaaaca gggatgggat aaagttgtgt gagaaggtgg ctactctaat 44820
tttgtgtatt taagaaaata ctgtctggca gagtgaaact taatctgaga tttgaatgaa 44880
aagagccagt catgacagtc agaccttggg aaggttattt caggaaagga gagaacatca 44940
aatgtaaagt tcccaaagtg aaaacaagcg tgatatgttt gaggggcgga aagcaagccc 45000
atgtggccag agagggtaga gaggagaact gaaagcaata cagttggaga gctgtgtact 45060
cagtggggaa gtatagatga agtatagaag tctctgtggt aaagaatttg aattttcttc 45120
taatagaagg gaggaaagag ttttgattac atttacagtt ttttaaacgt tcctctgcta 45180
ttgggttgag aatgtgctat ggcaagtgag atttgaaaga ggacaccagt tagaaggctg 45240
ctgcagttgt ccagatctgg acaagagatg gtggtagttg gatgaggggg tcagtggtgg 45300
acaagataag aaagggtgag atctggaata tattttagat caagtacaca aaactggcta 45360
gatgttggat ttagactgtg agagaattca gaattttggg aggaaaccta ggattttcgt 45420
ccaagtatct gtgaacttgc tagtgccatt gcaatggaaa agactggaag gatagcacag 45480
gaaggactct ttggggccct ttacatttga gatgcacatt gaacatccca ggggaggtgt 45540
tgagaaggtg actgtctgca ttgtagtgga gtcaggagac aggtcacagt tggaatataa 45600
atttgggggt cagctaaata tagatagcaa ttaagaccat gggactaggg gagagtccca 45660
tgtaactgac tttgtgcaac caataaccag ttttgataaa ctggaaataa aactgatatc 45720
atgaaattgt ctgatttcta aaaccttcac ttggagaggg aactgtcata aattatttct 45780
taaatgaagc cctgagccat gtgagaggaa gattagtaca gcagttacag atcaatagtt 45840
ttggagtcag ccatgcttcg tttgagtgcc accaagtaac ttcaccattc taagcctcaa 45900
tttcctcatc tataaaatgg ggatactatc tatttcatag gtttattgca gtgatattat 45960
aacaacttta cagtgcttaa cccagtgttt ggaacacagt aataggttga caaatgattt 46020
ttaaaaatta tattttcaca cagttcatca attctagatg cagtttttta aatatctaat 46080
ccctttgtga aacagagctg caccttaaaa tgggtagatc ttaaatctga tgaatgcaga 46140
aagaacagat ttaccacaat tatttttctc tcactttcta taagatgaaa agaagtcata 46200
cattatcctc acagtctgta aatcaattaa ctactggctc attttattaa aaactcctgg 46260
gctggacaca gtggctcacg cctgtaatcc tagcactttg ggaggctgaa gcgggtggat 46320
ctcctgaggt tgggagtttg agaccagtct gaccaacatg gagaaacctc atctctacta 46380
aaaatacaaa attagcaggg cgtggtggtg cgtgcctata gtcccagcta ctcgggaggc 46440
tgaggcagga gaatcgcttg aacctggcgg ggcggaggtt gcagtgagcc gagatcacac 46500
cactgcactc cagcctgggc tacaagagcg aaactctgtc tcaaaaaaca agcaaacaac 46560
tccttagcca caggaagatc agctagattc agcaactact tgtagtctaa ccattcagtt 46620
ccaaggttgg attctagaag agagtattgg agaaaacata aaggaggttc ccctcccaca 46680
ggtgcctcca tagacccgaa agagctttgt gtagtatgtg gaggattgtt tgcagtagga 46740
atcaggagac ctggggtcca gcccaggttc ctttggacaa atgctttaac ctctttgagc 46800
atcactttta ttattggcac ctgaacacag agatgttctg agcattcact atatgaaaga 46860
atatatacta aagtgctttg aaacagctac aaaatgctac attatagttt tacgatttcc 46920
agaattggaa ggttccccca ttccttggtc tttcatggaa cctggacatc gtaacagcaa 46980
tacccaaaat ggtatctgag ttgagatgga tatggaattg gctctgtagg gaatcaagtg 47040
gatttgctgt atctacttaa cacattgtta cccaataggg cctgtaaata ttcataggat 47100
atgaataatg aatacaatca atccaccatg gccactgata attaacagta tcctctgtga 47160
attttagtgc ctttgtctgt aaaatagaga taaaaatata cctacctcat gaggtgtttt 47220
gaaaaataaa tgaaataatg tacatacatc tcagtgctga cacatactag gtgctctgtg 47280
aatgtttgca gaaggttatg gtggtgatga tggaggagga gaagggaaaa ggaaaggaaa 47340
aatatgacag aaattaggaa gggaaagtta ctggccagga ttccagtcaa agaacgggtt 47400
ggatgccaga agcaaggtaa aggcagagtg ttgtcttaaa aattaggggg tagaataaat 47460
ggaataagac aaaccagaat aaacacccca tggacaacct cacctacttc cactctgcct 47520
tgggtcagtc ctgccaggga gagaactttt gatgcagaga agaaaacttc aatttgcttt 47580
tatccaccat ttctcaccca catatcatta tatgagcttc tacttcatca aatattcact 47640
gatcatcatc taaatgtctg gcttctagag acattaaagt tgtggcctca gcttttgaga 47700
ggagatggct ctttgtctcc aaataattcc ggcaaaggct cccgacaaac cacaacagtt 47760
taaaaataaa atatggaatt ctaggctccc cctgctgata gctgatatat gaccggctcc 47820
ctaactatca aaaataatat aatttctaaa tacattaata ctgtggaaaa ggttttggtg 47880
ttttcttttt taaatgaagt taaaaaaaaa aacttggaag attattttat caacctttcc 47940
ctgcccttga gaaccacgct cctggcacaa ttcttactag actgagatgg agctgtcaca 48000
gatctgacac acagtccttg cttcttcagc aaagcatagg aggcagctgg gatagtggcc 48060
taaccctggt cagaaaacct gccacacaac caagagccat tcgctccatg gatagcagac 48120
aaatcgcccg cccacgcagc tggctgagag cttgtgttca ctgcaaatgg gtcatttctg 48180
ctaagcatac ctcacccatt tttaataact tagtgttatt acaaaagtca tacagcctaa 48240
tatgtcacac atggaaaaca taaaaaaagc ataaagtaat aaaagttaaa accatttctc 48300
tgtaactcca ttgccccaaa ataaccacta tgttgacatt ttattgtctt tccagatttt 48360
tctatacatt tttaatcaaa atggtcttca catatactta ttttatagct ttttaaagcc 48420
aacagcctat tgtgaactgg tttttttaaa ccaataaata ttcttctacg ttactctttt 48480
tcatgactgc agagcatgca atggtatgaa tgcctgtctt ttgtttatca gtgatcctca 48540
accaggagaa tactgtccac ccaagggggc atttagaaag gtggggaggc atttttgaat 48600
gatctgattg gtcactattg gcatgtagta ggcaagaact agagatgata aacatactat 48660
ggtatgcaat gagaaaatct ccagttcaaa tccagtaaca tctcagttga gagacattaa 48720
accagttctt taccgtgagg tactttgctc atttccaatt tgggggagat tttaaagagc 48780
agtaataaat atccttaaac ataaattcta gtgctgattt ttattttcca gggacatatt 48840
cccagaagat actttatttg gtcaaaggtt gtgcacactt aagacttttg ataaattttg 48900
ccaaatgttc tccataatag tttaatcaat gtatactctg ccagtgcagg tgtacatacc 48960
tcaacttgct aagaagcaac tctgaacagt ggaagaaaca ggaactaaga tcccagagct 49020
aggtttcatt ccttatattc tataacattt taagcaagtc ttttaatttc ttggcgtttc 49080
aagttcatct gtaaatggaa ataacatcta ctctgcccat cccacagtct ttttgtgtgg 49140
gccagataag atcatatgtg aaaatgtgtt caagtataag agactgtttt taacagaggt 49200
cacatcagaa cagcttttct ctttggctgc aaaaacaaag gaatgtcagg tgttgcaaac 49260
tcaagtgact gcagggccag gcaggtggct tcagtaacct gggttaggtg taggggcctc 49320
agtgttagag ttgcttcagg gagtggcgag gattcacaac tcttgaatcc acatctagcc 49380
caaagaaagc agatgctact cagcttcaaa tagctttttt ctttgaaaat gtagagcaca 49440
tattgacaca tctaataatc ttgcaaaaga agccacaact ctacaaaaat ggtttcaaca 49500
ctatgaatcc aaacatccca catcttcagg caacatctgg cccagggcca tacattttca 49560
acctgaatcc tacaaggatt ctcatcaatc aaaatccctg ctctttttgc agaaatgggc 49620
gcctcttagg ggtttgtgcc agtgtggaca actgccgatt atttgttggg ggcatcccaa 49680
aaaccaaaaa gagagaagaa atcttatcgg agatgaaaaa ggttactgaa ggtgttgtcg 49740
atgtcatcgt ctacccaagc gctgcagata aaaccaaaaa ccgaggcttt gcctttgtgg 49800
agtatgagag tcatcgagcg gctgccatgg caaggaggaa actgctacca ggttagcaat 49860
accctcctca aagatgagat ttctctgctc tatcctgcct gcctccacaa agaaaataag 49920
catttttaat ttttttggct ctctatcttt cattatgttg cgttttaaat tttttatcct 49980
tcttcactat ctcacagttg attccattcc ctgaagtttt cacagactca gttttgaaaa 50040
atattcgttc tgtgcattga gggtaattta catgcactaa agaaacccag aactttaagt 50100
gacagcaatc ctacgatgaa taaagagtct tcttaaaatt gagtatatca atcacagtta 50160
cttttgtgta tagattttgt tatcaggctt attagaatta gggtatattc tccattacaa 50220
tgtagaaata aaaacctcaa gtgatacatt attccaatga caactaggtg acatactttc 50280
attatgactc cctgttgtct aataatttct gtctaatttg agagaagaga gataaaaact 50340
ctctttagaa agtcaccttt atttgttagt tattacaacc acaggataga tcccatttgt 50400
tgaataacta gcaaattctc tatccacccc agcactgcct cggtcagatc aacttaggaa 50460
agttgtttag ggttcttgac tcattctaca acattcacta caacttacac aggtttttaa 50520
atgaatacta aaataagaag atttcaagaa tgacagactg gacatattgg aatgaacttt 50580
tctcatgaaa attatgagag agccaccaga attcaaaaca aaacaaccac aacaaagacg 50640
tctacattta tgttgccttt gtacacactc ttcaaaacaa accaatacta gatcagcccc 50700
ctagatacct tcaaaactag gagacagctt ctagcttggg gaagatcttt caataatacc 50760
ttcatgaagg caacttaaag tgaaaaacaa aagaagacag ttccaaagat tgctgaatct 50820
tttacaggag taggtatttt taatgttgaa tctttcattc acaacttctt ccctcttcac 50880
cggccagcag tcaagtcatc aaaatcacag gtccatagat agactgacta agactcctca 50940
tgggggcata ctttttggtg acctggacat agtattttgc tatctgcttc aattcttctt 51000
tcttcttcaa catcgacaac tctaccattg aaaagtcttt tgtatccatc ctgttctcag 51060
gccaccactg aagtataaac acacatattc taaatcttat gtaatttttt tcaagatcta 51120
attattctcc cagctctgct ttctcttcca tgtgccccac cctccaactt ctccatcctg 51180
aacattacca ccagattaat gtttccaaaa tatcctatta tcctttcaat accttcttgc 51240
aaacagtagg aattcaatct caggaattca atctctatct ataggctgaa tgatgtctgt 51300
cactaactgg ccagttcaaa aatattcata actccttgtt gtgtataaga actaagtatg 51360
tgatttcatt atttaagacc ttttattcat ttcctggtct tttatgacca tatttgctac 51420
cttctatttc ccaataaaaa ctcttccttc tatcaggaca gacaacgcaa tgacctagac 51480
acttccatgc ttatgtctgt ctcctttatt tctaatgcta tatcctctac taggaatacc 51540
tgcccctcct tcacttgtga cagtcacccc agttcagcca gtaccttctt gagaaacctg 51600
cctccagtat tccagcccga attagtcact ttcctccctc aatgtaggaa gccattcatt 51660
atctgtaaaa acagatatgt gaaataattt tgggtgtagg ggagtaggag agtgaaagag 51720
ggtccaaaac aggtgaaaga cagtttccag ggtcaagaca atccagtaat cccggagaag 51780
ctcaacctcc tgaaagcttc cccatctctt caaagaaaat ggcacattgg cccactaagg 51840
aacttcttta tgtaagtcaa gctgactagg ctggccaggg cctgtcggat aagcttagaa 51900
attcttaagc acagtcctga cttttccttg tggattctct gtccagaata caccataggg 51960
aggctacctc ccctccccat ccactactca tattcaccat gatccaatgc aaccccctta 52020
cctatggccc tttgagccag tctcaggtgg atttcattca gctggatttt agtcagcaac 52080
taactcatca gcaaactaac aagatgaggc acagtggtga gtaagccagc cagagcaaac 52140
tccttcgcct ctaatgagat ctcagaacaa aacctatcac ccatttggat cattctacca 52200
gttaccccat tgcagactca cccacgataa aggaattctg taattgccaa ccctttgaga 52260
agctagttta aaagaacaag gagactgttg agaaaaaatg ataagtgaag acaacaagaa 52320
actttttctt aattgaccca gacttggaga cagagacaat ggttgtctaa agggatgtaa 52380
ctgctcctca gccagttacc tcctctctaa acagtggcag ttcccccttg acaaatctca 52440
cctttactga gctctttaga ggacgaagtt gctgcatccc actcagaaac tagaaaggca 52500
ttctaagaac gctctgaaga aaagtcctgg cagtgattct caacgtcagg ctgcatcagc 52560
atcacctggg aggcttgtta tagcacagat tgctagatcc caccaccaga gttcttgatt 52620
cagtaggtct ggtgtcaggc caggtaattt gcatttacaa caagctccca ggatgctact 52680
gctcccagga ctgcacattt gaaaaaccat tatttgaatc aatgattttc catcctaggc 52740
tgcacattgg aattacctga tgttttcaaa caatattagt acccatgtca gcctctaatc 52800
aattgaatct gcatcactgg aatataaagt tagggaactg gtgttttaag ttttccagat 52860
gattctattc ttcagtcaaa ttgtgtgatt cacagctaaa tctattagct aatgatactg 52920
ggtattcatc ttcatggcat gtaaatagga atacctggga atcgctcagt cagtaaatat 52980
ttattaagca tctagaacat atattgctcc cttctgaatg acatgagaga ttctaaaaaa 53040
aaaaaaaaaa aaaggagtac ctaaccattg cactcgaaga gtgcgtattc tgagaaaact 53100
atacacatac aaaaacagga aaaattatta aaaggagagt gtattgttga atcatcattt 53160
aaaagttatt aagtcttatc tgcatcatct tttcttgacc tcacaacaat agtaggttgt 53220
agataaggaa actgatgtta gataggatat gttttctagc caggatcatt gttctgacat 53280
ttgaacttgt cttacttcaa gttcatgttc tcaaatcact ctgtaacact cgctttcacc 53340
agaggccttc aaaaggatat tggtggaaat cattgcttcc tatatttact ctcatgtctg 53400
ttctcttagc cttatgcagc agttcatggt cctaggctga gaagactaaa gctagagcag 53460
tagtactcaa ctgtagctgc attttagaat taactaagct acttgtaaaa ctcctgagat 53520
ccagcccact tatatcagaa ttgggaaggg cagtccggag gtcagtaatg agctggtaaa 53580
tctttaacag ccagctccta gagaaaaaaa caaaagccct gatttgtagc atttgccaat 53640
ttccatggta ttaacactcc cactgtggct gatttcaagt taccaacgtg gctttaactg 53700
gctcacaaaa ttctgatact ttctttgtct atttatctgt tgatgaacat ttaggttgat 53760
tccataccat ggtaattgtg aataatgctt ccataaacat gggaatgcag gtatctcttt 53820
aacataatga tttcatttgg ggagaatata tacccagtat ggtgactgcg ggatcatatg 53880
gtagctctat ttttattttt tttgaggaac ctgcatatta ttttccataa tggctgtacc 53940
aacttacatt cccatcaaca gtatgcaagt attctcattt ctccaaatcc ttgaaaacat 54000
tatctttgat ctttttcata atggccattc taccaggtgt gaggtgataa ctcattttag 54060
ttttgattta tattttcctg attagggatg ttgagcattt tttcatatac ctgttggtca 54120
tttatatttc ttcttttgag atatgtctat tcaaatccat tgaccttttt ttttattttt 54180
gagacggagt ttcactctta ttgcccaggc tagagtgcaa tggcatgatc ttggctcact 54240
gcaacctctg cctcccaggt tcaagtgatt ttcctgcctc agcctcctga gtagctggga 54300
ttacaggcat gtgccaccac aactggctaa ttttgtgttt ttagtagaga tggggtttct 54360
ccatgttggc caggctggtg tcaaactcct cacctcagaa gatccactgg ccttggcttc 54420
ccaaattggt gggattacag gcatgagcca gcacacctgg ccttttgctc atttttaatt 54480
gggttatttg ttttcctact attgattgtt tgagttattt atatatttgg gatattaact 54540
ccttatcgaa tgtatgcttt gtaaatattt tttcccattc cttaggttat ctctttcctc 54600
cattgattgt ttcctttgct gtgcagaaac tttagtttga tgcaatccca ttcatctatt 54660
tttgcttttg ttgcctgtgc tttgggggtt atagccgaga aacaattttc cagaccaatg 54720
tcaagaaatt ttcccttatt gtttctttct agtagtttta ctgtttcagg tcttacattt 54780
aaatcttatt ccattttaac taggcttatg tgtatgttgt aagataaggg tcccatttca 54840
ttcttctgca tatggatatc caattttcct tacatcattt gttgaagagg ctgttccttc 54900
cccattgtgt gttcttggca tctttgcaaa gatcagttga ccttaagtgt gtggatttat 54960
ttctggactc tattttgttt cactggctta aatgtctgtt tttatgccag tatcatactg 55020
tttcgattac tatagctttg tagtatattt tgaaatcaag tagtgtgatg accccagctt 55080
tgttcttttg gttcagattt ctttggctaa ggtcttttgt ggccccatac aaattttaga 55140
attgtatttt ctatttctgt gaaaaacatc actggatttt cgatagagat tgcgtggaat 55200
ctgtagattg ctctgggtag cgtggacctt ttaacaataa taatgcctcc aatccatgaa 55260
cataggctat ttttccattt atttgtttct tctttaattt tttatcaata ttttatagtt 55320
ttaagtatac agatctttca tcttgttggt taaatttatt tctaagtatt tttgtggggg 55380
ggatggtatt ataaatgaga ttgttttctt gatttctttt tcagttttct tgatttcttg 55440
ttgttagtgt atagaaaggc tacttactta tgtatgttag ttttgtattt tacagctgta 55500
ctgagcttat tagttacaat ggaatattat tcagtcttta caaagaagga aattctgtca 55560
tttgcaacaa catgggtgaa cctggagcac attatattaa gtgaaataag ccaggcacag 55620
agagacaaat attgcataat ctcacttata tgtggaatct aaaaagttga attcatataa 55680
gcacagtgtt gaacggtggt taccagggca ggaggcagag gtatggagag atatttgtca 55740
aatgatacaa agtttccatt aaaatgaata atttctggaa atctattgta taatatgact 55800
atagttaatg tatttgtata ctcgaaaatt gctaagggag tagatcttaa atgttatcac 55860
cacaaaaaaa agtatgtgag gtgatggata tgttaattaa cttcatttaa tcattttaca 55920
atgtatacat ttatcaaaac atcatgttgt ataccataaa tagatgcaat tttgactaat 55980
cgtaacttta aaaagagtgg aaggagaaat gcaaaaataa tctatttttg caagtagaga 56040
agaactggct ctagtacatc attgggtgga atccaggttt cattattttt taaacctcac 56100
gcaatatggg gccaaggatg agcttggcca aaaccagagc taccaaaacc agagttacat 56160
gggagccttg gggatcttgg ggatcttggg ataatacaaa caaaaaaagt ctaatgtaaa 56220
gcataaaagg ggaagggaag agagtaatga agaaaactag cccctggaat gcaatacaga 56280
acaagacggt cacagctagg gtaacaagag ccagcttctc taaggtcggt tatctcttaa 56340
gacatgccta ttcttcattt gggttttaga atgccagtgt cgcggacact tttactgact 56400
gcttttcaag gaatataaag atacattctt attgaaaata actgcttccc atgtgtagta 56460
attaaacaaa taaaccctta ccaatactga gtattcctga ctttgttctc ttaagctttg 56520
tattgcttat gggataaagt ttgttcccaa acaatgaata aaaaacaaac tagatttcca 56580
atgaaattta gaacttgggt tgactctcac tcccctctca tcacttcaac aagatctgca 56640
ctgtgtaggg gtacaggagc agagtcacca aaaaaccaaa ccaaaacaac aacaaaaaag 56700
ggggaggcgg ttaagtagaa caggtctggg aaagttatcc tctctaaagc tcatttccca 56760
ttctgtaaaa ttgggagtca ttcacttccc cacagggtta ctgtgagaag gaactgagat 56820
agcacatgaa aaacagatgg tacagtacaa gacacccaat aaaatgtgtt tatagtaata 56880
caaaaatata tgtagccatg gagaacaact acccttttca gaagagttaa atttttcatc 56940
atagactctt ccattgcttg tcatctgtct tcttaattag gatttttaaa aaaatgtctc 57000
cagattccag atttattcat gttgtgaaag aggattaaga gggaacacag ctggtctaag 57060
ccttgaccaa gtgtgaggga cagaaaacaa gctaaggatg cctgagcccc acccaccttt 57120
gccgaaacac cttttgaaca tctcaattgt ggtacttagc ctaattaaca ccacagattc 57180
aaacagcagt aaatactctt cctagtaacc ttcttaatgt tctgtggagt cagactctat 57240
atctggaccc taaatccata cttttccttt ctcccttttg ctatcttacc ttaagtgact 57300
accttcatcc aatgagtgtt gttgtaagag ccaaatgtgc cctctgctgc ctcatttctg 57360
ttcaacctca aaccgcatcc tggttcccct tataatcaat agttataaca agtcactggt 57420
cacacagaac tcccttctag tcagttactc cattcatttg gaatgtctct taagatcaat 57480
actcaccaat tttaatggtc ttcttgctca ttcaagacct caagggtcag gccaatttaa 57540
aagaccatcg gtataaactg agatgatgtt gtcctgattt gtacataatt aatcataatt 57600
gtgatcattt tcaacaggaa gaattcagtt atggggacat cctattgcag tagactgggc 57660
agagccagaa gtagaagttg atgaagatac aatgtcttca gtgaaaatcc tatatgtaag 57720
aaatcttatg ctgtctacct ctgaagagat gattgaaaag gaattcaaca atatcaaacc 57780
aggtaggaca tatatacaag attagttttt caaaacattc tttaaaagca cctatgcttg 57840
agatgacttc ccataacttt aagtagaaat gcttttattt agctcatctc ataattgcat 57900
gcaaacctct caaactatgt tcctaacttt ggattagaaa atcaagccat atggtcctat 57960
aacatttatc aatattataa ttttatattt atctatgtga ttatttaatg aatacctatt 58020
ttcttcacta aactataaat ttcatgagtt tttttcccct cttattgttt cctccttcct 58080
cggacattta agctctgggg tacaatgatt gctcaataaa tatttactgt aataaacaat 58140
gcatgccata actatatgtc tgatgcaggg tttctcagcc tcaccactat tgatattttg 58200
gaacagatca ttcttggctg taggggtctg tccagtggat tgtaagatgt ttagcagcat 58260
cccaggcccg tccctgttag ataccagtag caacctccaa gatgtaataa tcaaaaatgc 58320
cttcagacat tgcaaaatat actctatggg tgggcaaaat tgccccagtt tagaaccact 58380
ggcctaacgg aatacacttg tgacataagt aaaaggtgac aatcctagga acctcattta 58440
aatgaagagg aagggaaagg aataaaggga aggtggaaga ggatagttag ttgctactca 58500
tcttgccaat atttttcagt atcaattcta agccaccaga ttgacttccc atctctttct 58560
tcttcatata ggagctacaa cactgagaga ggtagagcat ttcaagaaac aatgtgcaaa 58620
ttaccatttc ccaaaaacag ttcagaacat taattctata atcttttggt agatgttact 58680
gataaaagtg ctccatggtc aaataaactt gtaaacacca gattctgcaa aattaaatta 58740
atttcttcat tatggaactt atcagtcttt agccttctga catgctttga aattctccga 58800
gatacagaaa gcttcatttt tcaaatttct gaagcacgac tgctctttgt tggcatatca 58860
tcttgtggga ttactgtgtc tttaaacaca ctctgggcag cagtggctta gggttatcat 58920
agtagtaata tcctttcata actgagaatg tcccagcctc ctggcaaatt ctctaggttg 58980
ttaataaaca taggccatgg tactgtcatg ttaaagctgc ctgagaatat tcacttgcac 59040
atactcacat tgtctgtttc caactctggg tgctatttca gatagaacag aatgataagc 59100
tgatgatttg ctctgaagga tattcagtaa ggatgtcact gctccatttt gaaagactca 59160
ccaaggatct ttctccagcc tcaagaactc tgccttccct gaaatattag tgtcatggtg 59220
tggctccaca ccaacagctg tgaatccatg actaagctag aaactgcaaa cgatggacta 59280
ccttactgtg tgccaagcat tgcagtgggc cctttcacag catgtgtcat ttattcatca 59340
caactctata atacaggttg ctttattcat tccattactt tatagataag aaaaccagga 59400
cccagagtag ttaagtggtt tgcccagggt cacacagcta gcaggtggca gatcctggat 59460
ttgaactcga atctggtaaa ggacatgttc ttaaaaactt taatactctc atgcccaatc 59520
tttattgcat tcactcactc attcattcaa ctgtctttcc ttcagtagct cctatgtgcg 59580
aggcactggg gaaggaacca acaagtatga tgtgtgcgtg gaaaaagttt aagaaattcc 59640
agaaaaaata catcttaggc agactactct tggagtgaag agaagatttg tgtttcgaag 59700
tgacatctaa gctgagatct gaatgttgat gcagttgtag gcataggaac cataatgtgt 59760
gtgtataaat attgcccact attctcccct cattgcatgt tgactttcta ccttcccaga 59820
gtgaataata cttcttattt ttatctaatt aaaacagcac cctttttttg ccaagggtta 59880
gaatgagaaa ctactaaaag gctgcttcct ttcctagtcc ctggtcatta gctttcccag 59940
tctgtgtatt ggcatatatt gaagagacat gtgtgccaga atcctactaa ttatcgtgaa 60000
aataatgaac gtcacatatc tctctgttgc ttgctctctc actttctctt tcttcttggg 60060
actaaagtgt gtccagagat ttcaggtcat agtctgcagc tggtggcaca actctcaggg 60120
ctatataatg atgtgtggct tgttcttcct ggccctctgc aaaaaaaaaa aatatgaatt 60180
gctgaaggtg aacaactagc agacatctgc tgcattgaga gggaaacgtc agagctaact 60240
agtttgtttt atcttggaaa gtatgtactg tgccaaggct atacttatct agaaaaattt 60300
atggaaagaa acaggaaaat gactctttaa aaattccatt taaagtttag gtccctcaga 60360
ggaacctacc tattacctca aaatatttga ccatgtatca ttttaaccat gatgaacttg 60420
aataatacta tattgccact cagagacata aatgataatt attaaacaaa ctcctatgca 60480
ctaaagaaga aacatattaa aataagccat gtggtgaatg ctattgtgga gaaaaccaac 60540
ttttatgaca caaactctaa ctttttaact tgtctgtttt ataagactaa atttttaaat 60600
atcaaatttt ccaaaaccag atgcatctgg aaattatcca acagtgtaag ataatttgaa 60660
atatctgcaa acagaatttc agaaaatcta aattcattat catctgaaat gccacctaac 60720
tggtgtagat gacagaagtt ggggtgtgaa ttaactgata atattccctt attccatgtg 60780
tatttataga gtaactcctg tgtccaaggc agtagacagg aaccaggtga agatgatgcc 60840
acaaagtctc tgaagcaggt cctcgtctca gggagataac agtccaggga gtctaggtgg 60900
agaatgacat tgaaatatga actgagcaaa gactggaaag gtgaaggtca tcattggcca 60960
atgtctttct tctcaattac aaaaacgagt cgtgggattg agtcatgatc atcaccccgt 61020
gtgacactga aaggagtgaa gagactatat tggatattca gttaattata tgtcccatgc 61080
ttcatggtct cagagagctt tatttatcct tagcctggcc agatgatttt gctctgtata 61140
accattgcca taagaagtca agggtcgaat gttgaaggga gtgtaaagag aagtatcaca 61200
atgtctttaa attgtcctta tgttacaggt tcactattat tccaaaggaa gataattctt 61260
agtcattgaa ccatgtgaga gagtaaaaac tctaattacc tttgttacct tgaatctaag 61320
aggataatga aactttgata gggacagaaa ggacttcccc ctcttctttt ccctggaata 61380
atgtctcatc ctatgttgtc tccctagact ctcaaggtac acccaagtga gtgtagggta 61440
aaagaagata attggcatgc taaactaaca gtggttaaac aaatttccac cttaccttca 61500
ctctaagcaa aaggtctatt tttaaaattg agtaagcaac aacattttaa aaatacaaca 61560
tccaactatc tcggtacaac tatctttttc aattttatat gttgctatca tgttcagcag 61620
ttcctttaca taaaaataga tggtttgttt gggttttcta cacaaataac ataaataaat 61680
tttgcaaata tttgtaaaat gccaaatata tcaattacaa tatgaaaatc cccctcattc 61740
ttcccaactt ttctccccat tcctgaagta acccctgtta agagtttggt ctctatcttt 61800
tcagtttgct ttctgtataa gtgtatttaa attttgtgca tatatatata cagttttgga 61860
ttattaaaaa cataaatgct ataatattgt acttactatt ttataacttt ttaaaactta 61920
acagtagatc ttgggccagg catagtggct catgcctgta atcccaatac tttgggaggc 61980
cgaggtgggc agattacctg aggtccggag ttcgagacca gcctgatcaa catggtgaaa 62040
ctccttctct actaaaaata caaaattagc caggcacatg gtggcacatg cctgtaatcc 62100
cagctactca ggagactgag gcagaagaat cgcttgaacc agggtggcgg aggttgcagt 62160
gagctgagat cgcgccattg cactctagcc tgggcaacaa gagcaaactc tgtctgaaaa 62220
aaatatatgt atacgtcttt aatctttgca tgtaatcaca tacaggtcta ttttctgtat 62280
agactccttg gtgttggtat aaatgtagca gatttaatca ctcatgaaaa tagacattaa 62340
attgttttat ttttgctctt tcaacagtag tgtaattgat attcttatgc atgattcttg 62400
tacatgtgtg tgagtgtttc tgtatgagac attcctcaaa gtagaatagt agatatttac 62460
attgtttcca gtctttagct atcatgacag caaggcaggc aacttatctt ggttcccgga 62520
tgttcttgtg gaaacaactt tctttttctt ctttttgctt ttctatttaa agattaatgg 62580
ataaggatat agggaataca gttgtagttc ctctctgtgt ggactctaaa tctcagttac 62640
cttatcagaa ctatagttac ctaatattta agttttaaaa agtaaattaa agttaattat 62700
ataagacaaa agagataaag acattttgct gggatgaaaa gcataaaact taaaaaagta 62760
atcacctaaa tatacgtttg taaaatgatc aataattgag ttcaactcaa caaatatttt 62820
gccatgcaaa aggtactatc ttttacatta cataagatgc aaaggaagat ggaattccta 62880
cccttagaga ccttataatc taggaagtgg aaaacacaaa tccataacaa attataataa 62940
gtcagaatat aaattttatt tttaaaactg caaaaaaaaa atcttcagtt gaatgttctt 63000
gatgagatcc tttcttaaat atgagatatc catgaaaaaa tccaatactc tttgcagcta 63060
ggtgctaaaa tatatcactt tcaggcctct cttaagtttg ttaatggggc aactttcact 63120
ctattttaca ggtgctgtgg agagggtgaa gaaaattcga gactatgctt ttgtgcactt 63180
cagtaaccga gaagatgcag ttgaggctat gaaagcttta aatggcaagg taaggtagaa 63240
caaagaaaaa aatatgcaga ttccatccaa gtttggtgcg gacattacat tcaaaagcac 63300
agtcctgcga gtctgtctca ctccagcctt ctctgacatg gctgcctcag tccatttaag 63360
atgtactaaa gagaaatgat ggaaaataca atggaaattg gagatgtacc taatatatcc 63420
aactttagct ctattttttt tctaatttgg acaaggcact gaaactcaat ttccatggaa 63480
agaggagatt gaagtagatt atttcaaggt gtttttcaca attccagttt tctctcatta 63540
cttcaaagag attatcatca ttttattgca gtattttaga agctgatgaa ttaaaaacat 63600
gtcaagatag ctgttattct gccttcatag tttgatcttc cacttggaaa gcttagagtc 63660
tctcaccttg ccaagagtcg gggctgggga agcttctata tcctcactac tgagttgtat 63720
acagaaacca atataatatt tatgtatcaa gccaataaac atttaaaacc ttctatagac 63780
cacttatcat gctaggatac aaaaagaatc aaagatgttt gacaaacagt taaaagttgg 63840
ttggaggaat aagacaacta cacaaacatg tgcaaagtac agtcaagtaa atatcataaa 63900
aagagatcaa cgtggtgagc aagttcgaag gaagaagtgg gccataaaga ataaaacatc 63960
ttcatggata tgagaagata atatttcaaa gaagccatga aaattgggta taatttcaaa 64020
aatcaaaata tggaaagaca ggcagtctta gacagaggca cagaatttga gaagagcaag 64080
acaagattgg agaacaggaa aatgtggagt aacttggttg gaacataatg cacatgggac 64140
tgttttacct atcggatctg gcatcagcca gggtcccaaa agaaaacaaa tagcaaagga 64200
attaattaca aaagtgtgag ttggggctag ggaaatcaaa aaaagagtgt cagaatttgg 64260
ggctcacagc attctggagt caaaggtaca aggggctgga gaattaatag aaatcctgaa 64320
agcggagaga attgtgtaga gcagatctct ttgcaagaag tagctgggtg cagtggctca 64380
cacctgtaat ctcagcactt tgggaggctg aggtggaagg attgcttgaa cccaggactc 64440
cgagaccagc ctggacaaga tggcaagacc tcatctctac aaaaaattag ccaagcatgg 64500
tggcatggac tactatagta gtcccagcta ctccagaggc tgaggtggga ggatctcttg 64560
atcccagaag gctgagactg cagtgatcta tgattgtgcc attgcatttc agcctggaca 64620
acagagtgca accccatcat taaggaaaaa aagaaaagag aacagaaaga agtagtgatt 64680
ttggtcaaag gacacagtca gcccaaggtg acctttcaaa gagggatcca gcagaataaa 64740
tgccccaaat tcactgttgt ctctttctcc aacctcctac cagcattccc cattggctaa 64800
atccaatcac aatctagaag gctaaagagg accccatgta gaatagtctc ccagagcaga 64860
gagcaggctg gagctggtag gtggtgaatt ccatagggag tggatccaga tggcaaaggg 64920
aggatctctt agcctagacc cttcagacac tgtgaagcct cttgcatatt agctcctcaa 64980
gggcccactc aaactcaaaa atatttgagt gctggagggt gggttggaga atgtattcac 65040
tctgaaatac aaaaaagaca actgcaaagc aaaaactaat gcatagttaa atacatgtct 65100
ataaagaaaa gcattatttc atcttcattg attatcacat ttaatatcat aaagtgttat 65160
tacttggaaa acaatctata agttcgattt tctctatatg gaaacattcc tgagtataca 65220
cgatgattgc tgggaaggaa cagccatcac aaattaaatg ccaataatta cattggaata 65280
attacaatgg aaacatattc aaattattcc caatttttgc agctagatat ttttatagta 65340
atatttacac atattattta gttaaatata tatttaatat tatacttgac tataatacag 65400
tatggaaaaa tctaaagtaa gttttcctag gaactatggt ttttgagcat atatatagaa 65460
atttatattt aatttattag atgaggtgag atcttgaatt tttttgtgca gtaattatca 65520
catttacaat ttaggaaaat taacctagta agaattgcct ttttaataca ggtgagaaaa 65580
acatgtcata gaaactagtt ataaagctat tatagtcacc caaatgggac aaaataaggt 65640
cttgaactta ggtaggaatg gaatgcagga gacaaccatg tacagaacag taggggtaaa 65700
ttcaaaggac ccaggaactg attggagata ggggtgaaaa agaaggagaa gtcattataa 65760
gcttccaata tgggaggttg ttatgaaatt caggaaggga agcctattca gagagaaaaa 65820
taatgaattg agcttcagaa tgattattca tttattccaa gtctgtgaag tgaaagaaat 65880
tttactaagc ttgggttata ctgattaata agatgttgtc ctagctcttg aaatatctaa 65940
actaaataac taaaatacaa tattgagttt aaaatgcttt tggatgggac agaggaaggc 66000
agaacaaaat ttattacaag aaatctgaat ttgcagcaaa gaatcattcc atgcaaaatg 66060
tatcttgata tggaagtgcc tataagcaga gacctatttg agtctctcat cttcctcaag 66120
atcagactga agatataaat aatcttatac ccaaggtcct cccctatttt cagtatgcca 66180
gttctatttt ttctaattac atcaacatca atataagatt gttgaatatc agctggattc 66240
tatcagagta ttccatctaa cttatttgac actggctcct gctactaaaa agtaaggtaa 66300
atacataata ctggagacaa accgacccac aggctgaaca aaatggtcag gatgaccatg 66360
aagcacaagc tttgtccagc agacttcgat aatccaggaa ccactgagtc acggttgaaa 66420
tcagagggta agggtgcaca ctcagctgct gtgaatgtga atttctgtag aaacacttta 66480
aataaaagtc ttctgtatat aaaacagagg atcatcacat tcttattcaa aaaaaaaagc 66540
cacaaatgct ttctgacaat actttgttcc tttgataata aatacatcaa tctatcaaga 66600
atttgttgag agccatgttt gtttcttgtg taggtaagca atacatagaa gttagtagca 66660
catgtagatc tacatacatt cattatcttc gacatctgga gctgttcaca atctcaaaat 66720
ttgtggcaat aatttttgag gacaagtttt aagcggtgca tgatctgaga acctcaatac 66780
tactctcact cccaactact cctgaccact gtcatccctg tttattagtt cccaactgtt 66840
cagcagatca aaaggtggct tcacaaggaa gaacctgtgg caggcaatgc aacagcctcc 66900
cagattcctc ttcctttggt agagccacag tatgcctttc ttctcctgtg aaaatttact 66960
tgtgcggctg atttaaggag caaggcagtt agtaggctat cagctggatg ggcctgattt 67020
ggctgcccat gctaaatgct aataattgat aagatttcgt tattggtttc ctttcacctt 67080
catcttattg tgctaggtaa tggagatttt ataccatcca taacaaaact aaattttatt 67140
gtagttatat aattatatag atatgtaatt taaaacacat atatgaccta ataaaaatat 67200
tacataagtt tctgtctcag tgactgtaac cagattataa atttataatg aatatgtcaa 67260
tggacaccgg ccaatatgtc actgtcaaac ctgttggcat cttatgcatc ttaccaacaa 67320
aatgggtcat aaaaaattca actggcatac aaacacaaac ctataaaatg acaagataca 67380
atcaataaac ctacagcaag tagtctaaca cttagaagga atcatgttat tagggctcag 67440
ccacacttgg ttatctttgt atcatctcat gttgattttt ctttgctctc tacaacaggt 67500
gctggacggt tcccccattg aagtcaccct agcaaaacca gtggacaagg acagttatgt 67560
taggtacacc cgaggcacag gtggaagggg caccatgctg caaggagagt atacctactc 67620
tttgggccaa gtttatgatc ccaccacaac ctaccttgga gctcctgtct tctatgcccc 67680
tcaggcttat gcagcaattc ccagtcttca tttcccagcc accaaaggac acctcagcaa 67740
cagagccatt atccgagccc cttctattag aggtaactcc agtcagatct tgctttaggg 67800
taatcccacg atttcaaatg actcgaattg cagtagcctt agatacattg gatgggtcca 67860
ctgggagaaa agcactgaaa atttttttat taaaaatcaa gtattatatc aatagttttc 67920
ctttgatagg agtctttttt cacattacaa ctggttattg aaaaaacgtg gtcagaacat 67980
tgtgcaaatg agcctagtgc acagattcaa actttacatg ggtccataaa atttgcacaa 68040
actaaaacct agttctataa ctgttagctt cttttgtatc acttgtccac cattgtgcag 68100
tcatctgtgg ctcattacaa cacttctgga atagactagt atagtccagt ggaaaccaat 68160
tacctcaaat agcaaaaccc tttcaaggca tgtgtgtatt tgatggtgac tcagtggcat 68220
tgtcttaata tacaaatcac aaattattat aaatataatc taacagacac acgagaggtt 68280
ctcatctgac gtcctccaag aaatatgtgt tatactttct taaaaaccaa attattaagg 68340
aaattactgt atttctttag tacatggaga actaaataaa caccaaatag aaaaaaccct 68400
cagactgcta ataaaacaat aaacatttca catttgaatc ctgtaagaat tctaaatgtt 68460
tgagtagttt tccaagctcc atttcttcaa ggaaactaga agataaagaa agcctttatt 68520
ttatttccaa gaaactagct tatccctgcc tttttggctc cttcagatta gtttttctag 68580
gatatggcta atgctaactg aatcccagtt ctgtcctcta aatacgacat gaatctgggc 68640
aatttgataa ataaactgtg tatttaggtc tattcttggg tttgacttag aagcaaagag 68700
gcaaatctag attactgtgg aaacaattat cttactatgt tttactattt ttcagtataa 68760
ctgaattgat catgctagga gctctagtct tcaacggcct taaaagtttc atactcataa 68820
ttacttgccc caaaatttta atgcaaatta aataatcagg atttccttta ggataacttg 68880
tctatgtgac aataaattat atcattgtaa cattatgcat ttataatgaa aaatcacatc 68940
attaaccaat ccatacatta aatacaaatt gtcaaccagt tatgatgtag aaaaaaacaa 69000
actccactat aatggaaaaa aatgcctatc ttataacaag aaaggaatca atgaatgata 69060
ttcatggatg aagggtaatc aatttaattt tgtatctcta tgccaccaac ataaaatcaa 69120
agtagcaaca tggcaaaaca aaaatcaaaa ggaatctatg catgaaactc aatggaaact 69180
taagcctcac attgaccgaa catcagagag aggatggtga acctaaaagc atgctttcta 69240
aatgcttgtt ttccaataag tcactggagg tgggataatt agagatgcca gaatttattt 69300
ctaatatact gatcagcgac agtctctatg caagactgat ttcaaaacaa gtggtcgcat 69360
tatgttggaa tgttgtaata aatacattcc cagtctttat tagtctatat tagaaaatat 69420
caagaaaata tcaagaaaag gtaacctaaa gacaaaaatt gcaaaatttc tctcccaaca 69480
tttttaagtt gcttatgtac ttatcaacag tattgtactt atcagtggca tggctttctt 69540
ctgaaggtag tttttcaaaa aagagaaaga catctatctt aaaccttacc ttatgttgag 69600
tttcattaca ttagaatcct agagtttccc acccatcttc agggcaataa tcaacgtgaa 69660
ttgggctaac ttttccatta cagtaagatt cagggtgatt ttctggtggt ttgattcagt 69720
ttaatgcctt cttacattcc tagaaattta catgaatgta cctgtagggg ctgcgggagt 69780
gagaggactg ggcggccgtg gctatttggc atacacaggc ctgggtcgag gataccaggc 69840
caaaggagac aaaagagaag acaaactcta cgacatttta cctgggatgg agctcacgcc 69900
aatgaatcct gtcacgttaa aaccccaagg aattaaactc gctccccagg taggtaatgt 69960
tattccagaa atagtttctt taagttgtgc caatgagcat cattcacttt taccaaatga 70020
tttgacttga tccctactca agctatgggt tttttttttt cttttaatat ataaagcatt 70080
caatcaatgt cacacccttt gagggaatgc tgggcatcag gtgccgttat tctattatag 70140
gtcctttctc tttttaaaaa aatcttaaag cttaacacct tgaacaatat tccactgaaa 70200
tgcaaagaat ctgagagcta ttaagaatta tcaacccata ccctaaatga aaataaaatg 70260
aggcaaagac cccatctcag aataaatgcc tattgtatgt gagccaggtt ggttggcaaa 70320
tgaagggcat tatggcagag ccctgaaaag accatttagg acatcttttc ttggaaatac 70380
tgtatctaag agaaaactcc accatgatat ctaggtgaat tactaactag gagatgtcgt 70440
cagtcatacc aaattaactc ttcctccata gttatattgc ggcagtggca ttacagagag 70500
gggttttttt gtgttcattt aagagttcta agtttccata cttcaacatt aacctgtgtt 70560
ttttattatt ggaaaattaa aagttataca agtttcaata cggaaactga ctcccagggt 70620
taaaaataaa acaaaacagg gtctatgcta accctgagac tgttccctgt gggagtgtga 70680
taggtgctga tctctctgaa atatattttg gctgaataat cagttacagt ttgtgtgtct 70740
taaaggaaac ttccctattc ccatgacaaa ggtgggctta tagccccaca tttatggaag 70800
tagcccttat aatttcaatc cagaagaaaa cttggttttc taaaagctca tctggggtaa 70860
tttttcaatg ggatttctga ctttctttta tgcacaaatt agcttatcta aggtttctgc 70920
tagccccacc cagggaatta aaaaaaaaag aaagcctacc agagtgctaa acagcaatca 70980
tttgtttgtt cacaaaagat ttagtaaact tctcttatgc accatgtagt gcactaggtg 71040
ctggagatgc agaagtgaat ataaagaaat ccttaccact aaaaattaga tggcaatcca 71100
gtgggaaaaa aactgacaca taaacatata accataatga aatctggaag tgatatgatg 71160
aagtttgttc agaaaatata aaagccagtc acccagtttc tcttgggtta aaacccaaaa 71220
ccaagaacct gattaaagta ctggaatcct tagaaatctt ttaagaaaat aaaaaataat 71280
agacacaaat tctgtataat agtagttctg atagctgtga tagtatgaaa agagatctct 71340
tcgtttcaca tcaaactcaa gttagaaatt catcatgtct tatattaata tgtcagtaat 71400
aatctctatc aattaataaa agtgtctctg tccccagaaa aataactggg gacagccagt 71460
gtacccgctg cactctgcta ttggacaaga ccaaagacaa ctattcttat acaaaagaca 71520
aattaataat attgttctct gaccttctac aactatggct tagaaatgaa caccatgcca 71580
ccaccaacca atatagatgg ggcctaaaca accccaaagt agagttatga acttccagcc 71640
agaagcagag acaaatactg ccctgcaaag tcagcagtga gagctggtgt tccttccacc 71700
cgggtttgct cacctggcat aaacaggcag gcatcatatc taccagcaaa agctccatta 71760
gtattgccca agaactgtag agaatgctct gaggatgaca agagatccta cacaacaaga 71820
gtattaaaaa gaaaatgtca atagagaaaa taggaacaat ctacaaatta ataaactgga 71880
aaatatcatg ctattgcagc tgggttagtt agcataaatg aggtaagaaa ccccagagac 71940
acatcctgag gcactgttct gtcttccaga gttattttct cagccttatg ccctgctttc 72000
cacagtctac tgaatctgct gactaacgag agcgtcagga cctctggaca accaaaaatt 72060
gcttcagaat aaagaaacta tgaatcttta gaaaatattc agtttggagt aattacagaa 72120
gaaaacaacg tgcaggagga tgctaaaaag catattgtca ttaagcaaaa gaaaaaaaaa 72180
agccagaaat agtgtcttac caaacaaata aaaacattac aactgtcaac acccgtctag 72240
gaatgctcag taaataccaa tccattaaac tttttaattc tatttttatg aaattgtgag 72300
attaaaaccc tatggcaaat gacatgaaat aaaaatatat tcttaggtta tcatctctaa 72360
acgattataa acacagagac tgagggtaat aatgagtaaa tctatacaaa tctatgcaca 72420
cagtgttgga gcaacagttt ttacaaaaac aaatattcca aacaaatcat aaaattaagc 72480
ttttggtaaa aagttacagc taatggacta aactaaaaat atattacagt aaatggtgtg 72540
aaagtgattt tatgaactaa tagacctaac attttaaatg gagttcaaat tgagttcatc 72600
ttaaatttta tgagtcatta aaccatgtgg cattttatat cttctgatat tagcttgaac 72660
tctgaaaatt agagtttaaa aatctgaaaa cttgggatat aatgtgaatg tgtcatttga 72720
ggggaaaata acttttttta ttcttgtaga tattagaaga gatttgccag aaaaataact 72780
ggggacagcc agtgtaccag ctgcattctg ccattggaca agaccaaaga caactattct 72840
tatacaaaat aaccattcct gccctagcca gccagaatcc tgcaatgtgc gtaacttctc 72900
caaattcctt accattttag agcaggatac gcttctaaat taaatgcact taatcaccat 72960
ctaaacaaga tactgaggtc tactacctac tcatttgtca ttaaatgtaa gcattgaaat 73020
gtatagttgg gatgtgccag ccatgaagct ggcatataaa ggcccccaaa tttcatatac 73080
acaatgaagg ttgtgtagta tcaccaacca ttggaaaaca gtcagtagtg taaaatgtaa 73140
tagaaataaa aactatagcc cattcttggc tgggcgcggt ggctcatgcc tataatccca 73200
gcactttggg aggctgaggc aggtagatca cttgaggtca ggagtttgag accagcctgg 73260
ccaacatggt gaaaccccat ctctactaaa aatacaaaaa ttagccgggt gtggtggcag 73320
gcgcctgtag tcgtagttat tagggaggct gagacaggat aatcacttga acctgggagg 73380
tggaggttgc tgagatcatg ccactgcact ccaacctggg caatagagtg agactccatt 73440
tcaaacaaac aaagctatag cccattattt catctgtgca atgtttaagt tgaagcatat 73500
gaaattacca tttttataca taataagaca atggcccatc atttaatttg ggaccaaata 73560
tatgacctct ctgttagcgg atatcacctc ctgaatttta ccatgagcct gcatttctat 73620
atcttttaga aacaatttgt ttcacttgtg ctttagaaaa ggcatgtagt gaattatttg 73680
tatgtcccag gaatgtcata aaccactgat gttctagatc aatttgtaaa tattcctaca 73740
tgcaacttat atttagaagc tttaatagca aacagaatgt aaaacaccca ctcaaaaaac 73800
caccatccag tcattttaca aaactgatag tgccttaggt tttcacctga ctcagttgta 73860
ccagtttaaa aatgcctacc ctgactgact tgctttccag ccaccctttc acacctccga 73920
agctgagtgc ctatgtggat gaagcaaaga cgtacgcagc cgaatacacc ctgcagaccc 73980
tgggcatccc cactgatgga ggcgatgctg gcaccatggc tactgctgct actgctttcc 74040
caggtatggg aaaattgtgc cagaaatggc gccctgcaga gagtatttgg gaaacccttt 74100
tttggtacca ctgaatcata gaaatgtttg tgtaccccac ttacggcaat ctgacttgca 74160
ccacctgggg accaaaaaga gtttcccaaa cgagtgactc attaaaacac aaggcaagaa 74220
aatcaagctg ggcaacagag tgggttctgg tctcggctca gctttaaact gctgtgtgat 74280
cttgaatgag tcagtctctc tgagtctggt ttgttttggt ttttactttt agtaagagag 74340
tttgaaacta cctgtagata tatgatgttt actggagctc ttactgtgtg ctaggcactc 74400
acctaaatgg tcaggaagca ttataatatc ttagtaacgc tcatgatacc accaagagtt 74460
aggttccatc agcaagtcca gtacacaaat gaagagccca tgtatgaaaa gattaagtaa 74520
tttggccaat ggcaattagc ttttcagcaa tttttttctc cctctccaat cttcaatcta 74580
cttttattaa tttgattcca aaagagattt tttaaagtca aaaattgtgt gtgtgagagt 74640
gagagacaga cagagagcct ttcaatatgt gaatatacag gactcaactt atttgttcta 74700
taattttggt ctggggcata tgctgattgc ttaaagcaaa gcctatctgt ggatcaacaa 74760
tgcgttcaga ggtcacatgt taaaagattt gtccccattt attatgtacc cacaacaaat 74820
ggtaacaatt aaaaatgaat cctttagaga ctgaagggga ccacgaagaa agttgtttag 74880
aaaatttttt ctcagatgaa aattttatcc tttttttttt ttttttttag taaaagatta 74940
tttctattga agaaatctat cattttgatt tgtcattgtg tcagcatgtt ccacataagt 75000
ccaaattaga gctctaagta tacctagaaa catgacattc ttatcgatta attaattcat 75060
atactggtca tgcgtaggtg tgagaaattt tatattttcc tcacacccac tgcacctggg 75120
gctcattctc agcattttgt tttgttttgt tttctcaaaa gttgtgaata tatcctccat 75180
tctggtcagt gaggctaata ttaatgatgt ttcacatctg aaagtgacct caattctggc 75240
tttatttctc tgtaagaaca tggagacgct ctgtggtgag tccctcggag gttaccaagg 75300
taatagctga cactgcagag ggcaaggtcc ttcctgggca gtgcggggcc agcagccggt 75360
gcttgctttc cacataacag ggtgtttaca tgtccatgta ctcaggacgc ctgctagggc 75420
ttctcagttc ttagagaaag ttgagcccct gtcttgcaga aagctgcacc ccaaagacat 75480
ctaacaaatg tactattaaa ctaatgagcc actgtcagaa gaatttcaaa gtttgctttc 75540
acgttggaaa ggatttgctt ttacccaaga atgttttatc ttattctcac ttctattggc 75600
ttctgtgaaa agttaaaaat atttggggta tgagtgttgt ctggggaatg cctaagaatc 75660
tgagagcctc tcttataact ttgctgtgga gtcaagcaaa gaataatagg ctccaaggga 75720
agaatcggtt tgaaacccaa aacaccctgg cacttaacaa attgaccaag ttgaaaaaca 75780
aaattcaaaa tccctaaagg taaaatctgt gccacgaaca catgcatgca tgtgtgcaca 75840
cgctcacaca attatattac tcacttagtt tagaaatact gtttccaaaa ttatgaaagt 75900
aactgttaac acatgtctcc tatccttgga aaatggacca aacttctcta gtgcattaat 75960
cagcattact gaccaaagtg aatgcgccaa gaacggattc aatttttgtt caaaataatc 76020
caaccagctt cctgccacca ctttctgaga agccaccaga aaaaaatcaa tgtgtctggg 76080
gttgggcagg cttctaccgc acataaacca aatgaggttt aaaacaacaa tgaaaaacag 76140
gtgtccattt gtacttaagt acacttctgt ctttctcttg ttatctttta caatttctgg 76200
atcatctcag aaatactcag gtttttagac taaaacaatg cagagaaata atgctttaga 76260
tggtagctaa catgctctct tcttcaaaag tgaatgttca tccactagac acaatgctaa 76320
catgaaagcg catagatttt ttttttaatt cttggatact ttggttctct gagggggaga 76380
accagcatca aggcctctga atacaccaag cacaggcttg atgaggggct tgggaggtac 76440
gaaggtcttc tgccattcat agttagatct aaatacggac aggttaggca tttgctttta 76500
aggtattatg gagaactaca cttaaccatt acagtatttc tcctactgat ctcccagtct 76560
ctacacatct tctcgggtaa aggcaaatgt tttaaatgtt tcatttaggc aggtgtgggg 76620
ttgcaggaga accggtccca cagaactcca cctccccaca taccatgccc ggccagcccc 76680
tcagtcacct tttctcattt ataaatttgg aaaccttcaa aaagttataa atcacaagct 76740
ttaatcaact cagcctcctg ttaagtttct ctttcttggg ccctatccca agcatcttta 76800
attctcttaa gtatgaagtg attctgacac aggtggttga tcccactttt gggaacattg 76860
tcctaggact ttttgaatgt gattgaaaat cactgagtcc acatattgtg tccttaaggg 76920
cactttttaa aacatacata ttaactttta gctttaagta atatgttaaa agttcgtatg 76980
tctaaaagaa gacaaataag ccaaaaggga gcaaatgtga attcctttca tgaagttttc 77040
tctgcctctt cctccaggat atgctgtccc taatgcaact gcacctgtgt ctgctgccca 77100
gctcaagcaa gcggtaaccc ttggacaaga cttagcagca tatacaacct atgaggtcta 77160
cccaactttt gcagtgactg ctcgagggga tggatatggc gccttctgaa gatacttttt 77220
taaatttaag aataagacac acaaaactct att 77253
<210> 3
<211> 80232
<212> DNA
<213> 小家鼠
<400> 3
gtttgatacg atgattagaa tataaccaaa gtggcatgct gaattcgcca taatcaagga 60
accttttccg ggtggggaac ctcagaaatt gctcaggtat ggcccatgct ttttgtttgt 120
attttctgtt tcaattctgg gttgtagtgt ctggtagatt gcatgaaaac aacttgtgct 180
cttaactatc tctgagccta atgcagagaa ttgtcgtcgt ttgggaatga aaccaaccgg 240
aaagctaaac agtgtcttag actgagcggg gataaatttc atggtatact tcttgagtgg 300
gtatgcttcc acaacttgtg ggaagtggag tcatccgtgg gttcacaagt ggagcccatg 360
tgctgcaaac ctaacctcca gctagctgtt ggggagagct gtgtttcact gtctgtcctg 420
atctctagga cccgacaaca gaaatgtgat taagacatag tttcacatct cccacagcct 480
tctgagttct gtgtatcctc taatacttta gacaccacct attcaattaa cttctgtgtg 540
ctactacatt ataaaaaaaa atcaggataa attcttgcta tttcttctgc tattagcctg 600
ctaaccaaaa ataatatcct aagctacttt cttttgagtc tagcaaggaa agaaaacatt 660
atggaaaagt gtgtgttttg agtgtgttaa atatcaaccc tgaagtgtct atttattaga 720
ttgctttcac agactaagca accagcacag cacatgtatt tttgcaatat catttttctc 780
gcacctaaaa gataactaag agccaaaata caatggctct aaagtgggaa atagatcagg 840
gcattttctg tcctataaga aacctcaact ctctgcctga agagccagtg ttggttcact 900
ataaataaag caagccatca agcagcccca tgaaacacat ttctgtacta gtgcaaggta 960
cggatggaag tctccatgaa aactgagaaa tcatttgtgc atcctaggag attaacgttt 1020
tgtaagccaa atattagtaa attcccactc gagttgtaat ttaggagaat caaattgagt 1080
tggtctagct tgaaacacta aagtaaaagg cagcagcatg tactgtcagg gaatggaatc 1140
tggagataaa agggaagtca cttacctgtc caaacaatca ggagttccct ggctgacaca 1200
gagaagtaga cacacctggt ttatttttaa gaccatgttt tctggaataa tagtggtact 1260
tctcagctta agaaagtgca tacagcttga tgctccaatt tactatggat taaatatagg 1320
ggaaagataa aatacagttg gctacaaaca gattgtttta agtgacactc acagaacacc 1380
ataatggatc caaaatcttg ggtagccatt ttaactagac aagttaacct gtgatgtttc 1440
aatatcaaca ttacctctac tgcacttgag gagcataggg agtcacaaac atgcgtctcc 1500
aacagtcaat caaatgagct gagtaagaca acagagagca ggccatctta ccatctgggt 1560
gctcttcagt gtaacagtaa tcattgttaa gtgttagatt accaagcaca tttctaagca 1620
catgttctaa gtttaaattc atgttattct tagaataccc gtatgaggct aatactatca 1680
ttatactata ctactatata tcatactgtt attagattga ggctcagaca aattatttaa 1740
cagacttgat gttaaaggca agtgacatag ccaggttacg cagtcaggcg gtctacttgc 1800
agagcacatg ggtgctctgt accctgtcac taggattcac tctgtgtaca tgggtgttta 1860
tcattgggac tagccaaaag aacaagtaat gcagtttcct aaccttcctt tagagagaac 1920
ttcttcctcc aggagcattt gtctatcagc atctctccaa aattttactc gttaggctac 1980
aggctaagag taaaatattt ttgcagccca tgcctatttg caatgcgcag atcaatggaa 2040
atctccacat ttggattgat ctcagccaaa ccttccaaga aatcacattc tttcacaatc 2100
ctccacaaag ccatgcttag attaaaggct ttaaaattaa tcccagaaag agtgccatac 2160
tcttttacag acataatcag gctggaacag ttaccccaga cctccctggc ctgtgaagct 2220
gtgcacatta cttgagttcc tgagatctca gattcctcgg atgtgaaatg gatgtgtgat 2280
gtgcctacag gacattataa atattattaa gtagagcact ggtgcttagg aaccagttga 2340
cctcttctac catggtccca ttaataacat ttttttttca gaaaaactta aacttaccac 2400
ccactagctt tctcaaaaca attccattaa aatagaaaac tatataaata aagaaactca 2460
ttatttacaa aagccaccgc acttctttgg aacctgtaca catacacaca cacacacaca 2520
cacacacaca cacaaaacta caaacaggat aaatttcatt ttagagactt tctcaaagct 2580
gctactaaaa attcaacatg tctgtattga catctatagt ttcacactct gacattctga 2640
cactgtacat gttaacttta ttacacagac agatggttta aaaactattt cagtagctat 2700
caaaaaactc tggtatccct ttagaatgct gggtaatact ttgggtacta ttgcccaatg 2760
gctttcatta ccacatgtgc ctgtacacga ctcagaaagt tcaaacaaga cagtattgat 2820
cgacagagga taaacactgc tttatcttat ccatggacac agtaactagg tttctctcaa 2880
gtgcaactcc aacagtccaa acttcctcag gaaaggcagt tggaagagaa gcctcactct 2940
agaggtgacc atgcatattc aacatcaaaa cccatctgtc ccttagctta agactgcaaa 3000
tctagtcagt tatcattaac aaatatttac tgccaaatgg atcaggaaag atgatttatc 3060
attttaagcc atcaacccta ttccaaacag gctatggctt ttaagattat ttagaatttt 3120
atttttcaaa tttcgtcatt tttcccttcc ctttcctcct ctcgatcctt cccaagttcc 3180
tcccattgct cttactcaaa tatatgacct gtatatatgt gtgtgtgtgt gtgtgtgtgt 3240
gtgtgtgtgt gtgagtgtgt agggtgggaa gatgatagat agatagatag atagatagat 3300
agatagatag atagatagat agatgataga cagacagaca gacagataga gatagataga 3360
tagatagata gatagataga tagatagata gatagataga tagagagaaa tagatagata 3420
gatagataga tagatagata gatagataga tagatagata gatagataga tattcttaaa 3480
tatataaata caaccgactc agaccatatg gcattacttg aataaattta gggctgatca 3540
ttttaattta atacaaccaa agttttgtgt tgaatatttc tgatgactcc aaataaaaga 3600
ctaaaatata gtcacacact gataattggt ttggggattg ggcccaggac ctctatggta 3660
cccaaattct catatattca agtctcctat agaaaaaagt gcagtgtgta cacacaatgc 3720
ttgcacattc ttttaaatac tcttagttcg ctcggggcta cttcctgtcc cttgcacatt 3780
gtaaacacta ttaaagactt tcatgctgaa ttgtttatat cttattcaag ataaatgcct 3840
gtttatgttc aagacagatg tatttctttc aaataatttt aggttttttt aaagaattgt 3900
ttatgaattt tatgtatatc agtacattgt agctgtcttc agacacaaca gaagagagca 3960
tgttgtgacc cgctatgtgg ttgctgagaa ttgaactcaa gatggggaat tgaactcagg 4020
gcctctggaa gaatagtcag tgctctaact gttgagtcag ttttctagct ccatcctcca 4080
aatattttta atctgtggtt ggctgaatct atgggtagag aacctacaaa ttcagatgtc 4140
catgtatatt cgctattgtt ttgtcttcac taaactatgc tgacatatgc aactgtctat 4200
tttgacattt tgaaatatat ctaagcaaag tgttttcttt atggctttgt ggaggaaatt 4260
ttacgtgtac cagtgttcac aatcatgtga acatgttcca ggcttgcttg ttctactggg 4320
gattgttttc tagtgatact gagaggacat agtcataaag ttatgataat tccctatact 4380
tgcagagtgc tctgtgtcag taaataatat gtctaatgag aattaccata caacaattta 4440
accagactga ctgtctaaat aagcaaactc aattacaagt ctataaaatc ctatttttca 4500
atttggtagt aatgacttta cttccttcaa taattaggaa ataactatta gttgggatgc 4560
tctattgatt taaagaacac taggtctgag tatgggaatt ccttaccctt gtactttgtt 4620
accatggaat attctacttt ataaatgtat ttcagggcca gaaagatagc tcagcaggta 4680
aaagcaatca ctatgtaagc cggaacccca agttcaattc ccagaatgca taatgaaaag 4740
caagtactaa ctatccaaat ttctcctctg gcatttacac atccacactc atacccatac 4800
acatgcacac aataatcaac aatcaataac aacaataata acaataataa taattttata 4860
aattaaatgt atgttctttg acaatttcat acacacacac acacacacac acacacacac 4920
acacacacac aaacacacac acataaggtt gctttcaacc taacctctct ctcttttgaa 4980
aaatattagt gctaattctt tgaaaattgt atacactgta ttttgatcat atttaccttc 5040
aattcctcta tgacccattc ccaccttcca taaccctcac cttcatgtcc tttttaaaaa 5100
tgtaatacct aataaccgat caaatgaaat gtgtgctgtc cgtacacatc tgggtatgag 5160
actgtccaca gatggttgac ctatcagaag ccatacctcc tcttttacaa ttctatttat 5220
gcatttattt agatatcttt gaggatttca caagtactgt cttacatcat ttatcttccc 5280
taccatcctt tcaactcttc cccatgtccc cgcaacttcc tattgaagtc atgacttcct 5340
gttccataat tattatagtt agacacacac acacacttac aaatacaagc tgctgagccc 5400
ctttagtgct gctcatatgt gtttagacct gaccactttg aactggatga cctatcaggg 5460
atttgatccc tggagaagac tgattctacc tttcccatta gccattattt gccaatagct 5520
ctccacctct ggatggagcc ttaggagatt tccacaatcc acataagcat gtcagttctg 5580
gccttgttta tatgccatat tattgagatt tcatgggtgc atcttccatg acatacataa 5640
gagatcccat ccatcaagag attgcctggt cctctgatga gccacattct aaaataataa 5700
ataaataaat aaataaataa ataaataaat aaataaataa ataaaacctg cctcttcgag 5760
aagccatcaa ctgtacacag tttctctgtt aaggctggga ggctcatgaa gtccttctca 5820
ctctatgcta gatcactgac tggattgatc ttgtgcagta tgtaggtctt ctgtatgttt 5880
tcttcaggca tctacaactg ctgagttcat aaattctgca atctatcatg tcactttttt 5940
tttattttga cctgtctcca ccatcttctc ttacaatttt tctgcccctc ttctagaatg 6000
gtccccaagt aatgaggagt gagcgtgata tataggtcac aattgtagct gtcactctaa 6060
ggtcatttat tctctgtact gtgaccagat gtgagtttct acataaacta ttgtccaatc 6120
actacaaaac agaactttct gatgaagtct gagagagacc tacactaatc aacaagtaga 6180
aagatataaa tttataggga agtttgatac tatgtcagtt tagcagaata gtagtgtcag 6240
attcaaccct ccagcttatg agttccccaa ccatgtgttc ttggccaggt tttcagtaca 6300
aagcgtgagt ttcattctgt ggggcaggcc ttaactctgg tcagaaagtg gctggttaca 6360
cctataacat ttgtgccact atggtaccat gtcttaccat gccagttcaa ggattccaag 6420
ctaaactaag actctgaatg acttttttcc ctcctaggct gcatagcacc ttccagtact 6480
atgaaagcat tccaactgaa aggaggcttc ctagtcagta ctgacttgat tcctctatgt 6540
tctgtataca atgtgcatga tgtcgccagc agaaaagtat cttattcatt tcggttgggc 6600
aactaagcaa tgtcaatatc ctctattctt tgtgaggtct ctgggatacc tctgatcaac 6660
aactaaaggc aaggtattcc acctagcact agactttggc agggagggca ggctgtggtt 6720
tttgaaaagg catcatcctc ttcatcctct gtgtagagta acatttaact attttatata 6780
actacgtgta tatgtttata tatgttatgt gaaggttata aaaatggatt cctttatagc 6840
tttttcaaac atctctagtg ttaactatcc ttcctccaaa ctcctcattg tccctatatc 6900
tttttgtctc tttcatcctt gtcctgatta atcattttgt cacattgaag tcactttgtt 6960
ttgtttgtga cccaccgagt ttgcccacta gacagttatt atgatgctga gtttggaaat 7020
aagcattgga gactaatggg ctcatcaatg ggggcacaac tgaaaacact gtatcccatt 7080
ctcccagaat ccatcagttc agaagtaagg aatagggccc tgtaagcttc ttccccatcc 7140
ataactgatt gtttgcaaag cttgtcttat gaagacccag tgcaaataac tgtagttggt 7200
gtgacttcat ggttacaatg gccatgtcat ttctatagaa tagcattttg cagttcttct 7260
ccctatattc tggcttctat atgcttccca taccttcttc cagaataatc tctgagccac 7320
agagggagtc atataagtgt atgtttaggg atgagccttc aacctatcat tcttaaaatc 7380
ttgggcagtc atgagtctct tcattcactg ctattcatgg aagagagaag tttctctcat 7440
tagaagcaag aataacattt gtcatgtgca taagtataca tgtgcagagg gcagcttggt 7500
ggtaagtcta tttatctaaa gatcagtact aaattggcct ccaggatctg tgacctcctg 7560
aaacagaata gtattgtttt cctttttaac caagtttaca acgccaacca taaattccct 7620
cttgtggagc aggcctcacc ttacatcctg agagtacttg gttagcccca taacagtcac 7680
accactaatg tgtatgtgag catatttttg ataggttaat ataatagctc attctgtagg 7740
taactgagta agaccattga tatatttttt ttctgctagt atgctaagta gcagtttctg 7800
acactttcaa gctgtacagc agaatggaag tatctagttc agttacaact tgagatgtgt 7860
gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtctgtgtgt gtgtgtgtct 7920
gtgtgtgtgt gtgtctgtgt gtgtctgtgt gtgtgtgtgt ggtgtcatca gaaatagact 7980
cttatcatct agttctggtg agcaactaag attaaagatg ggaacctgta cccagcaatt 8040
cttgtaaaag catcccacac tggatggcta ctgcttctgc aggttttaaa gtatttcatg 8100
cctaagaatt taaatgagtt taatgtcaaa cttcttcatg ctcattttag tatgatctcg 8160
tttaaagtaa atgagttatg attcaccatt ccaaggattc aagatggtta aagaaaattt 8220
ttacctgttt atgtagaata ctagtgattc acaggtcttc agctattcta gtagttatca 8280
actgacttat caatcagtca gagactgaat gaaacaataa attaaggata tatcaaggtg 8340
actgaaaagc cagttccaaa gaggcttcag aggaaagcag ccctaaaaca aactgaacca 8400
ttcagttact atggaaggat gcagggggag aaatggaagc atagacaatc ataaaatctc 8460
ctaacagact gttgggagag tgcaagccat tacagacaga tgcaattgtt ttctgtttct 8520
agcagtgtta gtgatcttca ctttcgctgt cttattgggc ttctgaatag cacttatcta 8580
ctctgctggg gctgttagca cgaagcaagc ggcttattag atgtactcaa accctattgc 8640
ttctggtatt tgttctggaa gtcagaaatc taaatctgat accatggggg aatgaacaat 8700
gttggcagac aaatcttcaa atcttctttc ttgaagctgc ataacggcac ccccacacac 8760
aatcccagca ggatatggac atttactcct aaccaactag aacttgcaag ctgtaattat 8820
gagaatagtg gtattaatca taagttaact tcaacattct cccctggctc ttccacatgc 8880
taggcacttt ggtgaaccag tttaaccctt ctgcaaaata gatgctatta ctatatcata 8940
tttccaataa agaaactaag gcttaggaac atgaagaaca agccatgcca tacgcatcag 9000
cttgcaaatt aagagcagtc tgatgattct aaacagtatt gcagcttgga atgggaagga 9060
tctcttgaca gagagaaact aaaagaatgt cccaagaata gaggatgtct ttttcaaaat 9120
agtaatcaga attcaaaact gaagccttct agtgggacat tgctttggat taccactcac 9180
tgtacacatc tctaattcag cctggttgtc tgccaattct aggtggcgta gatcctccaa 9240
tgttaataag acctctctct tcattaagtc tcgctttctt ctctatgatc agattcatag 9300
acaaacagaa actcagttaa aggaaactca gctgtgactt atggactcag aagttcaact 9360
cacagaagaa atatgtgtgt gtgcaaaggt atagtttaca cagtggcagg actagtcata 9420
gagttatcac tgaacacatg aagcaattgt cataaaggac ttggctacct cacgtccaaa 9480
ttcttgtaat gtctggaaga taaattatct cctgggaaac gcagccttct ccaactagaa 9540
agaataacta gccctgtgtg tatacaggaa gtcctggatg agaccaactt tcatttggga 9600
ctttaaatga agacccaaat gctgcaaact gtgacttctc cagtctgaat agagtatgag 9660
tcatttagca gtagagtaaa tttcctctca tatgtttctt agagaaacaa attagttggg 9720
aggcagactg agttctagca ctcaaagcct aaacaagatt gagctatgtg tcatggtgat 9780
tagggaaggg aaagttgaat agtgcaggag agagtaaaat gaaggacttg aagcaggtgt 9840
ctgtgttaac ttattaaaca agtctaactt attagtcaag ggagcatcac atatactaga 9900
cactgatccc agcatgtttc tcactgtaac aaacacatgt tgcatgtgta gtgacctgaa 9960
ctggtgtcac cctgagaatg ttattatgtg gttctttaag atacctgagt gggaatccct 10020
aaaatggggc tggcaagagc acttgtgggc tggactgatc acctgaattt gacatccaca 10080
tcccacaagg tagcagagtg gagcagactt ctgataatca tcctctgact ccacacacat 10140
accatatttg cacctaacca ttaaagcaag caaagtagaa agatgaatct ttacagtaga 10200
gttcaaatct ctcgggcttt gttattgaca tagttacagc cagagaaacc aaaaccactt 10260
cacactcaaa gctacttata aaacttcagg tgattctttt aaaagatgac tattagtcat 10320
ctaatgttag tgttacaaaa atgcaggtat taaatacaat atcctgtccc aaaatcccct 10380
gcaaaagcat agaaacttca tgaagagcat accccagaag agaaaaccaa atgtcaaaga 10440
tagggtgggg gtggatggct aagtggatca tcaagactgc atcgaaagaa ttggatcagt 10500
tcagtatcca ctaagggaca ccaagaaaat tcttccttct atgtgggact aagtggtgcc 10560
cttctgctac caagaattct agcagctcgt cttgttccaa cagtcctaaa cattgttcta 10620
agcaatctcc actccacctc tagctccaca ttagttagca gctgaccatt cttgtgaaaa 10680
acacacaaga ctgatcctcc tgtcacaagt gatacacaga tgcctacttc cctgttgcat 10740
ctggatgctg gactcaccct tgaagaagtt ggagttatta taacaacaca cactcagaat 10800
tgacttaaat cgcatgtgcc agcacctcct catgtaactt tatctttttc taagtgcagt 10860
gttgcatgca aagatgacta tctaaaatcg aagaagtctc taaagttctc caactgagat 10920
taagtgatca acactttttt acagaggttt ttcctaaaaa actgtgtccc tgttaactat 10980
ggtaaactag ttgtttccta aaggcagaaa aagtattcta ttctttttta agttacatta 11040
ttattaattt ataagatgaa agagcccccc tcgctaaaaa gatacaggag aaaggtcaag 11100
taagctttga gtaccctttg ccaagttcca cgatgcatag tcatactctc cctaccctgg 11160
tgaattgcta ctgttcctct gtagagaagg catccctaac ctgaactcag aaggaagaaa 11220
cagcttaatt aacttaaccc aaatttgcaa agtgttaagt gaaagcactc cagtcttcaa 11280
gcatcagtca atcgagaatg atggcaccat aatcatgaat aataatcaat attagatgag 11340
agactctggg ttttaatatc atgcagcatg attgtaaaat tatgtaaagc agaacaaatt 11400
atgtctggaa tgatctgaga ggttgcatgt gcaaaattga ttattattca gttgtagaaa 11460
taatgaattg gaatagttgc aggaaaatgg ataagaaaag ggaacataaa cacatggtct 11520
tacttgtatg tgaatcgtag cctgtaatat acatagaagc agacagttgg gtataatagc 11580
atttaaaaag gaggccacaa aggggtaata gtagataagg aaggacagat tgcaggcgca 11640
aggacacacc gtgtcatgaa agaagatata aaggtaattg ttcctatagt ttcaaccgtc 11700
agagtagttt tcttttatgt atgatggata aacatataca gatataattg atagggaaag 11760
tgtcaaagac tagacacagc tttgtgtcat cggaagagcc attctaactg tacagaagtt 11820
tactgagatg tatagtttag aaataggcaa gtattatttt gagttgttat gtgatgtttt 11880
tactcatgag tttatttaat aaatatcttc agtaagtaca agcaataata aagtgtgggc 11940
gttaaccatg catgtaattc cagcataggg atactgaggc agacggatta caggtttcag 12000
gacaacctag gctgcacata gaaccccatc tcagagcaaa actaaataaa caaatagagc 12060
ttttcgaatt gtcatctctg taacaagcca cacaatttga cccatacaat taaccacagg 12120
ataaacttaa aggaagtgga aaactacgta tgttttctga tcctaaaact ctcttatctc 12180
caatcatcca cccagatttc ctaaacgaaa taagtgcagt ttctaccgtt aacattttct 12240
gaactctttt cttggactaa aaatttttta aaagccactg ttccctttgt aatttttaat 12300
gttgaaagag cagtagttgt gtctgagtat ctccatttca ttgtatctga tcttcctgtt 12360
atgctttcta agggattttt gtttccagga taatcataaa agaaaggaga aatagacagc 12420
atgcgttact gtcaccactg gtcaccaggg cttcatttgt ccttgtgcat agacatccac 12480
agtcattgcc agtctgtgag cacatagcta ctctcaagac attatggagt gggtatgaac 12540
ttgttttagc catagactgt gaaaaaggac aacatccaat aagaatatgt gtacatagga 12600
atcaagaata gtcaggatgt aggctcgctg aagctcctat ccagggtatt gggctacaca 12660
gactgttaaa agcctctaag gtatggtaag gtaaggtact tggctctttc ctatcctttt 12720
ggactcatgt gaaagtttcc tgacttgagc tattcattct ctcttcatag ctgtttcctt 12780
ccctctaaac accactacag attaccattt tgtaagttta tattaatatc tttattcagg 12840
tattaataaa aatacttctt agttggactt cattgagact aaattcagcc caaatcaatt 12900
gagccagatc taataatgat ctagtggaat gagattattt tagaagccaa ttatccattg 12960
aaagtcatga atatgtcgac aacaaattac tagagaaaat gtgggctcat tttctcctct 13020
gtgatctagt ttctaccttc cttcaaatcc tcttttcaat acatttttat gtgtcaacct 13080
tttttgacag tatacattca tttgttctca gttactttgt ttgaacacac atggtattta 13140
tattagagct ccaatgagct attattaact caattgccta gtgctgttat caagggacga 13200
tttatatcgt ttctacagat gaattgaatc acaaacacac acagacacac actcacacat 13260
acataccaca cacatacata cacacacaca cacacacaca cacacaccac caccaccacc 13320
accaccacca ccaccaccac caccacatca cacactatac acaaacatat accacataca 13380
ccttgagaag ggataacacc taagaggagc tgactccatc caggagtctg ttctctcttc 13440
aaaggcctct actatctcgt atgtgttatc agccagctct actgaggtta ccctcgggtg 13500
aataatagta aggaccagta cacatcatgg cacaaggata aggccttaaa gcaagcaact 13560
aaagtcagag ttaagaaatg cactcgggct agacacaatc tctgagcaga tgattgtggt 13620
gatgctgata aaagaagagg aaagggagag tcagtgctgc gaatggcact tgctaacctt 13680
taagatcaca gttaagtctc atgcctcctg cttcgggatg tggagaactt aatgcttcct 13740
cttctattct tcccttgtag gatttagttt caagctaaat cagagagatt taaagacctt 13800
ctctttgata gctagaggaa gtttcacgca gttaaatggt gaaatatctt tgaagcagaa 13860
aaaagcctgt ctctctaata cctgttttaa tgagactatt acttaactaa aaatgtttcc 13920
agtggaccac agactatata attttaaaca gatttttaaa taaaaatgat gattctactt 13980
acctaaagtt tgtcctcaaa caaacaaaca aaaacacaaa aacaaatcta tatatcagga 14040
ctgacttgca aaaatgataa tcaatgcacc atctgattat gttaaatttt tctcaagaat 14100
tctggaaacg ttttggaatt agattgtgcc ttagtgaaaa aaattatttt aacacagtaa 14160
gaaagttaaa taaaaattgg aaaatatgtt tcctcttcac tatgcatgct ttaatgcctt 14220
gacttagaac aaatttgaat gaatggatga atgaataagt aaatacttat attcattcat 14280
acatttgtga gtatgtgtgt ataaaacata caaaatatca tgtctatgag atatctgctt 14340
attatttttc tccagtaaac tctaagtcaa tagctccagt ggtccccccc cccacccatg 14400
cagttttttc ctgtaaatat tttattactg tgcaatttct cagcatttgg ggtttgttag 14460
ctcaagttac tctaagtatg acctcaaatg attctaaatc agatggtgtg tggattttaa 14520
gcataagcaa gagataacca tagtgactaa tggcccaaaa catccttgca aaagctgttt 14580
ctttagaaac ttgtgccttt caacattgct ctccaaaaat aatggaatgc tgtcagcaac 14640
tccttggcca tgagaatcat caaagatact gtagcaagaa taagagacag aggcagggta 14700
aggaagaggg attacaagta caactacctg ggctggagaa gcggctcagt ggtgaagaac 14760
actgattgtt cttccagaag tcctgagctc aattcccaac aaccacacgg tgactcacaa 14820
gcataactga ccagagagga caagacccca ctctcagggc catcatgttt agtgttgtac 14880
aaggttctgt aggtttggtg acccagcatc atacaacaca acaacatcag gcatttggtc 14940
cacagttgac ttccttctgt ctgactttct atagtctaga agagctaaag agctatggaa 15000
caaacttaat tctttaagca aattgaaggt agttccccca agccacacct acttctttca 15060
ttagaaaaaa gtcaattagg aaaagtttag ttattaaggg cagagatctg agccttagga 15120
catttagctt cagattgtct gtctgttact tgttacccac ggcatcttgg gcatgtcaac 15180
taacttctct ctttctggct tactgctttc tccactaatc gtagaaatgc taacacctac 15240
ttcacagaat tcttatgggg ataagaataa gtcatgtttt aaatgtgaaa cacagcatgt 15300
tggccttgct tattattctt acttattatt taaatttttt tccatataac agccaaaaag 15360
cagtaacggc attttaactt ggtcacaaaa ggttgtcatc tgtaagcttt gtgatggtgg 15420
tgacagcatg cacctttaat cccagcattt gagaggcaga ggcacacaga actctatgaa 15480
ttccaggaca gtctgctctt cagagtgagt tccaggactg ccagggctac atggatgaac 15540
actatctcaa aagaaccaaa ataattaatt ttatgatgat gatgatgatg ataatggtga 15600
tgttactatt gctattattg tggtttacat gtgacaataa tattgtaaaa atattattat 15660
cacatataaa tgacaagttt ttaagttatc tttattcctt tcgacccact ctgccctttg 15720
tttatctgtc cactgataga tgagtctctc cattaatgat ttaagcatgg ggggtttttt 15780
gttgttgttg ctgtttgcat tttacagata tcattcttat ctactattta tctgccaacc 15840
atttattgta gtcgctgcca gagtgacatt acaattatgt gtgcttgtga tttttatgta 15900
gttaaatctg gcagtccttt ccatgtggga ttttacactt actttgaaag actccatgcc 15960
acagagtatg agtttgttct tctgggttct ggtagttaca taatgcttat aaaggttatc 16020
tctttaatcc tcttagaagt tggacatagg ttattaggtg atagtccaaa tttatctctt 16080
tctcaaattg tccctgaccc cccccctccc gtgatctgaa ataacacctt ttggcaaaca 16140
ccaatctcaa aacaactaca aatgaaggct ttagattccg tgacgtggat ttttctgtta 16200
ttgggagtgt ttaattcctt actgttgggt aagctggctc aagatcattc catgtgttta 16260
ataaatcctg tggcaaccat cacatgtatt ttaaccgcca gaagaattat gaggttaatt 16320
tctcaggttt taaaataata gaatctaaat atgacagatg tggaagaaca gatttcctga 16380
cataatacac ttttcactta aactgttctt tagggttttc tgctaaactt tatcattttc 16440
ttcacatgat ttcgggcact tcttatgttt attatttccc tttattggtc agattttctc 16500
ctggtgtctt gtttgttctc ttagcaagca ttcattctta ccctcggagt gctctctgac 16560
tagctgcact acagtgttat tgaactgact ggcttattct gaataataat gaacagctac 16620
actgccctga tattacacct gtgtggtgcc tttatcaata caaggacact gagttctatt 16680
cctaatgcat ggagatcttc attttcttta aactaatata gatatctttt tatttagtac 16740
cacttgtctg tttattatga aatccgtgta tgttttcatt aatgaagaga attaaattta 16800
tagaacccct aatactcaat aatctttgtg ttttatattg atgctgtctc gtaatcttgg 16860
tgctgtgctg atagtccata tttaaactca tctgtgattt ttttctctta gttttctgat 16920
ttattatgta ttttgtggtt tttatcaaag atgtgatatg tccacaaata atttcataga 16980
tttacatcat tttccattct tcaaagggtt ttctgtaatg aaacaattat tcctttctct 17040
tttttatatt cattttattt gtttgtttgt ttgtttgttt atgtgtatgt gtgatgtgtg 17100
tgtaagcact tacacccagc aaagggcgtc agatccccct ggagttgtga gcatcctgac 17160
atgggtgcta ggtactgaat ggtgatcttc ttgagagagt agttaatatt cttaaccact 17220
gacccatctc tccagcccca atttcttcaa taatgtttaa aatatgccta ataaaactat 17280
ctgtttggaa aaaagcatta agtgtttttc aattcaagtc aacagttatt agtttatgta 17340
aaaccttgat ttatccttgg aacaaattta taaaaataaa atcacacttt cctaagtaaa 17400
tacccaataa accattgcat ctattttttt taattattag aagcaatata cccacttgta 17460
agaagtctct gacttgtgat atggactctt gtctcatttg aagaattcac atctctctgc 17520
ctgatcataa ggcctgcagc cgtccagttg attcttctct cctgtcacct ctcactcttc 17580
gtgtccagtc tatagaactt tgattagtaa ttctattttt gtctctggtc cctattggtc 17640
aactgtgatc atttcctagt ttcttctctt gagtagttat gtgcagtggt ttctgttttc 17700
agtaaatttt tttcagatta gggtttttga cccaatttta taatgaaaat tctacttcac 17760
caagtattca cattgtaaca aaatctgaat ctttatattg taaattttag aagccatata 17820
tcataagata aaaaaatata ttcatttttc taccacccag tttagccagt tagcctttta 17880
taatcaacaa ccttatgaat ataaatttaa cataaatgaa atttgaccac acactctttt 17940
tacaacttat cttccaatta ttttcccaaa aagtctaccg cacttgtgac tcctttgact 18000
ggcatatcaa ccggtattat attactgttc atgccaatat ctccttgtca ctaattactt 18060
gggcaatgtc taagctttct ttcaaactct gtgagagttg aaaaaagaaa aaaaaaacag 18120
tattcaggga gttaaaatca tggaagaaga acagaagttg aaatgtcgtt gtgttctcaa 18180
ccaatataaa atttactact gaggtttttt ttttaattat aaatacaatt gatagtcact 18240
aaaacaactt taatttcttt atttcaagat gatctggacc caaattaatg catcatacat 18300
taacagatgc cttaacaaca gaaaggttgt tctgattaat taattgactg atatatattt 18360
tgaagtaata aggtgataca ttaagacttt ttaaaatgct ttttagtttt ttaagttaaa 18420
atataattgc atcatttccc tccttctctt tcctcccttc aacccttgcc agtatcaccc 18480
ttcatttcct ctccaaatgc atggtgtcta tttttttaat ccatgtaatc gccacataga 18540
cctttggaat gtgtggatat gcatattctt tttctatctt tcatgatgca aactcaaatg 18600
aactattgat ttcatttgta aacatttttc taagtcccat tttgcaacta atttatactt 18660
cttttattga gcaatgcaag gtaatattta tttcacatca ccaagagatt cttatcacaa 18720
ccccttcatt tctgtgcaat ctggaactga attgcttctc aaaacaactt gtacatgttt 18780
tacaatagtt actgtacccc tcatttatat catgcatgac caggtcacaa taaaacatta 18840
gagaaaaaat tgatatgact tagagagatt cgaacagcaa gttacacctt caacaacttc 18900
aaatgcacat ggggtctggt gtcaccagcg ccctgaggtt cccacgcaat gagaaggacc 18960
ttccactcct gatcaagtcg cagtctcttt ccccatttag ttttcttgtc caaccccttc 19020
cagagcatca aataagaggg tggctagtaa ttggagcagc agaactacgc tttccaaatt 19080
ctaaactgcc aaagacagga aattcgtata gaggaaatca atatttattg gactcttcat 19140
taaagttgag gataactgtt tcattccact ttttttgttt gttttctaag gcatttttat 19200
tagatatttt cttcatttac atttcaaatg ctattcccaa agccccctat accctccccc 19260
caccctgttc cccaacccac ctactcctgc ttcctggccc tggcattccc ctgtactggg 19320
gcatatgatc ttcgcaatac caaaggcctc tcctcccatt gatggccgac taggccatcc 19380
tctgctacat atgcaactag agacacaact ctggggggta ctggttagtt catattgttg 19440
ttcctcctat agggttgcag actcctttag ctccttgggt cctttctcta gctccttcat 19500
taggggccct gtgttccatc caatagatga ctgccccacc cagggattca tcccatatac 19560
aaccatcaaa cccagacact attgcttatg ccagcaagat tttgctgaca ggaccctgac 19620
atagctgtct cttgtggggc tatgccaatg tcgtttcact tttaatcaag atgcacactg 19680
acatccacgg tctgcatctc ttttctgaca tctactctct gcacctcctt tttttctctc 19740
cctgtaattt ctgcttttac tttctaagct ctagtgtctt tgcttttaaa caggctctcc 19800
tcccaaatac attgccagtg tttgtctcag gccataccca tttcacattt ggcacaaact 19860
acaagtagaa gacagccctt ccatttatca tgcttacagg tcagggagaa tgagagtcag 19920
gggaacatta taacactgtg tgaggcagta cagagtcgtg caggctttcc tgagaacaaa 19980
gagaggatgg catctaatgc tacccaggga ggttgtcaaa gaaagcatca tggagcaaac 20040
agctttcaac caaatccaga tggaatcaat gagacccaac agtgaagtta gaagacacag 20100
gaagggaaag tgtaagcagt gagcctggag acgtgaagaa gcgtgtgagt gctaagagaa 20160
agggcatgtg aaggatgggg aaagcagaca tgggatgtgc tactgaggag catgtgccat 20220
actgatgaca tgggacttta tctaccacat ggagctatgt agagctataa tagccaacac 20280
tgtgcaagta ttaaatgcca gggaccattt tgagtattta ataattacct taatatttaa 20340
tcctcagaag actatgaaat aagatatact gctatccgaa ttttctattt aaagacattg 20400
aggctcaaag agcctggatg gaagtagaag gatatatggg aatgctttct ttttctttta 20460
acattggggt ctccttatgc agcccaggct aaccttaaat tcatgatttt cctgctgcag 20520
cctcccatat agacttgggt aaccgacatg accatcacac ttggctcaga gtctattttt 20580
atgtagctat attcagtggc atacatattt gagataagag tttcattgct aagaaaaata 20640
tagtcctaga gactatggag acattggccc gagactgtta aatggcagcg aggcagtgct 20700
agtgaagagc cgtggcattt ttgtatcata tttttcaaat gaatactgtc cagggagttt 20760
gtcctggtta tttttttatt gtaatttgac aaaaccttat aaccttggaa gagggaacct 20820
cctttgaaga attgcttcca tcagattgtc ctgtgggcat gtatatttat tgctaattga 20880
tatgaggggc cagcccacca tgggcagtac cattcataag caggtagacc tatgctgtat 20940
aaaacaacaa gctaaacagg attcagtgag caagccagga aactgcattc ttccactgtt 21000
tctgcttgag ttcctgtcct gaactcccta aatgatgggc tataccctgt aagttaaaca 21060
aaatcctttt ctttcctaaa ttgcttttgg tcatggtgtt tatcagagca gctttgaaaa 21120
taaactacga caaggccttt ctggatttac tttcttgccc ctgtatctca cagctgtcct 21180
ccgttatgac ttattagcag aaatattaaa tcacattgaa tcccatgtgc tagaatcaca 21240
gaatacatcc gaagtgtttt ctcattcatc ttcattacag ccacttgtcc acagcctgtt 21300
ttgactacga ttcacaaatg aaaagcctga cattcagagt gagctggaaa tttaattctt 21360
tcctgcaatg ctgccctgac cctcttccaa caacttctat ttttatctct ttatctgcac 21420
tgacaaacag aactgtgcca cggacctacc taagtttcca tagcagaacc tggcaattga 21480
aagtggaggt gcttggggat gccttgcctt gcctgcctcc tctgatgagt gctacgatcc 21540
aatgcctaat gatactctgt ggcacaacaa gccaggagct tttttccaaa gctgtatcag 21600
tatgttgctc tcctaagccc cagggtaaat gggggatatc attgctgcac gtgagacagt 21660
ttcgagattg aggaagacaa cggtgaaagg cagaaagaga acagaaaggc tcttcccacg 21720
ttagattctg cctgattctt ggaccttgga cagctcacct cccccattcc cagacctctt 21780
tccttgcttc taaactactt cagcatcctg gcgctcttat ccttatggtg ttccatctag 21840
atctccttcg atggatcttc cttatctctt ggcttcttga gttggagtta tctgcaggtc 21900
tgccttagat acacaccctc tccccagtcc ttacatgagc tcatccaatc tcaagactaa 21960
acatctgtca taggtcagct ccaagtcagt gtctcagctg aaactctccc ttgaaattca 22020
gacttggatt tctgtctacc tgtcactcag tttatctgtt tggatagcta aaggcactgt 22080
gaaaatcagc aaccccataa cccaacttct gcttcttctt ccacaaattt cctcaactct 22140
attcttgctt tgcctttttg ttttgttttg ttttgttttg ttttgggttg ggatgggttt 22200
tgtttgagag ttctggtgtc taaaccaagg acgtcaaaca tgtcactcaa gtgccatggc 22260
aggagaaaac acacccaatc cctgaagtgc cttaggctgc aaattgtgag tttcgtttta 22320
atgtgttgat tgcaatgatt tgagatttag atgtcgtaaa gaatttctca gaacttcaca 22380
ctgtagtcca atggagcaca gaggcctttc tgatgtcaaa atgtctttaa taacctttac 22440
taaatattaa cccaaactca tggcaggttt tgcaaacagc gaattcatca tgtaactatg 22500
aactgttacc tttttgatgg aaatgatgaa gtctagcaaa aaacaaacta cagcttagcc 22560
gacagactgt agactttgcc attgaaacta ttaaggcaca tagaaataac cttatcagat 22620
tccccagtcc ttcctggtcc tccaggataa gctaggcgaa caatgggaga acctgagagc 22680
tttctgatta aacagtaact ttaacgacat ttaataaatt tagcaacatt tacataaaag 22740
tagctttagg taaaatgtaa ctcttgcaaa agtttcttta taaatcttca aaaatggttt 22800
ttatagtttt atttacaaga ttagttcata gcaatttcta taactgtatg caccaacaga 22860
taaggattat aaattgaata tgggcatcaa cttatctatg ttttagtatc cataggaaca 22920
gtatgttctc caactacaga agtaaagcta catgacctaa cctgaattgc ttcataatgt 22980
caaatcacca ctatcatgta aaagacacta atttcctaat caaattaaaa gcaaggctat 23040
agcttctgga tagatgagat ggttcagcac atgttgccaa gtctaacttc ctcagttcaa 23100
tccccagaac ccaaatgctg gaagaagaga actaacttct acaagttatc ttttgacctc 23160
tgtgtgtgtt tcatgcatgt atacacacac acacacacac acacacacac acacacactc 23220
attcattaaa gtacataaaa attaaaaaag aaacttttct gtgaacacta aaatcttgtg 23280
agaagtgtgt gtgtgtgtgt gcgcacgcat gtgtgtgccc aaatgaattt taaaatcttt 23340
taaccagtct tgtttgactg tggaataaat agacaagtgt ctcttgcaaa acacagaata 23400
gacagacaaa gctcaatctc ataattttta cttcctacca tttctctctc tccctctccc 23460
tctccctctc cctctccctc tccctctccc tctccctctc cctctccctc tccctctccc 23520
tctccctctc cctctccctc tccctctccc tctccctcct ctcctctcct ctcctctcct 23580
ctcctctcct ctcctctctt cttctgcctt ccctctttcc gtatgtgtgt gtgtgtgtgt 23640
gtgtgtgtgt gtgtgtgtat gtgtatgtgc gcacacatgc acgtgtgtga catgcacatg 23700
tatatgaatt gcaagtgcac acctgcaggc ctgaggaaca catcaggcac cctactccat 23760
cactctctgc ctcacttctt tgaaccaagg tcttctgctg tataccacca gagccaggtt 23820
ggtggcaaac aaactccagg gatgccacta tggggctagg gttacaagtt ttgtaggggg 23880
tgctggagat tcaaactcag gtcttctggc ttgagcacca agcactgtta cctgctaagc 23940
catatccttt cacatccctt cccttttttt aattggcatg aactcatctg tttgtatatt 24000
tagtgatatc ttaaagtaac tgaactggga atgagtggac tatgttctaa ttagagaatg 24060
gatataattc agttttcatt tcaaaaggtt gaacatctaa aaattatata taattataaa 24120
cacatgattt taaaaaaaca aactgttgtc cagtcttgtt tgaatgtagc agttagcagc 24180
tataacctta aggattcctt taaagacctt tcctaaagat gcccttcact tgaagggcaa 24240
tgtagacttg gctatagtaa tttacttaat ttatcttaaa tttggtttca gtgagcaacc 24300
ctaattaacc tgattttttg ctgataatca ctctcaatgg aatcaaatca caaatccggg 24360
gatggattga gcggcaccca gaaggaagcg gcactccgcg cactggtcca gcgcacagga 24420
tatagcttgg tccaggtagg aacttcttgt gacatctgct gagactcacc actaaatcca 24480
gagtcctgga aacattaata tccctcgatg cagaaagcca gcagccctgg tatgactcct 24540
gtgtaaatgt ctttcagggg aaagatggga atagcatatt tcattcagct ctgaaggtaa 24600
tctggactct tcctacctgt attatccact agaccttaat ctgttgcttg aaagtataac 24660
ggctaaccac agtcatggag acaattacag tttcaaaagg ccattttaga atacaaaagc 24720
atggttagga tccccagttt ttagtgaagg tgaccttagc taatacttca ggagtcagtg 24780
gagaacaaac ttcaggaata atcactttgg tttcaagaga ggtccctgca gataaagact 24840
tcaagatgtg gcttccaaga aggtaacttt ttttttttcc tagctattct actttgtcta 24900
gtctatggta tttaacgaca acttctgccc atgttagacc tttgaaaggc aaaaatacaa 24960
gggccatgaa aaagacctaa ttattaagaa ttatttgtat atgactattg ccattgggat 25020
aatgcctttt agagaatata tgctgcatta atgagcaggc tagtgttaga atcatcaaaa 25080
ctatctcatt agaatacatt acaccccctt ttgtaataaa acaatgtatt tggacccaac 25140
aaccattagt tttcacctac atacttgtcc aataaactca aatctcccta ctgttcagaa 25200
tacaaatatt acatgtgagt agtgacagaa tatgccatgt cttggtttta ttagctctcc 25260
tagagttgga tttttggaaa taccctagat ttacttatac tgatgctgta aatcataaat 25320
gcatattata catgatacag tgcctcaagt atttatattt ttatcccaat aaggagtgct 25380
agtcaggact tttaagtact tcatgcattt ttttattctg tagtgacttt ttaaagtttc 25440
attaagtcaa gggagacact gagatatttg tttcactaaa agctgtgtta ttttagaatt 25500
agtgaactgt aaatgttttt aatctctaaa attaataaat agtttaaata tttgtgtatc 25560
ttttcgccac actaaaataa tcacagaaaa ttctaaagaa cttagtctac aaaagaaata 25620
tattatattt catgttattt ctttttacac atgtcaacag gcatagttgg ctgtaaaggt 25680
ggtctttctt ttttaaaaga gttgggtttt ttttctttcc ttttttagcc aattctttaa 25740
attttgtaaa cattttagtc aaattcttct gtaaatattg tagaaaaaga aagtgacttt 25800
atcagttttt tttggttttt ttgttttttg tttttttttt tttgttgtgt tttgttttgt 25860
tttgttttgt tttgttttct gggggtgggg ctttcctcaa gcctgaaaca tttattcagg 25920
ggaagcaaca gtgaaaagac attttaacct ttttaaaacc taatggtcaa ttttaagcac 25980
ataaaggaag tccacctagg atagaagtgt gtacaaacct gtcgagaaca gcaaagagta 26040
ccttgctatc acagacctaa gtcaaagaaa gtaaggaaat gattaaataa atagccagag 26100
ccttcaacaa gcaaaactca agagggagat cctacagcgt agagtttcag tttaacttta 26160
ttctcagtgt ggacagacca cgtgcaagat agaatttagg gcaggggaag cctaatgata 26220
ttttaggagc attcaagtga aaaaaaggtt tcttgtgaaa atgctaagat ttcagtcaag 26280
tataatttcg tagcttcaac tttccggttc ttgcctaaac acatcagggt ggaagagaat 26340
tcctcttgta tttctcagct tactctttgc tctgttaact gcaagttctc acttgacctt 26400
gaagcagcag gatggataaa gcaaaagaga gcagggagga ggtgcttgaa taatggtggc 26460
acaggggact aagaaactga agccactggg agcccctgta agatcgcaga gagccccata 26520
gcactgctcg gggaccctca cctggccaca ctttctttga ccagacatct ttgcactgag 26580
ctcatttaga cactagccac ctcgtgagag gatggaagat aagccatggg tcactttaga 26640
gaggtatgga ggcattcaaa aactaccttg ttggacaaaa gtcgctgcac tacttaagta 26700
atatttgtta gaatgattac tggatctgaa gttctctaat aatatggagg tacaacatcc 26760
caaaaactag gtgctctagt atatataatc taaagtaatt atatatatat atatatatgt 26820
atatatatat atatatatat atatacacat acacacacac acacacacac acacacactt 26880
tattgtgttt tcaaatacat acagaattaa atggctttgc attggcaaat gtgtcctgca 26940
ttgggctcaa aatgtagaat gtgacacaat caggaggtct gtagtctcac ctgctcctta 27000
tcgcacataa gatcttacac aagtttccta acttctgggg accttaattt cccctaacgt 27060
cagtaaggtc catccccaca ctgttagcct tgatctgtga tctgtatcgt ctcagcttct 27120
ggtggacagc taactggacg gagagtagac aaaacctccg gctcaatgat tcagggatac 27180
ctccctactc ttcctgatgt tcacagttcc tatgctggaa taaaggaatg actaatacaa 27240
aatagaagaa agtatcagtt ttaaaaaaaa tctctgagca aaaatgaaga tgttaactaa 27300
cttctgattg gaaggatttg tctttctgtg tctttccagt ggtatcaaaa tccaaaccac 27360
agaggtgaaa gagctgggca ctcttatcac cagcagggca aacacagcta tcaaaaatag 27420
aattttacaa gttacttaat aacataagct agcctttaat gtggcaactg atgcaacaac 27480
gtgtgcttgt acttatgaga attaaaagtg taaattggaa cctctttttt ttaatataac 27540
tggatatcct tctgtatttt acccaagttc tttgggaaaa gagattcaat gcaacatcct 27600
taaaaccaaa atatttaaat acatattgct cctaaatatt tggaaattgt gccacggttt 27660
taaaatgcaa atagcccttg ccatttgagg ttatgccatt tgagggtttt atttttctgc 27720
ttttccactc ctaattacat tccctagctt tctgaagaca gaaaatactg ttttgagagt 27780
caaaggggaa aagtcccagg acatggaaaa gtgcccacac ctcaacagtc agctttaaaa 27840
gctgaatgct tgaaataaca tgttatgaaa ctacatatgc attattttaa aactggaaaa 27900
taaaatagcc tctctaatta tgtaagcgtt ttcatgcctg atccttgtct ttgttttcca 27960
gtctttttgc agtgacagag ttatttgaag ggaaagtatc ataaaatata aaatactacc 28020
attattgctc aattagaaaa actgggcaat tttcacagaa gaaaattcac tatctcatct 28080
gggtgatggg tacctggagt tattgggcaa gccttgtgtt taatgtttgt ttcgtagtga 28140
cagagtccaa ccctcctctt ggaagttagg acaacttccc tagaattaca aaccacagac 28200
tgggaaggca atgagcaatc agccaagtat agctatcacc tgtatctaaa ctcagtgctg 28260
gatgcaaaca gcattatgtt tccaaagata atagtgaatg aaaaagaaaa agaaaagaaa 28320
aatagaaagg aggaggacat gaccactcct aaattataaa gatttttatt gtcgatacaa 28380
gggagaaagc agggagaggg aagagtgtag gctgaacatg gccggcagat aaaaccagac 28440
catgagagga gggagagcaa gagaggaacc actgacctac gaagagaggt gacgccaaga 28500
gactaagatg gcaaaagggt aaaagggctg acatagccaa aatggctgga ctatatggag 28560
aagagctgct gggggctggg ggtaggacag cccagcccag tccctgggct ggagaaattt 28620
aggctgcggg ggcatgccag ccatactctg taacagatag gaacagaggg atgctggaag 28680
ctggcagcca ggtctacttt aatatgttaa atagatactg gtttagccat ttgtcctggg 28740
aaacagatgc aaccttcttt atttccacca ttcatgctaa gtcaagcaag cactgagact 28800
ttacccctcc atgtattgat gtattgatag attccacaaa gagagttgta gtttcttcct 28860
ttgtgaagaa cattctcatt ggaaaacaaa atcaagaaag aaagaaagaa agaaagaaag 28920
aaagaaagaa agaaagaaag aaagaaagaa aaaaaaagaa aggaaggaag gaaggaagga 28980
aggaaggaag gaaggaagga aggaagagcg agcagcaaca attaaagtca ggtcctgagc 29040
accttgggtt tgatctataa gccaggtcac atgacagaat ggcaggtgac cttcttcagg 29100
cacgatgcca ctgaagctga gatttaggga ctggagcaag caaacctttc aagggtctga 29160
gaagacacca gcatccctgg cagaggaacc ctgtcttaac caaacttttg tcaaatgcat 29220
accacctttg aggaagtaaa gagattggtt tcaatgattg ctacattaac caggtatgag 29280
tctggttact ttaacaatct cccatcttta gttctcatct ttaaactcta catgtaggct 29340
gcctgattaa aggggtttca atggaattat atactcttag tctaatttgc aaacaatact 29400
aaacacacac aaatatatac cataaagtaa aaagaatgaa tggcattatg tcaacataaa 29460
tctgatttgg ataccaatca cgcttccctt tggaaaggca acccacacta agatgactag 29520
cctcctttta gttaaatgta tcaaactgtc aaagggtcag acaaaaagcg aatctggaaa 29580
gaacaccaac agaagagcaa caattgagat acaagagtgc ttagcagcca aagtttagaa 29640
ggaacaaact gttggccaag aacactgtat ccaagtaaaa gcagcattta gaaagaggta 29700
tcggaagtgt ctcaaacaaa agcccacaga acttatcacc accagacttg tcttagaaaa 29760
tatgttacag tgaaatcttc aggacaaaaa gagtaacatg aagattgctg agctatgctg 29820
gttccgaatc ctctagaaga ttaatcatgc tacgtaagtg tgctagcttg attgctgtaa 29880
taaacaccat gaccaaaagc aacttggaga gggaaggctt tatttcatct tccaagtgac 29940
aagtccatcc ttgagagaag ccaaggtaga aattcctgca gggcaggaac tttaagctaa 30000
agccatggaa gaacattacc tactgctggc tctttctttt ttataggacc agctcccctg 30060
gtttagggat agagtcacct acagtgaact gggccctctg gcaccaagga acaatcagga 30120
aaatgcccca caaacacatc cacatgccga tctactagaa gcaattcctc tgttaatgtt 30180
ccctctttcc agctgtgtca caatgacaca gaagattggg catcaccatg aattgcttat 30240
atctttagtg tagtgaacaa gataagaaat tattacaaaa tataacaaca tgaacccagg 30300
tagacctcgg agtaagactg tttgccaaca tttgcaagga cctggattcc acttccacct 30360
ctgcaagatg gtagtagtcc tactgatagt gataatagca ataatattag caaggaaaga 30420
tgtgttgcca aaggtgtaaa ttgtaacatc aattattctt taaaaacaac atcctagtta 30480
ttggttaaaa ataatttgtt gaaactatag aactgttttt taatgggcct cttgctaaac 30540
actaagcaaa acctcattac agggatctgg agagatggtg gctcagaggt taagagtaat 30600
ggggtttgat ttttagcacc caaatagcta acaagtatct gtaatttcag tttcagagaa 30660
tccagtatcc acttctgacc tctggatact aagcacacac atattacata ggcaatctgg 30720
tatcaaaaga cccatacaca tagggtattt gaggagcaca cataaaatta gtcctatttt 30780
aaaatcctca ttatatctac aattttaaac agaaatggaa atacactacc agagaaaact 30840
caattaacca agtggaagac agtaaaagaa ggaaggaata aacaatttac aaagcaacaa 30900
aatggaagta gttagtcttt aaaaatcaat aattaccttg gatataaatg gactggattt 30960
ttcagttaaa aagacagatt tgatacacac atatgcacac atgcactgct atgctgcttg 31020
caggaattca tgtcaccttc aggggcgtgt gaactgaaag tgaagcagta ggaagatatt 31080
tatgcacaga gaacacaaag aagttataag aagttgtgca gacaaccgtt gcacatatgt 31140
gaaataaaaa actttaaaga agacaaaggt tatcaaataa agaattcaat ttgtcaaaag 31200
gcttcaaatg gtgggataaa agcagtggac agcatgggga ctgcaggggg aatgcagggg 31260
gaattgcagg gggactcagg ggcaactgca agggggactg caggagaaat gcagggtaca 31320
ctgcaggggg tactgcaggg ggcactgcag gggaactgca gaggagacaa gctgctatca 31380
ccaacactgg ttcagaaaga ggcggatagc aaaatcagag cagctttaac ttagtctttt 31440
ccatcattgc acataaatcc taaagacaca gagaaaacag acttcacggt gaagcacagc 31500
ttctggtact ttctcttctg ttgcgagctc tcaccacctc ttccttccca ggctgtccaa 31560
aacttagatc atgtatgtca gttctaagaa cgcagagtgg gaagagtcaa attcttggag 31620
acatgagctt ctacacgctt gtccctccag ccactcacag gccaatttta ttttaaagct 31680
cagaagaacc ttgcttcttc tagacagaga tctagtaatc aaatgaagga acaattctgt 31740
gagccccttc atgagtgggt ccaacgtcat gtgtttggaa acttcctcat cccaggaaat 31800
acatgtgttt ctgcaactgt tttcaaatag tgatgaattg atcctcaaat accctaatag 31860
gaacttagca caagagattc taaacagaag agtcaatatc atcacaagct agcattgtgg 31920
tgccttccct cagactagag gcaaagaagt gttttatttc atcaatttaa aaattagtgt 31980
caacttcatt atcaaaatgt gcagaggcag acaggggctt taacattgga ctctgttttc 32040
aggcaatctc aagagtttcc taagagctat ccacttgttg attttggtta gcaaatagaa 32100
atatgtgaat cttcatcttt agactctgaa ccctagccag agataaagac aaaacagaac 32160
aaataaacaa caacaacaaa accccacaac atttcaaata cagatcaatg gagaaattga 32220
tgacttcagc tttgaatctt tataatgttg acctaaaagg agtgggcagg ttactgaggc 32280
agtcttacac gaaatgttgt aacagtatta agtaaagtta accccactca gaattattcc 32340
attttcaatt cattcaggct ttctggtaag gaaagttgaa gtcatatctt aatccttcat 32400
ccctggtaat cattcaaaca gaaagagcag gacaaatgat ttgagctctc agaagataaa 32460
ggtttcaacc aataatgtga tcatgatttc cttgttttgt aaatgtcttt aaaactatct 32520
tgatgtatac tatatccata cacacacaaa aaaaccacac atagatagat agattgatag 32580
gtaggtagat agatagatag atagatacat agatacatag atacatagat acatagatag 32640
atagatagat agatagatag atagatagat agatagataa aagtcattat atagctatgt 32700
atatgaactg gaaatttgct gatttttcaa actgtaagaa tagtacttgt aaggcttcca 32760
ttgattagca cacattcatc ctgtaaacat ttttacctat tccaatacag tatcaaaact 32820
ccttctgaaa aacatcctga cactcccaga agactactac aattacctag taaaggctac 32880
tttttaatag agtaaaagca agaaagatga gcactgtctt gctaagtccc tcagctttca 32940
aagaatcatc tttcacaaaa gtatgataaa aagaataaaa gataccaact aaagccagct 33000
gcattagagg agacagccct tggcatgtgt agaaataggg acagacagaa gagcaattat 33060
ccaaatccag tcttccttac catgtccatg tacacacgag cagtctatgc catttagcta 33120
gatctttagt tgctactcta ttagttagtt ttagaagtta tacctagccg ggtgtggtgg 33180
cgcacacctt taatcccagc actcgagagg cagaggcaag cggatttctg agtttgaggt 33240
cagcctagtc tacaaattga gttccaggac agccagggct atacagagaa accctgtctc 33300
gaaaaacacc cccccaataa aaaaagaagt tatacctaac ttgaatcttt taaatttttt 33360
ctattcataa cccccttttt gcctagtaag tttttgtgca tccatatata tatatatatc 33420
catatatata tatatgggta tataaaatag gcatacgaat caaacattga ctaataataa 33480
gtcaaagtaa atttatcttt aaaaaatttc ctttgatata tacgtggctt tatcactgac 33540
caaaattgaa agcaaactta atactctgag ctggtgccct tgcttcgcat ggagaattaa 33600
atcttggcta cacatttggt agtgaaaggt acagaccatc actaatggtt ttcagaactg 33660
attgatgttt tgatcttgta atcctcaatg ctgagaacaa ctcatcatat acacacgtga 33720
tacagattag tagaggctgg gacatttcag aaagtgttgg aaactatgtc ccaaaagcaa 33780
gccaaaattc atctaatgat tattttatga aactcaagtc agtaattcaa acaaattttt 33840
ttttaaaaat caaacatcct aacgtaataa aacccaaagg tatactaatt taatggttac 33900
gtaatgagag gtaagggtaa gaaaatagtc aattcgcata actaaatcat tatgctctgt 33960
caaaccaaat tttttttaat ttcattttat ttttaattca ttttttacac tccatattcc 34020
attccccgcc cctccccatc caccctccga ctgttccaca tcccacacct cctccccacc 34080
ccaccccatc tccacgtgga tgcccccccc caccccacct gacctctaaa ctccctgggg 34140
cctccagtct cttgacaaac cagaattttt tttttaatgt aagtaaaacc tactatgatt 34200
tgtgacatag gatagttttg aattcgagcc ctagtgtatt agatagcact cactagcact 34260
gagtggccca ataggcaatg ccatgtgtgc atgcctgcat gttgtatgtt acaaccaagg 34320
ctgcagcaaa gtttcaggat gcagtatagg tgagcgcccc cagaaacatc taggattcat 34380
cacacattta cttttggata cctttttttt ttgcttgttg agtgttaaga aactgactga 34440
taccaaaatg ttccggactc gatgtttatt gacacaaccc cccacaactc agcttggagt 34500
ttaacaagct ggggctacta gctaaagggc acactgtaaa agcccgaaac acatggatgt 34560
attggccaag ttcttcacca ttcatatcta aagttccaga ggcacctaga tgttggaacg 34620
atgcatgtcc aaaaccatga gtgcgcgtgg gcagagcaca gcgatctcag aactcagcag 34680
tgaaacacat gattcgctgc ccatgattat gcaaactgct ttacaaaatg cgagcaggtc 34740
tctgaagcta gttggcactt tcgatcttct cttttatgga gaaacaaata tgcatgctca 34800
gaatatgctt tctgacttct gattttatct atgcttgaat ttagtatcct tgtggatggt 34860
gaacaatgtt ataaggtatg ggttgttttt taaagaaagt tgcttttgaa ggcttcagac 34920
attgagatac tgattccctg agaagtttgc agcacgtgct cctcagagat aaagaagtat 34980
caagagatgt tgttaaaata gtccatttgt ttttttaaac tgtcttcttc tgtatgatac 35040
tactaataac ttaaaatgaa ggagggacta tgtaccaaag caattgatct tcaaaagtct 35100
ttaggcaaat gatattttat gtaactatat cttatacctt gcatagatta taaaaaataa 35160
ctaataagga tagtagatag atagatagat agatagatag atagatagat agatagacag 35220
acagacagat gagagataga tgagaggtgg gtagattgat agatgatagg tagatagata 35280
gatagataga tagatagata gatagataga tagatagata gatgatagaa agagacatag 35340
aacatagtga gtcaatttag tgttgctcgt atatacaggt atttgtattt caaaaggacc 35400
cacccagatg gacctggaga gcatcatcct gagtgaggta acacaatcac aaaggaactc 35460
acacaatatg tactcactga taagtggata ctagcccaaa acctaggata cccacgatat 35520
aagatacaat ttcctaaaca catgaaactc aagaaaaatg aagactgaag tgtggacact 35580
atgcccctcc ttagaagtgg gaacaaaaca cccatggaag gagttacaga aacaaagttt 35640
ggagctgaga tgaaaggatg gaccatgtag agactgccat atccagggat ccaccccata 35700
atcagcatcc aaacgctgac accattgcat acactagcaa gattttatcc aaaggaccca 35760
gatgtagctg tctcttgtga gactatgccg gggcctagca aacacagaag tggatgctca 35820
cagtcagcta atggatggat cacagggctc ccaatggagg agctagagaa agtacccaag 35880
gagctaaagg gatcttcaac cctataggtg gaacaacatt atgaactaac cagtacccct 35940
gagctcttga ctctagctgc atatgtatca aaagatggcc tagtcggcca tcactggaaa 36000
gagaggccca ttggacacgc agactttgtg tgccccggta caggggaacg ccagggccaa 36060
agggggggag tgggtgggta ggggagtggg ggtgggtggg taagggggac ttttggtata 36120
acattggaaa tgtaaatgag ctaaatacct aataaaaaat ggaaaaaaaa aaaaaaggac 36180
ccacccaaaa ctgctgctgg aagtttaaat tttgaaaacc aggctaaggg gaaactcttc 36240
tgtatgaaac tcaaaggcat gtcacagatt tataattatg agaaaattaa cccaccatcc 36300
tcaagtgcac aacactgaag tgtgtattaa aattttgtgc cagagctcaa ttttatcact 36360
aataaaacca tggctgtcct agttgcgaag gaagctagaa aagcaaatgg ctgacatgtt 36420
taaaaacctc aggaaggtat ttttcccaaa tatacataaa gttccaatgc atggtggaca 36480
acgtaaactt ttagcattaa ttctaagact tactgcccag catgacctat taaacaaagt 36540
tatctggttg tatgcagggt caagaagatg gtagccataa tttcatcaag aaaaacttga 36600
aacatctgag gaggaggaaa ttccaaacac tcttgacata aactgagtta ctaggcagcc 36660
tcagcatgcg ataaataaaa aaaggaacag ggcttgtagc tagaatcgag tcatttattt 36720
ttaattagac agttaaaagt tttctaccta tgtatgtggg tgaagaaacg aaaacgattt 36780
tacagacctg attagaaaga aaggtaaaag ttcccagcat tgaataaaca tcctctcact 36840
tttaagaaga ttctaagaaa aaatctctag tctatttccc taaactatta atatgtttgg 36900
gttgctgagg agaataaggc ccagaggaca tgagccagag gggaaaagca cggttctagt 36960
ctgcctttcc ctattttaaa ctcctcaact acaaaaatag ggcctgaaat atcagcccac 37020
tgtcctctca gagtaatgga cagctattct gaccccgtga ctaatgcccc aggcctgctt 37080
caaattgctc tgaacttctc ccgctggtgc attccaagcc tgatgggtgg ttcccagggc 37140
aaatgctccc cattgcatga acttcagggc atctctaaac cggtcggact ctgcaatccc 37200
caagactatt attgggcatt ttcttcatgt gtttatagaa accacaaaaa cacaattaat 37260
aagcttctga accacatgaa caagtggggc tctcaaaccg tgccgaacac atccatattt 37320
ttagtactac agcactcaag acaatagaaa tgagatttca aaagggcaaa ctgcttactg 37380
cttacttatt ttcaagccaa aggaatcttg tgaaatcaaa gactccagat gccactttgc 37440
cattagggaa tatgaattcg atttcccgtt ctgaggggta aaaatactgg ccaaattgat 37500
gcttgtattc taataattag ctgggtatta taaatatctg aaatgcacga gaaacaatac 37560
agcgtagaca gctatcacct cacccacata gtgatatttg gcccagggag ggaatggtga 37620
acagcgtcaa taatttgccc ctctgtgtac agtcagagta agatatgttc tccccagaat 37680
tttgtgtaat tgaatgactg gaaattagaa agtgttgagt gaagcaggac actttctgct 37740
tagtgacagg acattttcaa atgctgagtt taatgtctat gttggttgaa agtccctaga 37800
ctttccaacc ttaaggtcat aatatgtaat gattatgtaa tatataatta catattttga 37860
tacatacttt acatatatta tgtaattatg taatatagct aagaattaag ctgataaact 37920
caggctgact tcctatgttc aaactctgcc ttctctatat aactgcctta tgacctcagc 37980
aaattcctct ctgacctttt atcttctata aaatgtcact attatggctc ctggatcaac 38040
tactgctcta gggccaggat actatgcatg caggagctga tgtctgggta ttagctggaa 38100
aaccaaaaaa taaaactttg gcaatcttca caaatgtcaa attgatatgt ttagagaact 38160
cttggatggg ctatagatgc cacattcttg gcaggggtat actttttgtt gttgttttac 38220
taaaaacata aaaaatcatc atttctctgg ttttttagtg atatcaagat ttggctacta 38280
tggtaagact atagggtaag gaattacaag tactctatag gtgaagcttt gaagatttta 38340
gtaagatgaa gcctgcccaa tcgcttgaag cagaaatgta acccaggcat ccttttgtct 38400
tatcagttaa agcaacatca aatacaatac caagaataca aaggtgaacc tgatttcaga 38460
caccttttga aatactgcaa tccagagaac attagggcag actctgaaca aataatgtct 38520
aaagttagca tacactgaga gtaaaagtgg tattacaagc tgattcactt ttattctaaa 38580
caataaacag tcaccccaca aaacaatatc tttaaactaa aacatacgtc ttaagagtgt 38640
acatagaaaa catttggaaa ggcagactga agtttctacc agtaattact gttgaggacg 38700
ggtagggtga tacattgggg tgtttttctt tctattttgt atattatatt tgttattcaa 38760
caccatgcat cctggcacaa aactgcctaa tggattgatg gtgagttttg tggtgaatgc 38820
caacatttag cccctttaat agtcatgata aaacgtgatg gtctagtgtt ctgactgtgc 38880
tgatgtgcaa tgtggcttat cttcccccag caaatgaact gcagcatcaa gtagcactgg 38940
attgtgccca aactttggtc tttaaacccc taggaaaaca gatcattgga ggaaaaagcc 39000
agtatcattc ttctcccaaa agaccctcta ttaggtcaag agagaaaaat agaagtcagc 39060
tctatttgga ctgagaaagt tgtggttcct cacataaagc gacaacatta ggaaacatat 39120
cctactatcc ttcagaaaca tacttaaatc cctcagcagc tatccccaaa attagccagt 39180
tcacatctcc cagtgttgat cttcatgttt ttatatttag agggtctctc cattgcctgg 39240
cttgccctag gaaagaaggg aaaagaggaa ttagtaacag ctgagcattg gccaagagcc 39300
aagccttgcc tatttgatgt aggttaccct cttgacaaag gccactgctg ccactacttt 39360
gcacatgagg aaactaaggt gctgagagac tgtcatttac ctaaagtccc taagctagtg 39420
aataatgaat gaagtcaaaa ctatccagtc tgacagtgct tgcttctaca cacaattcta 39480
atgttaaatc agagcccaga tgtcaattgt aattgaccac ttgataatct gcctttgaga 39540
cattcataca acaataggac aaactatctc cttaattgtt aagcagctag gactcagtta 39600
agggttctac cacagtaaaa tgaaatgaca aagtgtataa atttcttaaa agacaaaata 39660
cagcgccaca gactttgact ctccagagct atggtgggtt ctgagtcact cctcagtatt 39720
agggcgcata ctcccacgtt gtaattaata aggaatcatg gaaatatatc tttgaataac 39780
tactattctt cagtacttta cgtgtcagcc gtgcttacct tgggcaagct tttgaagcag 39840
aaaagtgctg cattgaggca taagcaaatc tttttatatc ctagataatc aattattgtt 39900
acttgacaat ctcaaatatt tcccaaaata gtccttagct aaaatgattt ttacaaatga 39960
ggaaaatgaa ctaaagattt tgttgttttc ttttctccct catacaccat tcctccctga 40020
acacacagga aaatggacaa aggaagtatg gtggccctcc accaggctgg gattctacac 40080
ccccagaaag gggctgcgag attttcattg ggaaacttcc ccgggacctc tttgaggatg 40140
aactcatacc attgtgtgaa aaagtgaggc taaatttaat ttcttttttc aggagaaaaa 40200
tatcattctc tttagtttgc tctgactggt tttcgccttt ctttatatct ctgtgtatga 40260
tgcatgtgta ttgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt 40320
ttatgctcat gtgtgtgagt gtggatgcaa acctcatgca catgtgcaga ggccagagga 40380
cagcacccag tatctgccat cactttctct tatgtttgag tcgggggttt cttatcgttc 40440
actgctgtac atgcaaggct agctgacttc cagatttctc ccgtctcggc atcctggctc 40500
tctgtagaag ccctgggatt gcagatgtgt gctactgcaa ctggctttac atacatcctc 40560
ctgtttgtaa ggcaagcact ttgcccagtg tgccatctct ccagtgccca gtttgatggt 40620
tctctcctaa gtccacacat caagtatgga cagtgttaaa atcttccctg acatcaatga 40680
ctgtcccctt atattagcac ctctttgccc agctctttgt cctgttgagc tgatgaattg 40740
aataaccacc gctgacaact ttcaaattca tatctcttcc tccaatctca gggctggcag 40800
ctgaaccact gcaaattcaa tgtatctaac aatacaaagc agagtagcat tctgccaaca 40860
acaagatatt gctccaattt gacatcttac cacgacttta taaagaacag tatttcatat 40920
aaaaattaat gtatgcttgt catggcttaa atatgtatct gtatacagac ataaaagttt 40980
cttctgcaag tagaattgat tatcttatta atgcaatgaa cagattaaaa acatgttact 41040
caatgtcctt aagagcaagg ttactcaatg tccttaaatg attactaagg aatatatttc 41100
cctacttcca atactttacc aggtgcatat tttcagccca aacacttaat atgaggattt 41160
ggctcttccc ctacatgatt aaaaaaaaaa aaatcaattg tcagcatgtg tagtctcaga 41220
accggaaccc ctggttttat acacagaatc ctagctgtca tactaaaact ccggaaaaac 41280
aggtaaaaac tgtgctcatc ttacaggaag aagaaacgaa tccttctcaa tgagtccttt 41340
ggagttcagt agagaaaggc tacacagaaa gcagccaagc actgaagtat tgtgcaggct 41400
taatggcatc tcttcccata tgcctattgt ttacatttgg accaccctgc ttacaaaagc 41460
taggggcaat aaactgctta gcctgtatta ctcaggatag ttgggagtat agaggaagag 41520
taagggcaag cagggtagat ggagaacaag tatcctttcc tctgtggttc caatcctcta 41580
ccagctgcta gcactcctag agtaagggca agcaggatag ctggagaacg agtccccttt 41640
tctatgaggt tctgatcctc tatcagttgt attgaggcta gcattccttt tcatcctaga 41700
aactgctcaa ataagagtgc tccccaggcc acctatgaaa tacactgtat gcattctgac 41760
atcatcgcag tggggaaagt acagccagga agttaggtta gcaaggtccc aaaacgagta 41820
ccctcgtttc ctgttataaa tgtcagtgac agagcatagc caagtaaagg tcgaagcatg 41880
gagacgttag agaacaactc agaaggcatg ggcaaatcta ccaggaaact gtgcttccgg 41940
tgacaaatgc atttttgggt ccccaagaca ttacataaat ttccagatac ttgtatgaca 42000
aaggtcattt gctctgccaa aagtacattc tgttagctga ggctgaaatg ccatttgtct 42060
atattttctt tatttaactc ggcttttccc atgagttaga taattaatct aaagccagca 42120
taaaagtatg caaaccattc cccatggata caaatgccaa acatggcagg aggcagtttg 42180
gcaagtatgg agtgtgtttc tgtgtgtgtg tgtttcggtg tgtgtttctg tgtatgtgtg 42240
tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tggtgcatgt gtttacgcac atttgggaga 42300
ataaatatgt aaataagaat gttctgtttc tattcattac agattggtaa aatttatgaa 42360
atgagattga tgatggattt taatggtaac aacagaggct atgcatttgt aacattctca 42420
aataagcagg aagccaagaa tgcaatcaag caacttaata attatgaaat tcggtaagtt 42480
cctgatctgc ttgacacaag ctgatcctaa agcttcacct gcacctgctt catatcaaga 42540
tagcatacat gtgtaagcta gctaaactag gaataaaatg ctacatcttt cttcgttaaa 42600
aacggtctgg ttaaacattt atttaatctc attactgaat gagccataaa acccacagag 42660
acaaaattta ttaattaact aatttcatta atacgttctg aatactcttc cagatattag 42720
aaatatatca agatatcctc tgttcccata gaacacaaat acaaaagatt aaataaataa 42780
ctcgcaaaca taaaaccgag gaggggtaag attgtgcgga gagaatgcta cttgaatttg 42840
ttggttttaa gaaaatactc tatgaaaaag gcaaatttga tctgatgttt agatgaaaaa 42900
ttcagtcaag acagtcagac cctaaacaag gttattcaaa gaaaagagaa agcagcaaat 42960
ggcaagtaca aaaatcctaa aattgaaaca aaattgatgt gtgatgtgtt tgaaagacaa 43020
gaagaaaaat ccaggagggg gaaaagaaaa aaaaatggtt aaaggtggga cagttggaga 43080
acattggtcc ctgctggaga atctgatctc atttacataa agacctggaa ctggaggaga 43140
attttaagtg gctttatgat tttaaagcat ggttacagct gctggctaca cagccaacta 43200
cagtagagca ggacccgaaa gagggaaact gtgtcaaagg ctgaggcaca ttctagatcc 43260
agacaaggaa tgacagtgac tcagtgagtg accacaagca aatgggacaa aaaggattaa 43320
gaactagata tcctgaaggc aggggagggg cgaacaggat gactccatat cacattcaga 43380
atttgggcaa ataacatggg atttgattcc aagcatctgt gaaagaggct attccattgg 43440
gaaagagaga ctaggggaga gaaggaagcg tgcgaagtgt cctcgttgag gtatttgacc 43500
ttaaagatgc acatcagaca cctcaggcaa gatacagtgc aactgtatga gagtagaggc 43560
aggaggaggg tcacagttat agcattctgc agcattgtaa accatgagac cacaggaggg 43620
catgaccgat gatgtataac caataatctg tttctataag accatttttc tttaaaaaca 43680
aacaaacaag aaaacaccac cagggataaa acctgtaata aatcctttct taaagagacc 43740
ctggaccacc tgggagggcg aggaacagcc atgcaacagc taagtctttg ggccagccaa 43800
gcttcactca agggccagca agtagttgct tctttgtgtc tcaatttcat ttctttatgt 43860
atgagtatgt atatgtgcgc tgagtgtgca tgtgtgcgca tgtacatatg tacctgcata 43920
gtccagaaaa ggatccctga tctcctgtgt ctggacatag caggtggttt tgagctgccc 43980
tacatggatg ctgggagcca aattgggtcc tttgcaagag cagtacgagc ttcaactatt 44040
gacccatctt tccagcccca actctcatct ataaagtgga gattatatcc atttcccaga 44100
tttgattgta aagataagtc aaagagtttt gaaaacttag tgcactattt aggacatagt 44160
agccatcaga tgataaaact tataacagtt caactccaag attcagtttc catattaatc 44220
ccttttctgt aatgtggaca aaccttaaaa ttcctggaat cttaacttgg atggccacag 44280
acagagtggc ctcctctcta gtatttccct acttcttata tgaaagtaca ttgcctcaca 44340
atgcatcttc atgtcctggg aaggaattaa cagctagctc agttttcttc aactctttag 44400
ctacatgtag aatgactggg tgtggcaacc tttaactgcc taagctggtc agttccaagg 44460
ctggattcta gaacagtttg agagaaagca caagtaggcc tcctctcctc tgtggaacta 44520
aaaaaaatct gtgtggtatg cagaaaactg gatatcccaa tcaggagacc tgggggcatt 44580
ttcccctttg gtaaagcctt tgacttctta gaacatcgct tttatccttg tacttgatca 44640
tatcacacag agattctgta aatatcatac aaaaataata tacaccgaca aattcagaaa 44700
aggctttgca aaactgtcat ttaacttgct ttataaaaat cactttaggg aagtggggtc 44760
gcgtcagcga gcctgtgtgg cgggaaacct ggggacgcga ctccaacccc aagcacagcc 44820
aacccaaggg ctgccccttt ttcccccgcg tggtctgctc ctctagttca cctaaggata 44880
atggtgacag ctgaagtact gaacatgggg aagaaactct atgagggtaa aacaaaagaa 44940
gtctatgaat tgttagataa cccaagcaga gtcctcctgc agtccaagga ccagatcaca 45000
gcagggaatg cagctagaaa gaaccacccg gaaggcaaag ctgccgtcgc caataagatc 45060
accagaggca tatttcagtt gttacaggaa gctggtataa aaactgcttt caccaagaaa 45120
tgtggggaga ctgctgcttt cattgcaccc cagtgtgaaa tgattcccat tgaatgggta 45180
tgctgaagaa tagcaactgg atctttcctc aaaaggaacc ctggtgtaca ggaggggtac 45240
aagttctatc catccaaaga gatgttcttc aaggatgatg ccaataatga cccacagtgt 45300
tctgaggagc agctcatgca aaattgtgtt ttgctggcct tgttataggg aagactgacg 45360
tgggcatcat gagtcgtgac acacaagcta tttttgaaat tctggggaag tcctggctgc 45420
cccagaactg tgcgctgaag atatgaagat tgaatttggt gttgatgtaa ccacatgtaa 45480
ccaccaaaaa gattgttctt gctgatgtca ttggtcatga ttcctagagg ctatggccat 45540
caggagatcg gagccagcag aaagacaaac agtcttaaca ttgatctcaa agaagtaact 45600
ccggaaggac tccagatggt aaagaaaaac tttgagtggg ttgcagactg agtggagtta 45660
cttctcaagt cagacagtca gtgcagggtg gtagtgctga tgggctccac ctctgacctt 45720
ggtcactgtg aaaaaaatta agaaggcttg tggaaatttt gggattccat gtaacatcct 45780
ctcataaagg accagatgaa acgttgaggg ttgaaacaca atgtgaaggg gatggtgtac 45840
ctgctgcatt tgtagcagtg gcaggcagaa gcaatggtct aggcccagtg atgtctggta 45900
atactgcata tccggttatc agctgtcccc cgatcacacc agactggggc gctcaggatg 45960
cgtggtcatc tcttcgactg cccagtggtc ttggctgttc aactatactt tccccagaag 46020
gatcagctca gtttgctgct cagatatttg ggttaaacaa tcatttgggg tgggccaaaa 46080
acttcgagtg agtatattga acacctggat atccttaaag caggctgata agaaaatcag 46140
acaatgcaat ttgtgaaaga gcaatttaat ttttaggaga aaagttactt agtcctagtt 46200
tggatttaaa gaaaaacatc aggcaaaatc atttcacata agagaaaaca attcagttta 46260
ctaatgaaca actggtactc agtgtttatg agttggcaca ttgtcagtgg atattactaa 46320
tattttctag ctctacaaag tgatatgtcc ctgtaacctt agcactccag agcctgaggc 46380
agcaggatct ctaagttagg gccaccctga actgtgtatt gagactctac ttgcagggga 46440
gggaatcttt atagttagta aagttggcat gacattacta aatttattct caccctatgt 46500
atggtcattg ttgggtaaat atgtaattat ggaactggag caatgtgtct gctatatgaa 46560
ccactatgaa gaaccagtat ggctctcttg ccgacaacct gtatctgtca gtttggttcc 46620
cagtatctgt gtagattgcc tcacaataaa taacctttaa ctgaggggat ctgaccccat 46680
ggcttcctta tgtacctgct ctcaaataca tttccccacc caacacacaa aattttaaaa 46740
agtaaatttt ttaaaaagaa tattgtttct aaatggtaat agcatttttt tattaatcag 46800
tagataatgc ttgatctgag ttgatgcttt gaaaattaaa atacttgtat tgtgtataac 46860
aaaaaaaaat cactgtataa taatgaaatc acaaatgaaa acatacaggg ggctggagag 46920
ataattcaat ggttaagagc acctgaagcg cttgcagaag actggactgg gttcagttcc 46980
catcatcctc atggagagta gtaactgtct gtaactctaa tttcaggggc tctaacctta 47040
tgttctctca ggcactgggc acaggcctgg tacacataca cacgggtggg tactcataca 47100
tacacataaa attaaataaa tatctcttaa ataatacctt ttaaaaataa ggtgtaaaat 47160
tataccattt ttaaaagcat tcacctagat taaggtagcc actccaacaa agtatatatt 47220
ctagttagat ggtttctgga atgagaggat tcctcgtctc tccgtcttct atgaaataca 47280
gacattttat cagtaaggac aatcctaagg agggtttggt ttgaaatata tgtgaaattg 47340
actatgcagg agactgatag ctagttgtat ctattccacc tgagcttact cacagggtcc 47400
tgccaatggt attgaaaata gagaagatat gaaataaata ccaccatgct acagggtaat 47460
tattcatgaa cagtcttctc tgtgaatccc actgtctttt ctataaaaca gatgaaacca 47520
cttctctcac acagggtgtc atacaaataa caagaataag gtacttaaat ctctggccct 47580
caaaggattg ggtgttctgt aagttgactg gcaactgtgg gggtgactgg tggggagggc 47640
agagaaagga gggaaatata ataatttaga aagataacgt attcaagaac agtcagttct 47700
ccatttggaa gccagaagca aggtaaagaa acagagaatc tttacaaatt aggaagtggg 47760
ataaattcaa catgaactag tcaggaagag accacagagc tgccttcacg acttccattc 47820
tgctgtggtc aatctgccag agagagagag agaaagaaaa aaaaaacctt ccttccagaa 47880
aggaacaata acctttactt tgctgtcagc cgccatttct ccagggatgg atgaggccat 47940
tacccagaaa agacctgcag ttatcacatc atcttcctcc ccatcaaata ttcactgagc 48000
atcctctaaa tgctggcttc tggagacatt aaagtcatgt ccttggcttg tgagaaggtc 48060
cattttgtct ccagacaatt ctaggaaagg atgttgacca gccatacaca tttagaaatt 48120
ctagactctc tcctgctggc aaatgatatc agaacagtcc actaaccatc aaaaagaaaa 48180
acaaacaaaa ccagtgtggg catccttcct cttactatag gcagctctgc aaagctgaat 48240
aaacagaggc cccagggcca gctgcacctc tcagaatcaa taaggccttg accaaatcac 48300
ttaatttctt ggaatctcaa gttcattatc tataaaatag aaacatcacc tagtttgctc 48360
atcttgcagg cttttttgta tgggacaaat aatagaagaa aatctgttac agacaagaaa 48420
ctatttctgt tttattttat tttatttatt ttgtgtgtgt catgtacacc atgagtgcat 48480
ggtggtcaaa ggacaacttg tgggaatttg ttctagcctt ccaccaggtg agtccacagg 48540
tagaacatag atcatcacac ttacaatcag gcaccattac ccactgagcc atattgctgg 48600
ctctttgtaa ttttgggatt gggggcagtg cattttttac ggtaatcata tcagaaccgc 48660
ttcttgattt ggcagtgaca tacatgcatc atgagtagta gcaaacccca gtagcacagg 48720
gtgagtcggt gaagtgagga gcagggccca gtatagacaa atgccttagt gctgagacat 48780
caggatatgg agaaaacgat gtcaaatggt gaacccacat ccagtctaaa gagaccaggt 48840
tccaatcagc tttccatcta gtttcccttc ttacaaagtt cagaagtcaa gactgcgaac 48900
atccaggagg ccagtggcag aatctgtgta gcacacacaa tggtcctggt accacaaaag 48960
aaaagaggga aggggtatga gtctatactg aaacatcttt cctctaaaga aaccatattg 49020
tatttggaag tgttatacac ttgcgacctc taccaccacc ctccattaca cacagattct 49080
cacttatgaa aactgcttaa ttttccccca ccccgtttag gactggccgt ctcttgggag 49140
tctgtgccag tgtggacaat tgccgattgt ttgtgggagg aatccccaaa accaaaaaga 49200
gggaagaaat cttatcagag atgaaaaaag tcacagaagg agttgttgat gtcattgtct 49260
acccaagtgc tgctgataaa accaaaaacc ggggatttgc ctttgtggaa tatgagagtc 49320
accgagcagc cgccatggct aggcggaggc tgctgccagg taaaccattt ctgaacagag 49380
actcccagct cgcagcagac cccggcatga gcgtccctgt tgatcttcct ttaagctctt 49440
catcttgttt atttctctca cagttgattc agttccataa aatgcttata gatgtgtatt 49500
ttggaaaagt cacacctctg cacatcagga gaactttgat cgatagcaat cccacagaga 49560
atcctccgcc aagaaacttt ttaagattaa agaaacccat catggatata gctgcatgaa 49620
agttcacagg cgagttagaa ttgggctacg tcacctatca cggtgtacat gcacaccagt 49680
gtgtgacaca ccatcccaag gatagccaac agacatgctt tcaatgtgtt tcccagtttg 49740
taataatttc catctaattg gagataagaa atatgaatgt tcttcctgta cacctctatt 49800
tagacacttc agacacacat gtgagcacca atcatcaatt catgagttta acgacacacc 49860
aacactgcct aggtcagact aacacaggca aatatgcaaa gttccttggc ttgctgtaaa 49920
atagtcacta aaactcaaca cagtcgaatg ccaaagtgaa ttcataataa tggaagaaac 49980
tatctaaacc actagttctc aactgtcata atactgagat tcttttttaa tacaggtcct 50040
catgttatgg tgaccccaac cataaaatta tttcattact atttcacaac tgtacttttg 50100
ttactgttac cactcattat ataaatatct aataggaagg atatctgatg tgtgacccac 50160
aggatgacaa ccagtgatct agagtgttaa gtagctggca ctagggtcta ctcttatgaa 50220
aactatgaga gatggtgggg gaggtggagc aggacaaaac tctgacatta ttttgacttt 50280
atacagtctt tcctgactgt actttttgtc tttaatggtg gtgttgattg aacagagggt 50340
cttgagctac ctaggcccac attctgccac tcagctatgt ccttgctctg tgtacgttcc 50400
ttataagtta ccatctaagg cattgggtat cattgaggta tgttcagtgt tttggtagac 50460
tctcttcccc ctcatcttct tttctttacc tcctctgatt ctcagacagt tgtgagcctt 50520
ttgtaggctt tcagaattga agtcaagtca tctagagggg cagctatgct cctaacagct 50580
gggtcgtccc tccagctccc gttactattt tatatggttt agaatagagg tctgatttcc 50640
acgtgtggat taggataccc cactttaccc agaaatcttt taaatattat ttagcattgc 50700
ctgacctcaa atctgagctc ctccttcctc tgcctcatca ggtaccacta tgcccagtgg 50760
agcctagtgc tatttattaa agagactaca ctttctgttt gtatgctttt ggcacattct 50820
gccaaagacc acaattgatt tgtaagaaat aagagggtgg acatttgctt cccctatata 50880
ataattacac caatagatcc ttcccgacac taataataat ttctgatttt gttctgtcca 50940
gttctgtgtt ccctacaaga taaaacttac ttccaaacag tgaattaaac aagcaaccta 51000
tattttccac aacgtgtaga aactgagttg atctctcacc cttatcccac cacttcaacc 51060
tggagcctcc agggatatgg tggctgagtg gcaaaatccc aaggggaaag aagtagtgat 51120
aggaagttac tgttcggtgg caatctttga agctgtaaaa gtgggtgctg ccccccctcc 51180
ttccacaaga tcatgataag aaagaactga gaggctcatg ggaaacacac agcatagtag 51240
gaagcacaca gtaagttact actgtagagt acatgaacct ctgctgactt gggtcacacc 51300
cactctttta agacaacaag ttacaatttc ttatcatcaa ctgtcttctt agtcttctct 51360
gaattgggac ttttaaatat acatatacat atacatatac atatacatat acatatacat 51420
atacatatac ataacatata catatacata catatatgtt ttctccgaga tcccacatta 51480
cctgtactca gactgagaat gtggaaggag cacagttggt ctgagccctg gatcaaatct 51540
gagagaccga ggacaaagaa tgtttggccc catccaccct gactcctttg tgtatgtcta 51600
agtgatggtg tctggctaat agcaacacat tccaactacc gcggatgctg tccaaatgac 51660
ctcttaatgt ttcatggagt cagactctgt gtctgagccc taaatctgct ctttctcccc 51720
ttttattatc tcaccttaaa aactacctcc ccccccttga aaaagctgtc ctgagagtca 51780
aatgcaccca ctgcgtcctc actctttctc catttcaaac cacatcctgc ttctctctat 51840
acattcaatc attatgataa gccactagtc acactgaaga ctctcctacc agactctcac 51900
tttatttaaa tgtctttaaa aatcaataat aatctttttt agtggtcttg gtcatttaag 51960
accttaacgg tcagttcaat ttaaaagacc atcagcatgc gctgagatga tgtcgtgatt 52020
tctaaataat tcatcactct tctgatcatt gtcaacagga agaattcagt tgtggggaca 52080
tcctattgca gtagactggg cagaaccaga agttgaagtt gatgaggaca caatgtcttc 52140
cgtgaaaatc ctgtacgtaa ggaaccttat gctgtctacc tcggaagaaa tgattgaaaa 52200
ggaattcaac agtattaaac caggtgagac aaatgtgcaa ttacttcttc aaaatgtgct 52260
ctaaaaacac ttacaccaga ggccattacc cacaatgtta aggggaatgg cttttattta 52320
gtcacttctc ctaataagtt gtatattgtt caggtatttc accatttttg gatccaaaag 52380
agacatgtgg tcctacagca cttaggaata ttacggttta tattcatctg tgtagttatt 52440
taatgaatac acatcacctc tgccaaacta aattctatga gttcccctcc ctctagttag 52500
ctcctctgtc cctagaccct cagactaaga acaaagtaag catttactat gttaatgatg 52560
tctggctctt actgaaggtc taacctctaa cacacctttc cttgggggca aatcatcctt 52620
ggtagattga acagggtatt gaacaacatg caaggtccat gccttcccct gccagctata 52680
gcaacctgcc caggtgacaa ccaaaggcat ctcctgacat ttcctattca tctgtctggg 52740
aatgtcctca gtcacgccag cctgtgtcta tcataaaaac atcttcatgc aactgagagt 52800
ttcttgggca atttctatag gatgctaaca aacatgggcc atgatgctgt cctactaagc 52860
ctcctgacag tgtttacacc ctcagattgt aagtggatgt gatgttacat gtgtattaca 52920
atggtaataa gcatataact ttttttaaca gataattagc agggctatca tctttttcag 52980
ttgagagatt ctcaaacatt tctcttcctt caccctcaag aactctgcct tccctgacat 53040
tcagtatcat ggtatggttg gataccaaca gctgtgaatc catagttact acagaaactg 53100
ggagaaaaaa tcctctagaa ttagagtggg cgtgttcaca tcacatgcca tttagcatca 53160
taatgcccta tcctgcaggt tcccaggtgg tgtctattat ttcctataat gcggaaaaaa 53220
cagagctcag agtagttaaa tcgtcacaca gctagcagct ggcagacccc agatttaaca 53280
accttctgaa ccctcacacc agccctcatt cctttcacac attcattcat gcagctgcta 53340
ctccatggta gctccagcat gccacgcact gtgggaggaa ttaacagatg tgagctgtgt 53400
gtggaaggaa tttatagaga agtcacagct aaattatcct gtgcttggaa tgcagagcaa 53460
aatccgaaga caagtcactc atggataaat ggtagacctc aatgcggttg taccggactg 53520
ggaactagta catatgtgta taggtttcac ctgctccagg ttgggttttg tttttcccag 53580
agtgaataat acttactttc ccttccaatt aaaatggcac ttttgttttg aaagaggtta 53640
gagtgaggaa attttgaaag actaactctt ttctttatag tgagtgatta tcagtccagt 53700
ctaaacatct aagataaata tgcctagact atagtgtcct agaagctgta agaaaagaat 53760
gaatgccaac ttgttccttc ttgcctcttc ttcctttctc ttcccccatc tcctcccata 53820
tcttcagtta caaccacccc cagcataata ctatattatt attaaaacat ttccagcaat 53880
cctggggcac ttcttagacc agtggcacac cacttggggc tctataataa tgtgtgtgat 53940
gcctaaaaga ttatgaacaa ctagaagata tatatcctat ggagatagag aaaaaaatcc 54000
acaaatttct tctccagtgc tacaatataa tgtatcaaga tcgtattgtg gaaagagaaa 54060
aataacatca atttttatct ttttaaagat ttgggttttt gagagacctc attattcatt 54120
gaaaaaatct aactttgtat atcatttgaa ccctggctga cctaggaaaa tacggcatca 54180
atattctgga aaacaaatga cagtggtcac agaaacctcg ggccattgat actttgttct 54240
catgaagtct agggtatctg ctgtcgtgct aagtatggta ttctgtaaaa tctgttccct 54300
taaacagctc gacagtagca gaatcttctg aaggactgct gaaagcaaat tgcttacccc 54360
atctggttga gtgtacactt ttgtattgca tttcttacat ccccagatgc agctaatgtt 54420
actgagtaaa gaactaccct ttgagcgtgt tttcctaatg cctgttagga tcacagatct 54480
agttcttctt tgccgatggg taagccatga ataatgatag caagcactga ggaggaatat 54540
cttaaaggaa agcctatggc cattgctatt ctacagaagc tagtcaaccc tggatataaa 54600
taactctgaa tgtggtggct cttgtttggt ctctaagtag ggttagacca gggtagtatc 54660
tagatgggag aaattcatgt tgtattattc aaacccctac tttctaattt actttctatg 54720
ctcaaatttt cacaaataaa actttccata agcagagtct gaatattgct gctaaaaaag 54780
cataaaaatt tcaatattag caagaatttc agaacaccca aatccattat caatacaaat 54840
gctacataat taacatgact gatggggtat atggaaattg attgataata cattgtactc 54900
tgcgtgttta ctgagagact agctcttgta tccttgacac taaggaagag gtaagtgaaa 54960
atgatatttt gtgcagctaa agcacacaca cccccacaca caccttagga aattatagct 55020
cagaagagca gagtggaggg gaggggtgga ggccgtcctg gatgatcctt ggttctcatt 55080
gaccaagaca agcgtgggat gaagccttct cacccttccc tctaacactg aaggactaag 55140
gagattgact taaaatctca gttaattata tgtcctgtgt ttcatgggtt catatgcctt 55200
tatttcattg tctcagtctg gccagataat tttgctctgt gtaattattg tcatgagaca 55260
ctaagggctt cttaagatac taaatggaga gagaactact gcaatagttt aaaattaccc 55320
ttagatcaca tgtctcccgt tgttccaaag gaaggtaatt catggtcatt gaaccatgtg 55380
gtacagtatg agctctaaat gctccagtga ccctgaatct agagagcaac tgaactctga 55440
taggagaggg attttctttt cttctgattc ttcctgagaa cagtgttacg tcatgttgac 55500
tctgagaact acatgttaaa tgaagaaacc cagcctttca aaatcacgcc agctgaaaga 55560
taagcagtgt gctcaggtgg tagtgaaaca agattccact taagcatcaa ctaaagaaaa 55620
catttgtttg gaatactgag tgggcaacaa tatgcttaaa agataacatt aagcatcttt 55680
gtccaactaa ttttttaata tgttatcctt aatatgtaca acggcctttc tacataaaaa 55740
taggagaggt tgctttctgg atgtttgtac acaataaact aaacgaatct ttataaaagc 55800
aggtcaatta aaatgttttc atcgtgggac tggaaagctt gcactgttct tgtagaagac 55860
cccaattcag ttgctagcat tcatgtcagc tggctcacta atgcctgtaa cttgaactcc 55920
ctgggatcta tcaccaactc ctggcctcca caggcccctg cactcacatg cacataacta 55980
cacagacaca cacagacaca cacacacaca cacacacaca cacacacacc tatatttaaa 56040
ctgctttcac tttccccaac acttttctct gttcctgaag taagcatgct tagcagtttg 56100
atatccacct ttccaggtat ctctgaatat aggtggactt gagtttgtct gtatttacat 56160
gtgggttgag atatttaaaa cagatactca cattttatcc cattataaat tttagaaaca 56220
gacaataggg tttcgatctt tccatgtaag tgcatataat cttactctaa tctctttaaa 56280
gactcaatgg agcttgtaaa aaaaaaagcc tcaaattgaa tcatttctga gaaaatgggt 56340
cttgctttac tttgttattt ctacggtggc ctaaccagca tctttataga aaatccttgg 56400
gcataggcag aaactcttca gtataagaaa caagttagaa atagtagata agtagttttt 56460
tccaatcttt caaatactac atgcagaaac tattttagat ttcagatgca ctttcagaag 56520
caaaattttt ttttgggggg ggggaggttc gagacagggt ttctctgtac tggaactcac 56580
tttgtagacc aggctggcct cgaactcaga aatccacctg cctctgcctc ccaagtgctg 56640
ggattttttt ttttagattt atttattatt gtatataagt acactgtagc tgtcttcaga 56700
caccatgatt actacttttt ttttcatttt tattaggtat ttagctcatt tacatttcca 56760
atgctatacc aaaagtcccc catacccacc caaccccact cccctaccca cccactcccc 56820
ctttttggcc ctggcgttcc cctgtactgg ggcatataaa gtttgcgtgt ccaatggacc 56880
tctctttcca gtgatggccg actaggctat cttttgatac atatgcaggg ggtactggtt 56940
agttcataat gttgttccac ctatagggtt gcagaaccct ttagctcctt gggtactttc 57000
tctagctcct ccattgggag ccccgtgatc catccattag ctgactgtga gcatccactt 57060
ctgtgtttgc taggtcctgg catagtctca caagagacag ctacatctgg gtcctttcca 57120
taaaatcttg ctagtgtatg caatggtgtc ggcgtttgga tgctgattat ggggtggatc 57180
cctggatatg gcatgcgcca ccacttaaag atgttaatta agtgcatggg acatatgatt 57240
ctagacctta ggtagctgtg tgctgtgtga attacgaacc cacctttgtt agaactgtaa 57300
cttcctcgta tttatataaa agtaaaataa aattaactac acagtaatta gcacaccaca 57360
ttggtaacag ctcccctaat tccagatttc ctttatagac aataaaatag ggtattctca 57420
gcagagtgag tgtggcgttt ctaatgggag tgagttaagt ctttcccacg ggcttctaca 57480
gtgcccagaa tcacactcca ttgacaccat gatcacttac cagtaaatga cttcatgaaa 57540
agcctaggaa gatagtactg agctgtgaag gaagtgtcgc agataccaca tcacattctc 57600
gtgacactgg atattcatgt gacctgattt tccttctcct cccagcagac ctggatgaat 57660
gttccaccat agggcacagg atcaggcact ccatggagcc acactaacac ataatagggg 57720
gtgggaggga agtcagagca gctaatactc ctggctgaaa tctgaccaat gggaatagac 57780
tgggaaattg tgacttctct catgcccatg gatcattgca cagtattgtt tcttctccac 57840
aacagagact gggggaagac ttcagcagcc aggggatata cccgcccctc ctctccaagg 57900
ctgcatgagt agttccctgt tcatcccctt gctctagctg caattgcact ttctcacttc 57960
tataccttgg ttgaacctcc aagatacagc agtattttga agtaaatgag ttaaataaat 58020
atatgtgtat aagatgacca atatcaagct agtttagtaa cacattacct tgtatagaat 58080
attatctttt atatttctta ccatttatat ttttatatct ccttactaag atattattct 58140
ttcctttaaa tttcctataa tctagggtta gaaaacttag ttcataacta taataaatca 58200
ggttatcagc attttatgac aagtaaaact tatattgact atacagaatt ctaaacctag 58260
acatgcaaag gaatctcacc tttggaagct agccacatca ctgtctcaag tttgctaata 58320
gtgtggctgc catcacatca acaggtgctg tggaaagagt gaagaagatc cgagactacg 58380
cttttgtgca cttcagtaac cgagaagatg cagttgaagc catgaaggct ttgaatggca 58440
aggtaacata agaaagaaga aaatgcacac agattccatc catacttggt ataggcatgc 58500
tctaccaaag agcaacctct ggagtccatg ttagcccagc tctctttccc caccactgac 58560
ccagaagctg cagtcctttg gggatgtatg gtagagaaat ggcaggaaaa gatacagaga 58620
acaaggaagt ggctaggtag ctaattctaa cacttacttc tttttatgac ttgaacaagt 58680
cactgacctc aatttttatg tgaagaaggg attcaagttt ttccagatgt tcccctagtc 58740
cttgctagtg ttctattgct gtgaagaagc accatgacca agacaactct tataaaagga 58800
gccatttcat tggggtcttg tttatagttt cagaggtaag cccattatca tcgtgacaga 58860
aaacatgcca cggcaggcag gagagtagct gacagctcta catcctggtc tgcaggcatc 58920
aggcagagag agacacttgg cctggtttgg gcttttgaag cctcaaagcc ccagaaacac 58980
acctattcca acaaggccat atcccctaat ccttccaaac aggtcatcag ctgggaacta 59040
agaatacaaa cacatgagcc tgtggtgcac attctcattc aaagcaccaa atcccccaag 59100
ttccaattat ttctaattat tgtactttat aatgcagtga tttaaggaac attagccaga 59160
aaaaaaggtc aagatagctg tcattctgat ctcggtattt gatcttccca tcagggaggc 59220
ttagaattcc tctccttgcc aggagtgaag gctaggagaa agtcaacttc taaattccta 59280
ctgtttattt gtctacagaa acttatatag tatttggatc aatcaaataa acactaaaac 59340
ccatctatgg gccactgatc tgtaatgtcc agaatgcaaa attaatcaaa gcaaagatgc 59400
ttatcaaggg gttgagagtc tggagaacta agttaggccc acaaacacct ctgcaaagta 59460
gtcatctcga tgttattaaa agacatttaa aagtaagaag ttcaaatgaa ggagttaaga 59520
aaaccatcat gtattagaag attctgtgca aaagaatgta tgaaaattgg atatactttc 59580
aaagggtaag ttatggcaag gcgagtctgt cctaatggca gaatttgaaa tattaagaaa 59640
acatctgagg acagcaaatt gggtcagagc acaaggccca ggagactgct ctgcccatta 59700
agtcttctat cagttcagat tccagtagag gttgggtaga aagaaattca ctccacaaat 59760
gtgagaaagg gggattcaaa aatagagtgt cagagactag cactcataga tttctggcag 59820
taaatgcaca atagaaagag caggtaagaa atgcctcagc aagttcatct gaacaatgct 59880
tttaataccc tccacccttg ccccattggt cccatgaaag catctcttct aaacagcagt 59940
taccaaatgg ttgtcattgc ctgcgccagc aatccttggt ctctcaggca gtcctcaact 60000
tgatcctcct gcaggagatg cttttgaggt tgcacggccc ccagggtttt cacagaggtg 60060
gccaccactg ttcctcctac aggagctgaa gagttagtag aagcccaaaa tgagaccaag 60120
ctgtagagag caagcccctt ggaaggaaca ctgatctaga atcatactac cctgaggctg 60180
ctgggtcttc tccaaaaggt cttgggttaa atcatatagt gggtccaaga agacatctca 60240
gggaggaaac caggaaaaca catcctaagt tcactgtagg ctcatcccta tcctcatagc 60300
caaggttcct gttagccaaa ctcaatgaca aatcagaggg cccaggagcc cgaagaggaa 60360
cttatataga ataatcacca gaacagactg cagactggac actggtggga actggatgtg 60420
aagaacaagg gaaaggcttc ccagcagaga ttccttcaga cctgggggag catagggcat 60480
gtgcaatctt agggacctgc aacactcttg tagggaatta agcggtgact ctgaagtata 60540
tatatattta aacaaaactg taaagtaaaa tcaattgata tttaaatgta ccttatgacc 60600
aaaacgttat ttcttcattg attactatat tagcatcttt agaatgatac tacttcaaaa 60660
acaatgttta aggtagcttt ccctcaataa acatgcctga attcgcatgg tatctactga 60720
gaagaaccag caaccataaa cccagtgcta aataatacac tggaataatt ccagttgaaa 60780
agtgtttaag ttataccaat ttttaaggct ttgttttggc ttaaagttta agaaaagata 60840
gtccattttg gatcccggga ttccggcaac cagatgaccc acgctaccgt ctcgccagca 60900
aaacgcacgc aggccactcg gatccttctg cagtacagct ttaatatatc tcgagagata 60960
gatgatcagc ttcaggagag gagacccaga gagcagaaaa cccttccctt ttatttattt 61020
ttttttcctt tgaactgttt tattgagata attataatga caaaaagtca taacttacac 61080
agacctatag taatggttgt gacttaaaag taatttaaaa ataaattgtt catcaaagtt 61140
tcatattaac atttcttttt tttttcattt tttattaggt atttagctca tttacatttc 61200
caatgctata cccaaagtcc cccataccca cccaacccca ctcccctacc cacccactcc 61260
ccctttttgg ccctggcgtt cccctgtact ggggcatata aagtttgcgt gtccaatgga 61320
cctctctttc cagtgatggc cgactaggcc atcttttgat acatatgcag ctagagtcaa 61380
gagctccagg gtactggtta gttcataatg ttgttccacc tatagggttg cagatccctt 61440
tagctccttg ggttctttct ctagctcctc cattgggagc cctgtgatcc atccattagc 61500
tgactgtgag catccacttc tgtgtttgct aggccctggc atagtctcac aagagacagc 61560
tacatctggg tcctttcgat aaaatcttgc tagggtatgc aatggtgtca gcgtttggat 61620
gctgattatg gggtggatcc ctggatatgg cagttccctt ttataggctg cggaaaaaaa 61680
cggttggaga cgtgcaccac tgggattggc tgcccactat cagtcagtta acgccacgag 61740
agaggcaggg ctcaggtaat ggaacgatac cctgacgcct gcgcacattt tactacgagc 61800
aacggatgtc agcgccatct tgtaacggcg actgtgaggg cggctcctca cagtggggaa 61860
gggatgaaga tgaactagtc caattctttc cagacttaca gacagaaaca atggcattca 61920
ttataatagt ctctatgcca agttcaagtg gctgtattac gttgggatgt tttaataagc 61980
acatacagaa tattatgact ctaaaaaaaa attaataaac atgtaactaa aaataattta 62040
aattactttt ttacttatca atccccttat ttatactgct ttcttccaaa gtagctggag 62100
gcagtggtag gagcatggga tagctagtca cactgtatcc agtcaggaag cacaattatt 62160
atttgtttat tacatagaca cttctataac aatgtttaca aatatgtagc taaatatgtg 62220
cttaatatta ctagtaaata ctattaattg ctatttttaa gcataatata aaaattatgc 62280
attagttttt ctaagctgag tattatacct atggttattt ctatttattg ggaaaagtta 62340
gactttgggg atcttttgta agatagtgat catattacaa tttaaggaga ccagtgaaat 62400
gccacacggt ggctagcaag atcactcctt tcctttaaaa aaaaaagatt tattaattaa 62460
ctaactaatt aatttgggta cttaagatag agaggggtat ctctttgtag gctagacttt 62520
ctgggaactc actatataga tcaggctggc ctcaaactca cagagatcct cctgtctacc 62580
tccctagtgc tgttattaaa ggtgtatgcc acctgtctga ctattgcaat aattcttaag 62640
ggcatttttt gattttttaa ttagatattt tatttactta catttcaaat gttattccct 62700
ttccaagttt cccctccaca acccctctat cccctccccc accccttaat tctatgaggg 62760
tgctcaccca cctacccacc cactcccacc tcactgccct ggcattctcc tacactacaa 62820
catcgagcct tcacaggacc aagggtctct cctcccattg ataaggccat cctctgccac 62880
atatacaact tgagtcatag gtccctccat gtgtactctt tgtttgatgg tttagttcct 62940
gggagatctt ggggggtggg ggtgagctct ggttggttta tattgttgtt cttcctatga 63000
gttgcaaacc ctttcagctc cttcagttta aggccatatt ttaagtggta tctgacttga 63060
gagttctcag tatccctatt acccatatcc ctgacatccc tatttagaaa cttccaactt 63120
cacagtaggg caaacatttg caacagtcta ttaggttcct cttacttgag tagaatctaa 63180
ctaggctcct ctccctcccc aggaaaaacc tattaggtag ctgccccaat gagccttttg 63240
ttgagcctgg caagacttgc tcaccagagt gttaataaat gataagatat ctttactggt 63300
ttctatcacc tgcattttat catgctgcat aacctgtatt tcacccataa agatccccag 63360
ctgtttatac ttacataact atgtgatttt aaacacaagt atcacactta atagaaaata 63420
ttgcattatt ttatgtctca gtgactgtct ctgtattata aattcagtag tcaaaatggc 63480
attgttaaac ctgttgccat tctgtgcaac tatcaacaag actactcgga gacttgtcaa 63540
ctgatacaga agcatgggct tggtaaggga caaaaccatt aagaattgca agtcaccaga 63600
tggtagacca agacttgtcg gatgacttct cagcttggct tttcctcgct ctctacaaca 63660
ggtgctggat ggttccccaa tagaagtgac cttggccaag ccagtggaca aggacagtta 63720
tgttaggtac acccggggca ccggtggcag gaacaccatg ctgcaaggag aatacaccta 63780
ccctctgagc catgtttatg accctaccac aacctacctt ggagctcctg tcttctatac 63840
cccccaagcc tatgcagcca ttccaagtct tcatttccca gctactaaag gacatctcag 63900
caacagggct ctcatcagga ccccttctgt cagaggtaac actagctagt tcttgtcttt 63960
ccataactcc taaatttcaa atgactaata aactatagtt tagatgaact acaaactata 64020
tagtccagta gccttaaaga gattgggtgg aatcactggg agaagaaaaa acaaagagta 64080
gaaaactgtt tttaaaaatc gaatatatca gctctcttgt cttatagaat ctattttttc 64140
acattacaac tggttaatgg aaatacttgt tagaacatga tatgaatgag cccaatatat 64200
aaattagatc cttgagggat ccacaaagta tgcacagaat acaacctagc tctataacca 64260
ttgctccttc ctccttatta gaccaactag actgattaca gaactttcaa gggagagcag 64320
tattgcccga tgagaacctc ctccaatgag gcattctcat atgaactcct tcgcagatat 64380
gtgtgtcata cctttgttat tccatgtgtt tgtctgcatg ttggtcacaa gggcttactg 64440
tatattccag gctgctcaag aactcccagc acctgcctct gcctcctgac tgctggagtg 64500
gcagatgtgt aacccatcta tgtgcaatca ctttgaaaag aggcaagcaa ttaaagaaat 64560
taatatttct ttagtataac ggaaaccaaa tacattgaaa taggaaaaaa aactcaatct 64620
cactgccaga ctgtgtttta tgtttaaatc ctacacagat tcactgtttg agcaggtttc 64680
tgagctcaga aaattcagta aatgataaaa gtaatttgtc tctgcctcgt ggtatctttt 64740
attgtagttt ttcttggtta tagccaacat tatatggatc ccaatcctgt attccacata 64800
tgatagcaat ctagaaaata gaaacaaatg atgtgtttaa atacactctt gggtgtaact 64860
tagaataggc ccatccagat tactatggaa acaattctct tactatgtta cattattttt 64920
catgcgagaa aaatgaattg aacatcttag gacctcttca gcggccttaa aagttctttt 64980
ctcacaatac aattacccct accaaaattg ttatacaaaa gtgacaatga agattttatt 65040
tgaaatactt tctatatatt ataacaaatt atgtcatgag acattatgca tatatatgta 65100
atgcatcatt aattaatcca tatatcttac atattatcaa ccagttgtga tgtagaaaaa 65160
aagcaaactc cattccaagg ggaaataata catagcatta acaaaaacat aatcaatgaa 65220
tgatatttat gggcaaagag tgatccactt aatggtttat tcctttatgt caccaatagg 65280
aaatcactgt agaaatatgg ataaacaaaa atcaaaaagg aatctttgta tgaaactcaa 65340
caaaattaag cctcacatca acagtgcata agagagtggt gaacttaagg aaaagatgct 65400
gcctaaatgt ttgtctgatg acccaccatg gatgtgataa tcaaattcac ttctgcctta 65460
ctggcagagt ggcgtttact ctaatagtct ctatcccaga ctagctataa ttcaaatagt 65520
catattatgt tgggatattt taataagagc atactgaacc ttagtgattc tgccaaaaat 65580
tttaacaaaa ctagttaaaa aaaattcctt ctgacaaaat ttgaagcggc tgtgtactta 65640
tcagtctcct tgaaggaatt acttccttcc gaaggagatt taagaaagca agagtctatg 65700
gtgagcctta cctgaggttg agtttcatta cattagaatc ttaggttatc tgtccgtcct 65760
ccgggcaata atcaatgtga cttgggctaa cttttccatt acagtaagat tcagggtgat 65820
tttctggtgg tttgattcag tttaatgcct tcttacattc ctagaaattt acatgaatgt 65880
ccctgtaggg gctgcggggg tgagaggact gggcggccgt gggtatttgg catacacagg 65940
cctgggtcga ggataccacg tcaaaggaga caagagagaa gacaaactct atgatcttct 66000
gcctgggatg gagctcaccc cgatgaatac tgtctcttta aaaccacaag gaattaaact 66060
tgctcctcag gtaggtaaga tcaatccaga ggttgttaag ttgggccagg gaccattgtt 66120
ccgatgttta gagttggtct taatttggga tactgttctg tggcaatcag cttagcatac 66180
ttcgagtggc tgctgagacc agctgccatt ctggcactaa atggaacttc atcaagaccc 66240
agcaaaatga aaaacaaacg aaatcctgaa aaggaatgtc aaccaaaatc ttaaatgaaa 66300
ataaaacaaa gcacagaccc ccagttcaga ataaatgtct actaaagcat gttggtcaac 66360
aactgcagag aagaggtccc agagccggat ccctctgtgt actgtttagg actattcttg 66420
gaaacatggc attaacagaa caacaccaat agacatgcca aagtggatgg gtaaaagtcc 66480
tgtagacccc aacctccaaa aaaaaaacaa ctatagcaac tgagtaactg tagccaagca 66540
gagagcagga ccctttccta gagtagagca caccaattgg ttgtctagta ccaaatggaa 66600
aatggtcagc cctgaaatat acatacaagt aacatatata tatatatatg tgtgtgtgtg 66660
tgtgtgtata cacacatata tattcacata catatatata tatacataca tatatatgta 66720
catatatatg tatgtatata tataggcatg caataacaat taatgaaaaa agagacaacg 66780
aatttgaagg caagtaggga gggcatgtgg gaggctttgg agaaagggag gggaagggag 66840
aaatgctgta atgttctctc tctgtgtctc tctctctctg tctctctctc tctctccctc 66900
tcctttttat taaaattgtg gaagacattt gaccatggaa cctaggtaaa tcctaagctg 66960
taaaatgcca tcaataatat aaagccttct gtactggggc agcgttatga tggtaattgt 67020
gtcatgatgg tatctactat tgtgtttcta tgtttctgtg tgactgtctt tttttttaat 67080
tggtagaaac tgaaagttat cattattatt ccaataggga aactacatac tatgtttgat 67140
aaattaaaac aaagcagact caatccctct taagcccagg ttctcctatt actgtgcatc 67200
acctgctctc cctccgaagc cactttggcc aaatagctat agttatagtc tgtggattgt 67260
aagagaaaca tccttgctct caggaggaag gtagaactct gatttaagaa aacaagtagc 67320
ctcagagttg caaccaagag ccaaacaagc atggtatttg gaagcttgac cagagaatga 67380
aagcagaggc attatcaatg atttctttta tgtaacttta agtaattttt cttaaagtat 67440
attcaggcaa tcagaaaaat aaataaataa ataaataaat aaataaataa ataaataaat 67500
aaacagagga atgtctatcc ccatggcaaa caggaatcat tagtttcaaa aataacactt 67560
attgagcttt tctggtgtag catggttgat agacactaga gatgcaaaaa tgaatataac 67620
aaagatcctt gcaatcataa atcaagtagc tacctagtgg gataatactg acatatgaac 67680
agacgattac aaggaaatca ggtaagggtc gtgatgaaaa tattcgttct gagccaaact 67740
ctctgcttac acattaaagc tagatgagag ggtggccata atgagagatg tttgactaag 67800
gtgtctctaa attttttcaa atagagttga aaagttgaag accaggccac cccagccaat 67860
gtggctggag actaatcccc cgttagaggt aggaatcgcc aaccagtaga cagggatcaa 67920
gaagtgccct gcccaagagg aagctgcaga gaccatgcct ctcagtgtat ttgttcaact 67980
ggcataaaca ggcagacagc ctatctacca gtcaaaagct aactgatatg gctcgggaac 68040
cttagagcat gcttataaac gatgggagat gctactaagt gctttttaat aatggaaaaa 68100
taacttcagt cttcaaatta ataaactgga aaatgtcatg ggagacagca gctgtattaa 68160
tgtgagaaca atgagctagg aggctcaaga gaactgggct tggggctggg ggaggcactg 68220
ttcctttata ttttatatgc agtttcttct gacacagata ctaaatctac tatgtgaatg 68280
gagggtcagg acctcagcat ccccaaaact ttagggtaaa gtaaacatga atcttttggg 68340
ggaaatctct gttcagggtg attacaaaag taaagagtaa ataagagcag cggtcgccat 68400
cttggtccgg gacccgccga acttaggaaa ttagtctgaa caggtgagag ggtgcgccag 68460
agaacctgac agcttctgga acaggcagaa gcacagaggc gctgaggcag caccctttgt 68520
gggccgggga cagccagcca ccgtccggac cggaggacag gtgcccgccc ggctggggag 68580
gcggcctaag ccacagcagc agcggtcgcc atcttggtcc gagacccgcc gaacttagga 68640
aattagtctg aacaggtgag agggtgcgcc agagaacctg acagcttctg gaacaggcag 68700
aagcacagag gcgctgaggc agcaccctgt gtgggccggg gacagccggc caccttccgg 68760
accggaggac aggtgcccgc ccggctgggg aggcggccta agccacagca gcagcggtcg 68820
ccatcttggt ccgagacccg ccgaacttag gaaattagtc tgaacaggtg agagggtgcg 68880
ccagagaacc tgacagcttc tggaacaggc agaagcacag aggcgctgag gcagcaccct 68940
gtgtgggccg gggacagccg gccaccttcc ggaccggagg acaggtgccc acccggctgg 69000
ggaggcggcc taagccacag cagcagcggt cgccatcttg gtcccgggac tccaaggaac 69060
ttaggaattt agtctgctta ggtgagagtc tgtaccacct gggaactgcc aaagcaacac 69120
agtgtctgag aaaggtcctg ttttgggcct tcttcttcgg ccaggaggag gcccaaatac 69180
aagatatctg cgcaccttcc ctgtaagaga gcttgccagc agagagtgct ctgagcactg 69240
aaactcagag gagagaatct gtctcccagg tctgctgata gacggtaaca gaatcaccag 69300
aagaacaatc tctaaacaga gtcaactata actactaact ccagagatta ccagatggca 69360
aaaggtaaac ggaggaatct tactaacagg aaccaagacc actcaccatc accagaaccc 69420
agcacaccca cttcgcccag tccagggaac cccaacacac ctgagaacct agacctagat 69480
ttaaaagcat atctcatgat gatggtagag gacatcaaga aggactttaa taaatcactt 69540
aaagaaatac aggagaacac tgctaaagag ttacaagtcc ttaaagaaaa acaggaaaac 69600
acaatcaaac aggtagaagt ccttacagaa aaagaggaaa aaacatacaa acaggtgatg 69660
gaaatgaaca aaaccatact agacctaaaa agggaagtag acacaataaa gaaaactcaa 69720
agcgaggcaa cactagagat agaaacccta ggaaagaaat ctggaaccat agatttgagc 69780
atcagcaaca gaatacaaga gatggaagag agaatctcag gtgcagaaga ttccatagag 69840
aacatcggca caacaatcaa agaaaatgga aaatgcaaaa agatcctaac tcaaaatatc 69900
caggaaatcc aggacacaat aagaagacca aacgtacgga taataggagt ggatgagaat 69960
gaagattttc aactcaaagg tccagcaaac atcttcaaca aaattattga agaaaacttc 70020
ccaaatctaa agaatgagat gcatatgaac atacaagaag cctacagaac tccaaataga 70080
ctggaccaga aaagaaattc ctcccgacac ataataatca gaacatcaaa tgcactaaat 70140
aaagatagaa tactaaaagc agtaagggaa aaaggtcaag taacatataa aggcaagcct 70200
atcagaatta caccagattt ttcaccagag actatgaaag ccagaagagc ctggacagat 70260
gttatacaga cactaagaga acacaaactg cagcccaggc tactataccc agccaaactc 70320
tcaattatca tagagggaga aaccaaagta ttccacgaca aaaccaaatt cacgcattat 70380
ctctccacga atccagccct tcaaaggata ataacagaaa aaaaccaata caagaacggg 70440
aacaacgccc tagaaaaaac aagaaggtaa tccctcaaca aacctaaaag aagacagcca 70500
caagaacaga atgccacctt taacaactaa aataacagga agcaacaatt acttttcctt 70560
aatatctctt aacatcaatg gtctcaactc gccaataaaa agacatagac taacaaactg 70620
gctacacaaa caagacccaa cattttgctg cttacaggaa actcatctca gagaaaaaga 70680
tagacactac ctcagaatga aaggctggaa aacaattttc caagcaaatg gtatgaagaa 70740
acaagcagga gtagccatcc taatatctga taagattgac ttccaaccca aagtcatcaa 70800
aaaagacaag gagggacact tcattctcat caaaggtaaa atcctccaag aggaactctc 70860
aattctgaat atctacgctc caaatacaag agcagccaca ttcactaaag aaactttagt 70920
aaagctcaaa gcacacattg cgcctcacac aataatagtg ggagacttca acacaccact 70980
ttcaccaatg gacagatcat ggaaacagaa actaaacagg gacacactga aactaacaga 71040
agtgatgaaa caaatggatc tgacagatat ctacagaaca ttttatccta aaacaaaagg 71100
ttataccttc ttctcagcac ctcatggtac cttctccaaa attgaccaca taataggtca 71160
caaatcaggc ctcaacagat tcaaaaatat tgaaattgtc ccatgtatcc taacagatca 71220
ccatgcacta aggctgatct tcaataacaa aataaataac agaaagccaa cattcacatg 71280
gaaactgaac aacactcttc tcaatgatac cttggtcaag gaaggaataa agaaagaaat 71340
taaagacttt ttagagttta atgaaaatga agccacaacg tacccaaacc tttgggacac 71400
aatgaaagca tttctaagag ggaaactcat agctctgagt gcctccatga agaaacggga 71460
gagagcacat actagcagct tgacaacaca tctaaaagct ctagaaaaaa aggaagcaaa 71520
ttcacccaag aggagtagac ggcaggaaat aatcaaactc aggggtgaaa tcaaccaagt 71580
ggaaacaaga agaactattc aaagaattaa ccaaacgagg agttggttct ttgagaaaat 71640
caacaagata gataaaccct tagctacact cactaaaggg cacagggaca aaatcctaat 71700
taacaaaatc agaaatgaaa agggagacat aacaacagat cctgaagaaa tccaaaacac 71760
catcagatcc ttctacaaaa ggctatactc aacaaaactg gaaaacctgg acgaaatgga 71820
caaatttctg gacagatacc aggtaccaaa gttgaatcag gatcaagttg accttctaaa 71880
cagtcccata tcccctaaag aaatagaagc agttattaat agtctcccag ccaaaaaaag 71940
cccaggacca gacgggttta gtgcagagtt ctatcagacc ttcaaagaag atctaactcc 72000
agttctgcac aaactttttc acaagataga agtagaaggt attctaccca actcatttta 72060
tgaagccact attactctga tacctaaacc acagaaagat ccaacaaaga tagagaactt 72120
cagaccaatt tctcttatga acatcgatgc aaaaatcctt aataaaattc tcgctaaccg 72180
aatccaagaa cacattaaag caatcatcca tcctgaccaa gtaggtttta ttccagggat 72240
gcagggatgg tttaatatac gaaaatccat caatgtaatc cattatataa acaaactcaa 72300
agacaaaaac cacatgatca tctcgttaga tgcagaaaaa gcatttgaca agatccaaca 72360
cccattcatg ataaaagttc tggaaagatc aggaattcaa ggccaatacc taaacatgat 72420
aaaagcaatc tacagcaaac cagtagccaa catcaaagta aatggagaga agctggaagc 72480
aatcccacta aaatcaggga ctagacaagg ctgcccactt tctccctacc ttttcaacat 72540
agtacttgaa gtattagcca gagcaattcg acaacaaaag gagatcaagg ggatacaaat 72600
tggaaaagag gaagtcaaaa tatcactttt tgcagatgat atgatagtat atataagtga 72660
ccctaaaaat tccaacagag aactcctaaa cctgataaac agcttcggtg aagtagctgg 72720
atataaaatt aactcaaaca agtcaatggc ctttctctac acaaagaata aacaggctga 72780
gaaagaaatt agggaaacaa cacccttctc aatagccaca aataatataa aatatctcgg 72840
cgtgattcta acgaaggaag tgaaagatct gtatgataaa aacttcaagt ccctgaagaa 72900
agaaattaaa gaagatctca gaagatggaa agatctccca tgctcatgga ttggcaggac 72960
caacattgta aaaatggcta tcttgccaaa agcaatctac agattcaatg caatccccat 73020
taaaattcca actcaattct tcaacgaatt agaaggagca atttacaaat tcatctggaa 73080
taacaaaaaa cctaggatag caaaaactct tctcaaggat aaaagaacct ctggtggaat 73140
caccatgcct gacctaaagc tttactacag agcaattgtg ataaaaactg catggtactg 73200
gtatagagac agacaagtgg accaatggaa tagaattgaa gacccagaaa tgaacccaca 73260
cacctatggt cacttgatct tcgacaaggg agccaaaacc atccagtgga agaaagacag 73320
cattttcaac aattggtgct ggcacaactg gttgttatca tgtagaagaa tgcaaatcga 73380
tccatactta tctccttgta ctaaggtcaa atctaagtgg atcaaggaac ttcacataaa 73440
accagagaca ctgaaactta tagaggagaa agtggggaaa agccttgaag atatgggcac 73500
aggggaaaaa ttcctgaaca gaacagcaat ggcttgtgct gtaagatcga gaattgacaa 73560
atgggaccta atgaaactcc aaagtttctg caaggcaaaa gacactgtct ataagacaaa 73620
aagaccacca acagactggg aaagaatctt tacctatcct aaatcagata ggggactaat 73680
atccaacata tataaagaac tcaagaaggt ggacctcaga aaatcaaata acccccttaa 73740
aaaatggggc tcagaactga acaaagaatt ctcacctgag gaataccgaa tggcagagaa 73800
gcacctgaaa aaatgttcaa catccttaat catcagggaa atgcaaatca aaacaaccct 73860
gagattccac ctcacaccag tgagaatggc taagatcaaa aattcaggtg acagcagatg 73920
ctggcgagga tgtggagaaa gaggaacact cctccattgt tggtgggatt gcaggcttgt 73980
acaaccactc tggaaatcag tctggcggtt cctcagaaaa ttggacatag tactaccgga 74040
ggatccagca atacctctcc tgggcatata tccagaagaa gccccaactg gtaagaagga 74100
cacatgctcc actatgttca tagcagcctt atttataata gccagaaact ggaaagaacc 74160
cagatgcccc tcaacagagg aatggataca gaaaatgtgg tacatctaca caatggagta 74220
ctactcagct attaaaaaga atgaatttat gaaattccta gccaaatgga tggacctgga 74280
gagcatcatc ctgagtgagg taacacaatc acaaaggaac tcacacaata tgtactcact 74340
gataagtgga tattagccca aaacctagga tacccacgat ataagataca atttcctaaa 74400
cacatgaaac tcaagaaaaa tgaagactga agtgtggaca ctatgcccct ccttagaagt 74460
gggaacaaaa cacccatgga aggagttaca gaaacaaagt ttggagctga gatgaaagga 74520
tggaccatgt agagactgcc atatccaggg atccacccca taatcagcat ccaaacgctg 74580
acaccattgc atatactagc aagattttat cgaaaggacc cagatgtagc tgtctcttgt 74640
gagactatgc cggggcctag caaacacaga agtggatgct cacagtcagc taatggatgg 74700
atcacagggc tcccaatgga ggagctagag aaagtaccca aggagctaaa gggatcttca 74760
accctatagg tggaacaaca ttatgaacta accagtaccc ctgagctctt gactctagct 74820
gcatatgtat caaaagatgg cctagtcggc catcactgga aagagaggcc cattggacac 74880
gcagactttg tgtgccccgg tacaggggaa cgccagggcc aaaggggggg agtgggtggg 74940
taggggagtg ggggtgggtg ggtaaggggg acttttggta tagcattgga aatgtaaatg 75000
agctaaatac ctaataaaaa atggaaaaaa aaaaaaaaaa aaaaaaaaag agtaaataag 75060
cagacaggta acaaaaacag gttctcgtaa aaatagctaa aagtggcaca ttgccaactc 75120
aataaaacaa gtcaccgctg tgaatacgga ctaatgttaa tctgtaaata ctgccccaaa 75180
ggatggaaag gtggatcagt ggttaaaaac atttgatgct cttgaaagga tgcagtcaga 75240
tccctaacag ccatatacag tagctgacaa ctgtaactcc agttccagat tgatgccctc 75300
tgtgggcctc tgagggcaca tgcatgtgat gcagatacac ccaggcaaaa cacttgcttg 75360
tatgcataaa ataaaacaaa tgaaataggt gagaaaacaa atgctaaccc ataagacctc 75420
ctgatttttt tttcaatgtg aagttaaaaa aaaaatttat gaatggcaag aagtaaagat 75480
atgttctcaa gttaactgcc ttaaccataa caataaccat aaccataata atcctaaccc 75540
taaccctaac cctaacccta accctaacct aaccctaact ctaacccttg aaccctaacc 75600
ctaaccctaa cctaacccta accctaaccc ttgaacccta accctaaccc taaccctaac 75660
cctaacccta accctatgaa caagggctta aatggagata agagagaaat ccacccacat 75720
agtgctacaa ccacaacttc ctaaaaactg gaataaatac acacacaaaa agtaaagtta 75780
agctcttggt aatacatgtg cattcatata atgtgtgcat gtatacacac acacacacac 75840
acacacacac acacacacaa acacacacac acaaacacac acacacacac acacacacac 75900
acacacacac acacacatat atatatatat atatatatat atatatatat atatatatgg 75960
actaaactaa aactactaga gtaaatggtg tgagaaaatg attttatgaa ctataataaa 76020
tgttcacagt ttaaatggag tccaggttaa gttcaactta aattttatga gtcattacac 76080
ctcatgacat ttttctctct tctattagtt gaatctgaag ttcagagctc gaagcctaaa 76140
atctagagaa gcaatgcaaa tgtgacattt gagggagaaa ccgttgtttt tctcttgtag 76200
atattagaag aaatctgtca gaaaaataac tggggacagc cagtgtacca actgcattct 76260
gccattggac aagatcaaag acagttattc ctctacaaag taactatccc agcgctggcc 76320
agccagaatc ctgcaatgtg ggtaccttct ccaagctcct agtaactgaa attttagata 76380
aaattagcct gggtattaac tgtgtttgat catcactcca ataacataac cagcccactc 76440
ccttgtaatt aaataaaaca gcaggcactc gctcggctgg tatttatgca ccagctgtta 76500
gaccggtacc taaaagccac aaagtctcaa acatcaggaa ggctctctag gataactgac 76560
taatggaaag gagaggtgat tagagcctgt aagtggttcc ttcctgcagt gtttaggttg 76620
atataggtga cctgtgtaaa gttgccactt caccgtataa ccctctgtcc caccttttaa 76680
atttcatatc aaagacccga tcattaaaag atatcacctt ccagattcta ccaccaggct 76740
gcatttatat atatttagga accatctttt accttagaag agtcatgcag caaaaattac 76800
atgtgttccc aggaatatca tctgctaccg aggtgctgga tcaatgcaca aatatgcctg 76860
cgtaggctta tatgtagaaa ctttttacaa caaacaggaa acacacacac acacacacac 76920
acacacacac acacacacac acacacaaaa tcccatcatc caatcatctt taacctgagt 76980
acttaaattt ctgaataatt aacattgctg actgctttcc agccaccctt tcataccacc 77040
aaagctaagc gcctatgtgg atgaagcgaa gaggtatgct gcagagcaca ctctacagac 77100
actaggcatc cccacagaag gaggggacgc tgggactaca gcacccacgg ccacttctgc 77160
cactgtgttc ccaggtactg gggagcaggg atcagtcacg ccagaatcag caggctgcag 77220
aatgtctggg gggaagggga gagcttcttt gtagaaccct caactacatg cagacagaaa 77280
agagaggggg aaacagaacc aaagcagcct aagctggttg gcatctgtct gcctcttctt 77340
tgaatggccg cgggatcctg aatgagtcag cacccctgag actgttgact tgctgagtct 77400
gaattggtgt gaattggctt ttactattat taagtgcttt ggtactacta ttagctggta 77460
tttttctgag ctctagctat gaactgggcc ctcactaaag tgctcagcaa gctacatatt 77520
ccccccaacg acccttatgg tgcccagagg tcagggtcag ctgctttgct ccattacact 77580
ctacctcatc ttttttaaat gaaggaagga tatgtgtgtg tgtgtgtgtg tgtgtgtgtg 77640
tgtgtgtgtg tgtgtgtgtg tgtgtgttta catgagtgca acttcctgaa gaggccacag 77700
gtgttagatt cactgaagct ggagttgtag gcagttgggc agccaacatg agtggatcct 77760
gtgtgcaaac agtatgtatt caaccacaag ccatctatct ctccatcccc tttatctcat 77820
cctttgagac agaggctatc actgaacctg gtgttaccag aaagactgga atttctttcc 77880
aggattctta ttgtttaata caaaaatttt aaaacagatt aaaataagct tgaggacagt 77940
taagttatag ggatagatag acagacaaat agacagacag atgatggatg gaagatagat 78000
agatagatag atagatagat agatagatag atagatagat agatagatag atagatagat 78060
agataggcag gcaggcaggc aggcaggcag gcagataaca aataggtaag caagctgtaa 78120
tctcagcagc tgctcgaaag gcaattgaaa aggaaggaaa gtaagccaag ctgtttgccc 78180
tggaaatccg caaaaagcca cgtggcaaaa ggaattgggt gggactgctt cagaaaaagt 78240
aagaaagcca cagtaccagg gaaagcatgc ttagcttata tccaaacaac agagaaagaa 78300
aaggtatcat ttccattggt taaataagat agcttttaca gttctccgtg tatccataga 78360
gagaccctgt ttcaaaacct acaaagagca aacccaaaaa tggacaacta aaaccaatgc 78420
ttttctacac aactaagccc aggtgctgga tccccttgga gcacattttc aacatacata 78480
ctcacttgtt ataagcaata tgttaattct atagtactgc taaaagacaa caatgtgcca 78540
aagagggagg gaatctgaat acttttcata aaattgtctc tgcctcttcc tccaggatat 78600
gctgtcccca gtgccaccgc tcctgtgtct acagcccagc tcaagcaagc agtgacactt 78660
ggacaagact tagcagcata tacaacctat gaggtctacc ctacttttgc actgaccacc 78720
cgaggcgatg catatggaac cttctaacga tccctgtcct ctaagaataa gcctttatag 78780
aaggatctgt agaagatacg aacctctagc cagatccctc atgaccacaa gtcatacctt 78840
cccccaaagc aatgcctttc ctgagaccac aagatttatt cgtcgtatta ctcatgaaat 78900
gtgaatatta ttcttcaaca aaatcaaatg ttaagcagaa acctgaagat ccacggacag 78960
caaaagttgt tcttccaagg atcctgagtg tctcaggaag aggataacac cctgacaaat 79020
tagcatatgc tcttagtaca gagagctggg cagtccgtag taaggcacag ccagtaaaat 79080
gcccatctta gtcactggct ggcagctgct tcttcattca cagaacttag acaccagagg 79140
aaagcaggaa gctctgtaag aggccttcag cattgcatac agtgtggagt atgatcccag 79200
gctgagctca gcaaaactgt ctgaaacatt atagattcct tctcactttt ggtctggaca 79260
ttccacactg ttcgcctgtc ataggtcagc atcctcctgt ccctgcaacc tctggggact 79320
ttctagaaat cagtacaatg tatttcagat atgcttgaga caaatccaag ccctgtattt 79380
attcaactct ttaagccact gttttccttc agaatccttt ccctgctcaa ggattcccaa 79440
atcacagaaa ccatgccagt accaagttct agagtgaaag atgacttttt ttgggggggg 79500
ggggtgtcag gaaattctgg cttgtccata ctcatttgct ttcatctcag actcattttg 79560
ctgatcccaa aaactacaaa gtaaatcaga tctacataaa aatcactatg atattttcat 79620
aatcagaaac ttgaccaaaa agtcatttca aagagaaaag tgtttggctt ttgtctcgct 79680
gggtagccca ggctcacctt gatattgatc ttgtgatcct cctgcctctg ctccccccat 79740
gctggtgttg tttacacaca acaccatact catctccaag aagttgcatt aaaattgagg 79800
ttacctttga gttctctacc cagttcatat taatctacca aaaatcactg tccatcccat 79860
cttttgattg tctttcaata tgtgcagctg gctttactat gactgagtcc cttgatagtg 79920
aaactattcc aggaaagcct tacacccatc atggttgctt agagaccatc ccttttagca 79980
ttcagtaaaa gtgttgcttt ccaaaatgtc ccaatttaga ccatctgata gtgactgggg 80040
gagggaggct atatacatgt aaaaaggatg taatgttctg atacaaatta gatataactc 80100
cagccttatt agggatttta ggagatacgg cacttgaatt cccattaaaa caaaacaaaa 80160
acaaaaaagc ttttggcttt tgtgaaagtc tgtagaactc aagagacaat aaagacaaaa 80220
gtacagaaaa ta 80232
<210> 4
<211> 9221
<212> DNA
<213> 智人 (homo sapiens)
<400> 4
tttgatatga cgattagagc ataacccgag tgacacgttg aattcgccat aatcaaggaa 60
accttttccg ggtggggatc tctgaaatta ctcagtgagc aaccctaatt aacctgattt 120
tttgctgata atcactctca atggaatcaa atcacaaatc cggggatgga ttgagcggca 180
ctcagaagga agcagccctc cgcgcactgg tccagcgcac aggatatagc ttggtccagg 240
aaaatggaca aagaaaatat ggtggccctc cacctggttg ggatgctgca ccccctgaaa 300
ggggctgtga aatttttatt ggaaaacttc cccgagacct ttttgaggat gagcttatac 360
cattatgtga aaaaatcggt aaaatttatg aaatgagaat gatgatggat tttaatggca 420
acaatagagg atatgcattt gtaacatttt caaataaagt ggaagccaag aatgcaatca 480
agcaacttaa taattatgaa attagaaatg ggcgcctctt aggggtttgt gccagtgtgg 540
acaactgccg attatttgtt gggggcatcc caaaaaccaa aaagagagaa gaaatcttat 600
cggagatgaa aaaggttact gaaggtgttg tcgatgtcat cgtctaccca agcgctgcag 660
ataaaaccaa aaaccgaggc tttgccttcg tggagtatga gagtcatcga gcagctgcca 720
tggcgaggag gaaactgcta ccaggaagaa ttcagttatg gggacatggt attgcagtag 780
actgggcaga gccagaagta gaagttgatg aagatacaat gtcttcagtg aaaatcctat 840
atgtaagaaa tcttatgctg tctacctctg aagagatgat tgaaaaggaa ttcaacaata 900
tcaaaccagg tgctgtggag agggtgaaga aaattcgaga ctatgctttt gtgcacttca 960
gtaaccgaga agatgcagtt gaggctatga aagctttaaa tggcaaggtg ctggatggtt 1020
cccccattga agtcacccta gcaaaaccag tggacaagga cagttatgtt aggtataccc 1080
gaggcacagg tggaaggggc accatgctgc aaggagagta tacctactct ttgggccaag 1140
tttatgatcc caccacaacc taccttggag ctcctgtctt ctatgccccc cagacctatg 1200
cagcaattcc cagtcttcat ttcccagcca ccaaaggaca tctcagcaac agagccatta 1260
tccgagcccc ttctgttaga ggggctgcgg gagtgagagg actgggcggc cgtggctatt 1320
tggcatacac aggcctgggt cgaggatacc aggtcaaagg agacaaaaga gaagacaaac 1380
tctatgacat tttacctggg atggagctca ccccaatgaa tcctgtcaca ttaaaacccc 1440
aaggaattaa actcgctccc cagatattag aagagatttg tcagaaaaat aactggggac 1500
agccagtgta ccagctgcac tctgctattg gacaagacca aagacagcta ttcttgtaca 1560
aaataactat tcctgctcta gccagccaga atcctgcaat ccaccctttc acacctccaa 1620
agctgagtgc ctttgtggat gaagcaaaga cgtatgcagc cgaatacacc ctgcagaccc 1680
tgggcatccc cactgatgga ggcgatggca ccatggctac tgctgctgct gctgctactg 1740
ctttcccagg atatgctgtc cctaatgcaa ctgcacccgt gtctgcagcc cagctcaagc 1800
aagcggtaac ccttggacaa gacttagcag catatacaac ctatgaggtc tacccaactt 1860
ttgcagtgac tgcccgaggg gatggatatg gcaccttctg aagatgcttt tttaaattta 1920
agaataagac acacaaaact ctattaaaaa aaaaaaagaa ataaacctct aactcggtcc 1980
ccaatgatca taaataatat gtttcctaaa gaaatgcctt tccagagact gtatagctta 2040
taccaattat agaatcatga agtaagaacg ttattctgaa atgaaatcaa atgttaaaga 2100
gccttttgtt taacagaaag ctggagagcc actgccccaa aagttgttct tccagtcttc 2160
ctgagtgttt ggggagtatg tttacaaatc ctgccagggt gaagagagat cttgtagctg 2220
gcaagatttg ggagggatgg agcagacctg ggcagtcagt aataatcaag ggaagccaag 2280
taaactccag agtcttacct ctggctcaca gctgcttttg tgatacacaa agtcacaaag 2340
aggaaaaggg aagggaggag gttgcttttc aaaatgcatt caccatggct cactgtgtgg 2400
ggcatgattg caggcctgag ctcatgaaag actgtccaag attttgtggt ttcaacctct 2460
cttcagcctg aaaattccat ccagtcgatt tgtcacagat caggatcttc ctgtcccctg 2520
cagcccatgg ggacttccta gaaatagata tgatatgttg tagatgtggt taaaacaaat 2580
ccaggcccca ttgtttattc agctcattag tccacaccta tttttcccta gaactcctac 2640
cttttccaat aatcatgcca gcatgaaatg accttttcta ctttaaaatt ttttgacttg 2700
ttcatattgc ttgattttca tcatctcaga ctcatttttc tcctacctaa tatcataaaa 2760
aagtaaatca gatatacaga atatcattta tgatacttct tcctttcagc aaattgactg 2820
aaaagtcatt ttaaagagag aagtgcagat ttgctctcat ttctttgata ttgttgcagt 2880
atccacccca ccatctagca atcagagatg cttatattaa cttgggatta gctttgcatt 2940
atctaaccca tttattttaa atctgccagg aaatcctcta actttccttc ctttttgttt 3000
cagtaagtat caggcagctt caccatacct gagtcctttt gtcttgaagc tgccacagaa 3060
aaatcttaca gcaatcattg ctgattagaa actgtttcag acaatcagca tgggtgttat 3120
ttaccaaatt ccccccagag tcctaggcct cttctccaga aatatctgat gatgaagtga 3180
ggggagggca acggtgctac aaaacacgga acagaggtaa agagaaggca ctactttctt 3240
gccatacttg taaatgattg ctttgttcaa acataaataa tcttaagtcc aacaccaaat 3300
acctgttact cctacatcaa tctcattagt ggtttaagac acagtactag aattttcatt 3360
ttttaaaatc ccttggccct taaaaaaatt tacagaacac aaaggaaaac ataaacacaa 3420
agacatggaa aattttgtca actccttaat ggaattctgt gatcaaaaag caggccagat 3480
tctaatcaaa atcaggtaaa ttttaatcac aatcagaagt acttgtaaca tttcagttgt 3540
cctaactcca atgagataac aaagcctcca aggctacagc tgaaactctg aaaggccctg 3600
tgctttctac tttacattta gcgtctaata tttcctagga cagtagttcc caaagtaggc 3660
tgtacattag aatctcctgg agagcttttt aaatgctaat gccaataaca tatctcataa 3720
aatttacact agaatttcct tggatgggtg cctggcatca gtatttttta atgatcccta 3780
ggtgatttca atgtgcacct aggtttggga attgctatat tcttgtattt atactctatc 3840
tctttatttc ttttcctttt tatttcactt ttagtaaata gaaaaatgca attaaaaaat 3900
catctaagtt aagacaaata gccaaatcat atttatccca taaatagtat gaatttaaat 3960
gtaacttacg taggcttcaa actaactcta aaaatgagaa agtaaaacaa tcttgtccta 4020
aaacaattct tagatccaaa tttacactcc cctacagatc tgcttttatt ctcaaagaca 4080
gtgattacat tgacataaca aatgtccatt ggggcaggca aatttctact gagtctaaaa 4140
agcattccaa attctaggag caaaagttct gattttcctt aaaatctttg caaataaaca 4200
gcaaagggta ttctggatgt cttgtcaatg caaattaggt ttgatttaga gaagttttaa 4260
atttaatcgc aatgaaaaga ttagttaata catgaatctt tttatgagaa aaaatcatta 4320
ttctggataa agtcataatt gtttgtttac aatattaaga gcagacacct aaacatacaa 4380
taataccaaa gtattgagaa aattaccact ggaacaccat ctcaagttat cacaccattt 4440
acctctttag agccagtttt gtataagtag gtagaagtgg ttttggtttt tttgctaaaa 4500
ttttactttg ttttagtaat atctagggaa tactttgaat tccattaaaa taccttcata 4560
gaaagtgtta atgtgtctac catgccatat gtttattttt actttcccca agttaggtag 4620
atagagcaag tcctgctacc ataagtttaa aattattaag acaacgggct tttttaaatt 4680
gctggtagaa ccaaaggcta attttgcata ggtttatatt tttagactta agaaattagc 4740
acctatataa taccttcata ccttctgcat cactatcaat ttttctgtaa tttcttattt 4800
gaatgcttcc taattcttta cagaaaaaat taaaatttgt cacccaacca ggtgataata 4860
acaaaacaat aatttaggaa catccagtaa atttgaatta gttctctaaa ttttggtaat 4920
taatagctta ttgataatta aaatcagcct aatgttgctt aagtaggagg aaattgatca 4980
gcaatgggat tgggtatcta ttttctttcc tataaaagtg ctgcctcttc tcaaattgct 5040
ttatttctct cccactgcat tagtatatct agaacagcac cttcaactgc aacaaaatat 5100
aattctccta gatgactagg atatcctcca atctggtatc atgccaaaca acactatgtt 5160
tggggaacag cacccgaaat gctgctaaaa agctacctca tgtcaagaaa atatggattt 5220
caaaaaatat ctggcacagt ggcccatgcc tataacccca gtactttggg aggccaaggc 5280
aggaggattg ctggaggcca ggagttcaag accagcctgg gcaacatgga gagactccgc 5340
ctctacaaaa aaaaaaaaaa caaatttaat ttaattggcc agttgtggtg gcgtgggcct 5400
gtggtcccag ctacttggga agctaaggca ggaggattgc tggaggcctg gagggcaagg 5460
ctgcagtgag ccatgttcac atcgctgcac tccagcctgg gtgacagagc aagaccctgt 5520
ctccaaaaaa gcaaaaataa atatctaaca aaaaggaacc tgtttccaaa ccacagtttc 5580
ttaacttttt catgatggaa tagaaattaa actataagta tatactgata atagctgtgc 5640
aggaaattgg tttttatttt acttaaaagt attttttaga aaaaatgtta ttctgattgc 5700
atagattagc aaaatattgc atcaatataa tgttccattt ttattaattt ttgttatatt 5760
ctaaatgacc gttttataat tctgtcttgg acaactgggc cacagttaga atccacatag 5820
acagggaggt tcttaggtgt gccatttgta gaataaaggg caatcaagtt aatattcggg 5880
gtaaattttc attgcattct aacctatgaa gtttgataaa gtatattatt attgaacaac 5940
tctaacacta agatttccta aaagtaactt acaacaaaaa atgaactatg tgctcaatat 6000
tcacataaag tcatgattat tctcttcttg cattcatata aaagttccca gggggaagaa 6060
aatatatcta aaaattagac tagaaacttg gcacttttta tgtattgtag atacactttc 6120
atatattgta aatacatctg ttaaagataa aactaagttt ctaacatagc actacaagga 6180
aactttggat aaatattttt aaaaagaaaa tgttaatagg ataacttaag attttgtata 6240
tacttattgg aagacaggaa gaaactaggc agtaaatatt cctacctgac gtgcaaccat 6300
tgtcaatcag gttttgttaa actgtcaaat ttgattttga aattttagtt tgcccaaata 6360
atatcttgaa aatgctctga attttactag aacatattca tagaaagtgt aatgtatcta 6420
ccaggctcta tgtttgtgtt tgccaacatt agaaaaacaa agtaagttgc gctataatga 6480
gtgaaactaa ggaaaatgag atttttctga ctcccattcc ctctcttaaa aagtaaaata 6540
tttaagcttt ttttattaaa ggaaaaatgg gtacagaata ctctattgcc ctccaaatgt 6600
ccaacatttt taaagccatg ttgtccaaca atgtttatac agaaaataga atgcataggt 6660
ttaatataga tagcaatgta tatgtaggct catttgtggg agattgcaaa ctttatgtgc 6720
ccccagttct ccttggtttt gtaggaaagc taaaagaaaa ccttgtactc tcactaataa 6780
tgaaattcat agccaattta gaaagggaaa ataacctgaa aaccaaaata cctcattcat 6840
ctgaagatgc ctggaataaa atatggaatt cttctgtacc tacctccccc ttacagactt 6900
ttctcctatt ttgagagaga aattcaagaa gaagaataca gcttgttctc tttccacaaa 6960
tgatactttg tctaagggaa taggagatac caagaaacag tatctttaaa aaagtaagct 7020
gcccacaggc cttcttggag aatgaagaat atcagcccca ttcagggttt accaatgtct 7080
ctctgaggtg acaatacatt ctggttttcc aggacagtcc tggcttaggt ctgctgtcct 7140
tctataaata ttaacaatga tccctcttat ttccaaacgt gtcccagttt agacaacaaa 7200
ttatacagtg tctgccccca acacacacac acacacccca ccatctttat gggttgttgt 7260
tgttttcttg ttgtttttaa ttttgtagaa ttggctttgt cttctccaaa gcagataaca 7320
gcttaaacta aagagcctag ctacttcttt ctgactgagc agggtcatag taaacagaga 7380
agaatggatc acttcctcct ctgaaatctc catcaatcca ctttctgtcc aactatctct 7440
ctacccagcc tatttttggt cctagttttc ctctcataac ccctgggctg tgagtcctga 7500
gttctgcctt catatggcag agcaagctag tcattattat gccaggttag gtggtggggc 7560
aagacaaaag atagctcttg gggacacttg cttggtctgt agagatccac agggcactag 7620
tagggtatta gagcatttat tggtttcttt cttccttgag ttgagttact tctatcccaa 7680
aacagacagg tcttacgtta accttcacct taaaaaggat attgcctttt ttccttctgc 7740
ttcacaaatt tgctccaaca ctaattccct tgcatttgat ttcatcatta tgattgttca 7800
tcaaccattc ttcacgaaaa atcctcacat cacgtcatat aaaggtttta ttatttttaa 7860
tggaaaataa cattgagaga ttattttcct ttttcataaa atttcccttt ttccctccct 7920
ctattctctt cactaacatt ggaaattaaa caagttttac aggctctatt gttattaacc 7980
ctcaaatcta ttcttcagag aatatatgat cagcctgtgt ttactatgca cctactctta 8040
taccagaaac tgtgaataca aatacatata tttcctactt ctctctttaa ttggggcaca 8100
cagtcccatg gtccattctg catttttcaa aattgaatat aattgcaaca cctgataggt 8160
tttgccactt agaattctga aaataaatca actctgttct aaaccttaag tttccactat 8220
tattgccaaa ctctggactg atacaataag ccttttaaaa ggtgaattta acacttcacc 8280
tattatggtt atttaagtaa aatgagtttt caaatatttc ccccaggaga aatataaagg 8340
actatgcaaa aatagaagga gaaaaaggtt agttagaggt ccagaaggag aattaaaaca 8400
tggaattgat aaattcacct actgatttat gatgttaatg agcaggtacc tatacatttt 8460
atttacttga aaacattttg gccattaact atttctgttt tctaaataca tttgtgttta 8520
taaaatttta aaatctatat cacaagactt agacatgcct ttctttgcaa taaagtatat 8580
ataccttttt acaaatgtaa attttatttt gaaacttggc attttcttta taattcctaa 8640
gatatctttg ggcacacaga ctacagataa atctatttaa atcaattcat cattatcact 8700
ggtttaaata tttaatgtaa ccattggaat ttttattctt attccttcag agaattctcc 8760
ttttcttcta tgtttctgac tgcaatacag cccgatattg ttattcccta tatcttaatg 8820
aaaagcaagc tgtcagcaaa atgcatttat agtttccaga tgtttaacaa tctctttctt 8880
cttttctttt ttgttattat ttttatttat gtgaagttag ttagctgagg taccaaaaaa 8940
gagacaaaga cagtattaaa aagtgtgcat aaagcactta tttttgtact ttagtacaat 9000
gttttataga actttgtgat ctatctaaat atattaagta aaattacacc attcacttgt 9060
tgggaaaata atctttggtt tggaagatat taacataatg ggcatcttag aatcataaat 9120
cacatgaaat gagagacaat gcaatattgt ataattcctg gatgatgcaa ttgttttaat 9180
tgaattttca agtgccatta taaagtttta aaaattatca a 9221
<210> 5
<211> 9517
<212> DNA
<213> 智人 (homo sapiens)
<400> 5
tttgatatga cgattagagc ataacccgag tgacacgttg aattcgccat aatcaaggaa 60
accttttccg ggtggggatc tctgaaatta ctcagataac agtgctgtgc caaaaacctg 120
tggattttct ctacaaaaat tatcatgact gttatctttt tgatggaaaa gatgaagttc 180
agcgaagaac aaatctacaa cttggccaga agactgtaga ctttgccttc aaagagtgag 240
caaccctaat taacctgatt ttttgctgat aatcactctc aatggaatca aatcacaaat 300
ccggggatgg attgagcggc actcagaagg aagcagccct ccgcgcactg gtccagcgca 360
caggatatag cttggtccag gaatttagag gttcctatag atggaagcag tgtgtctggg 420
cacatgccca gagccagaag cgagcatgag cacagcaatt cctggcctca aaaaaggaaa 480
taatgctttg cagtccatca ttttgcaaac tttgctggaa aaggaaaatg gacaaagaaa 540
atatggtggc cctccacctg gttgggatgc tgcaccccct gaaaggggct gtgaaatttt 600
tattggaaaa cttccccgag acctttttga ggatgagctt ataccattat gtgaaaaaat 660
cggtaaaatt tatgaaatga gaatgatgat ggattttaat ggcaacaata gaggatatgc 720
atttgtaaca ttttcaaata aagtggaagc caagaatgca atcaagcaac ttaataatta 780
tgaaattaga aatgggcgcc tcttaggggt ttgtgccagt gtggacaact gccgattatt 840
tgttgggggc atcccaaaaa ccaaaaagag agaagaaatc ttatcggaga tgaaaaaggt 900
tactgaaggt gttgtcgatg tcatcgtcta cccaagcgct gcagataaaa ccaaaaaccg 960
aggctttgcc ttcgtggagt atgagagtca tcgagcagct gccatggcga ggaggaaact 1020
gctaccagga agaattcagt tatggggaca tggtattgca gtagactggg cagagccaga 1080
agtagaagtt gatgaagata caatgtcttc agtgaaaatc ctatatgtaa gaaatcttat 1140
gctgtctacc tctgaagaga tgattgaaaa ggaattcaac aatatcaaac caggtgctgt 1200
ggagagggtg aagaaaattc gagactatgc ttttgtgcac ttcagtaacc gagaagatgc 1260
agttgaggct atgaaagctt taaatggcaa ggtgctggat ggttccccca ttgaagtcac 1320
cctagcaaaa ccagtggaca aggacagtta tgttaggtat acccgaggca caggtggaag 1380
gggcaccatg ctgcaaggag agtataccta ctctttgggc caagtttatg atcccaccac 1440
aacctacctt ggagctcctg tcttctatgc cccccagacc tatgcagcaa ttcccagtct 1500
tcatttccca gccaccaaag gacatctcag caacagagcc attatccgag ccccttctgt 1560
tagagaaatt tacatgaatg tacctgtagg ggctgcggga gtgagaggac tgggcggccg 1620
tggctatttg gcatacacag gcctgggtcg aggataccag gtcaaaggag acaaaagaga 1680
agacaaactc tatgacattt tacctgggat ggagctcacc ccaatgaatc ctgtcacatt 1740
aaaaccccaa ggaattaaac tcgctcccca gatattagaa gagatttgtc agaaaaataa 1800
ctggggacag ccagtgtacc agctgcactc tgctattgga caagaccaaa gacagctatt 1860
cttgtacaaa ataactattc ctgctctagc cagccagaat cctgcaatcc accctttcac 1920
acctccaaag ctgagtgcct ttgtggatga agcaaagacg tatgcagccg aatacaccct 1980
gcagaccctg ggcatcccca ctgatggagg cgatggcacc atggctactg ctgctgctgc 2040
tgctactgct ttcccaggat atgctgtccc taatgcaact gcacccgtgt ctgcagccca 2100
gctcaagcaa gcggtaaccc ttggacaaga cttagcagca tatacaacct atgaggtcta 2160
cccaactttt gcagtgactg cccgagggga tggatatggc accttctgaa gatgcttttt 2220
taaatttaag aataagacac acaaaactct attaaaaaaa aaaaagaaat aaacctctaa 2280
ctcggtcccc aatgatcata aataatatgt ttcctaaaga aatgcctttc cagagactgt 2340
atagcttata ccaattatag aatcatgaag taagaacgtt attctgaaat gaaatcaaat 2400
gttaaagagc cttttgttta acagaaagct ggagagccac tgccccaaaa gttgttcttc 2460
cagtcttcct gagtgtttgg ggagtatgtt tacaaatcct gccagggtga agagagatct 2520
tgtagctggc aagatttggg agggatggag cagacctggg cagtcagtaa taatcaaggg 2580
aagccaagta aactccagag tcttacctct ggctcacagc tgcttttgtg atacacaaag 2640
tcacaaagag gaaaagggaa gggaggaggt tgcttttcaa aatgcattca ccatggctca 2700
ctgtgtgggg catgattgca ggcctgagct catgaaagac tgtccaagat tttgtggttt 2760
caacctctct tcagcctgaa aattccatcc agtcgatttg tcacagatca ggatcttcct 2820
gtcccctgca gcccatgggg acttcctaga aatagatatg atatgttgta gatgtggtta 2880
aaacaaatcc aggccccatt gtttattcag ctcattagtc cacacctatt tttccctaga 2940
actcctacct tttccaataa tcatgccagc atgaaatgac cttttctact ttaaaatttt 3000
ttgacttgtt catattgctt gattttcatc atctcagact catttttctc ctacctaata 3060
tcataaaaaa gtaaatcaga tatacagaat atcatttatg atacttcttc ctttcagcaa 3120
attgactgaa aagtcatttt aaagagagaa gtgcagattt gctctcattt ctttgatatt 3180
gttgcagtat ccaccccacc atctagcaat cagagatgct tatattaact tgggattagc 3240
tttgcattat ctaacccatt tattttaaat ctgccaggaa atcctctaac tttccttcct 3300
ttttgtttca gtaagtatca ggcagcttca ccatacctga gtccttttgt cttgaagctg 3360
ccacagaaaa atcttacagc aatcattgct gattagaaac tgtttcagac aatcagcatg 3420
ggtgttattt accaaattcc ccccagagtc ctaggcctct tctccagaaa tatctgatga 3480
tgaagtgagg ggagggcaac ggtgctacaa aacacggaac agaggtaaag agaaggcact 3540
actttcttgc catacttgta aatgattgct ttgttcaaac ataaataatc ttaagtccaa 3600
caccaaatac ctgttactcc tacatcaatc tcattagtgg tttaagacac agtactagaa 3660
ttttcatttt ttaaaatccc ttggccctta aaaaaattta cagaacacaa aggaaaacat 3720
aaacacaaag acatggaaaa ttttgtcaac tccttaatgg aattctgtga tcaaaaagca 3780
ggccagattc taatcaaaat caggtaaatt ttaatcacaa tcagaagtac ttgtaacatt 3840
tcagttgtcc taactccaat gagataacaa agcctccaag gctacagctg aaactctgaa 3900
aggccctgtg ctttctactt tacatttagc gtctaatatt tcctaggaca gtagttccca 3960
aagtaggctg tacattagaa tctcctggag agctttttaa atgctaatgc caataacata 4020
tctcataaaa tttacactag aatttccttg gatgggtgcc tggcatcagt attttttaat 4080
gatccctagg tgatttcaat gtgcacctag gtttgggaat tgctatattc ttgtatttat 4140
actctatctc tttatttctt ttccttttta tttcactttt agtaaataga aaaatgcaat 4200
taaaaaatca tctaagttaa gacaaatagc caaatcatat ttatcccata aatagtatga 4260
atttaaatgt aacttacgta ggcttcaaac taactctaaa aatgagaaag taaaacaatc 4320
ttgtcctaaa acaattctta gatccaaatt tacactcccc tacagatctg cttttattct 4380
caaagacagt gattacattg acataacaaa tgtccattgg ggcaggcaaa tttctactga 4440
gtctaaaaag cattccaaat tctaggagca aaagttctga ttttccttaa aatctttgca 4500
aataaacagc aaagggtatt ctggatgtct tgtcaatgca aattaggttt gatttagaga 4560
agttttaaat ttaatcgcaa tgaaaagatt agttaataca tgaatctttt tatgagaaaa 4620
aatcattatt ctggataaag tcataattgt ttgtttacaa tattaagagc agacacctaa 4680
acatacaata ataccaaagt attgagaaaa ttaccactgg aacaccatct caagttatca 4740
caccatttac ctctttagag ccagttttgt ataagtaggt agaagtggtt ttggtttttt 4800
tgctaaaatt ttactttgtt ttagtaatat ctagggaata ctttgaattc cattaaaata 4860
ccttcataga aagtgttaat gtgtctacca tgccatatgt ttatttttac tttccccaag 4920
ttaggtagat agagcaagtc ctgctaccat aagtttaaaa ttattaagac aacgggcttt 4980
tttaaattgc tggtagaacc aaaggctaat tttgcatagg tttatatttt tagacttaag 5040
aaattagcac ctatataata ccttcatacc ttctgcatca ctatcaattt ttctgtaatt 5100
tcttatttga atgcttccta attctttaca gaaaaaatta aaatttgtca cccaaccagg 5160
tgataataac aaaacaataa tttaggaaca tccagtaaat ttgaattagt tctctaaatt 5220
ttggtaatta atagcttatt gataattaaa atcagcctaa tgttgcttaa gtaggaggaa 5280
attgatcagc aatgggattg ggtatctatt ttctttccta taaaagtgct gcctcttctc 5340
aaattgcttt atttctctcc cactgcatta gtatatctag aacagcacct tcaactgcaa 5400
caaaatataa ttctcctaga tgactaggat atcctccaat ctggtatcat gccaaacaac 5460
actatgtttg gggaacagca cccgaaatgc tgctaaaaag ctacctcatg tcaagaaaat 5520
atggatttca aaaaatatct ggcacagtgg cccatgccta taaccccagt actttgggag 5580
gccaaggcag gaggattgct ggaggccagg agttcaagac cagcctgggc aacatggaga 5640
gactccgcct ctacaaaaaa aaaaaaaaca aatttaattt aattggccag ttgtggtggc 5700
gtgggcctgt ggtcccagct acttgggaag ctaaggcagg aggattgctg gaggcctgga 5760
gggcaaggct gcagtgagcc atgttcacat cgctgcactc cagcctgggt gacagagcaa 5820
gaccctgtct ccaaaaaagc aaaaataaat atctaacaaa aaggaacctg tttccaaacc 5880
acagtttctt aactttttca tgatggaata gaaattaaac tataagtata tactgataat 5940
agctgtgcag gaaattggtt tttattttac ttaaaagtat tttttagaaa aaatgttatt 6000
ctgattgcat agattagcaa aatattgcat caatataatg ttccattttt attaattttt 6060
gttatattct aaatgaccgt tttataattc tgtcttggac aactgggcca cagttagaat 6120
ccacatagac agggaggttc ttaggtgtgc catttgtaga ataaagggca atcaagttaa 6180
tattcggggt aaattttcat tgcattctaa cctatgaagt ttgataaagt atattattat 6240
tgaacaactc taacactaag atttcctaaa agtaacttac aacaaaaaat gaactatgtg 6300
ctcaatattc acataaagtc atgattattc tcttcttgca ttcatataaa agttcccagg 6360
gggaagaaaa tatatctaaa aattagacta gaaacttggc actttttatg tattgtagat 6420
acactttcat atattgtaaa tacatctgtt aaagataaaa ctaagtttct aacatagcac 6480
tacaaggaaa ctttggataa atatttttaa aaagaaaatg ttaataggat aacttaagat 6540
tttgtatata cttattggaa gacaggaaga aactaggcag taaatattcc tacctgacgt 6600
gcaaccattg tcaatcaggt tttgttaaac tgtcaaattt gattttgaaa ttttagtttg 6660
cccaaataat atcttgaaaa tgctctgaat tttactagaa catattcata gaaagtgtaa 6720
tgtatctacc aggctctatg tttgtgtttg ccaacattag aaaaacaaag taagttgcgc 6780
tataatgagt gaaactaagg aaaatgagat ttttctgact cccattccct ctcttaaaaa 6840
gtaaaatatt taagcttttt ttattaaagg aaaaatgggt acagaatact ctattgccct 6900
ccaaatgtcc aacattttta aagccatgtt gtccaacaat gtttatacag aaaatagaat 6960
gcataggttt aatatagata gcaatgtata tgtaggctca tttgtgggag attgcaaact 7020
ttatgtgccc ccagttctcc ttggttttgt aggaaagcta aaagaaaacc ttgtactctc 7080
actaataatg aaattcatag ccaatttaga aagggaaaat aacctgaaaa ccaaaatacc 7140
tcattcatct gaagatgcct ggaataaaat atggaattct tctgtaccta cctccccctt 7200
acagactttt ctcctatttt gagagagaaa ttcaagaaga agaatacagc ttgttctctt 7260
tccacaaatg atactttgtc taagggaata ggagatacca agaaacagta tctttaaaaa 7320
agtaagctgc ccacaggcct tcttggagaa tgaagaatat cagccccatt cagggtttac 7380
caatgtctct ctgaggtgac aatacattct ggttttccag gacagtcctg gcttaggtct 7440
gctgtccttc tataaatatt aacaatgatc cctcttattt ccaaacgtgt cccagtttag 7500
acaacaaatt atacagtgtc tgcccccaac acacacacac acaccccacc atctttatgg 7560
gttgttgttg ttttcttgtt gtttttaatt ttgtagaatt ggctttgtct tctccaaagc 7620
agataacagc ttaaactaaa gagcctagct acttctttct gactgagcag ggtcatagta 7680
aacagagaag aatggatcac ttcctcctct gaaatctcca tcaatccact ttctgtccaa 7740
ctatctctct acccagccta tttttggtcc tagttttcct ctcataaccc ctgggctgtg 7800
agtcctgagt tctgccttca tatggcagag caagctagtc attattatgc caggttaggt 7860
ggtggggcaa gacaaaagat agctcttggg gacacttgct tggtctgtag agatccacag 7920
ggcactagta gggtattaga gcatttattg gtttctttct tccttgagtt gagttacttc 7980
tatcccaaaa cagacaggtc ttacgttaac cttcacctta aaaaggatat tgcctttttt 8040
ccttctgctt cacaaatttg ctccaacact aattcccttg catttgattt catcattatg 8100
attgttcatc aaccattctt cacgaaaaat cctcacatca cgtcatataa aggttttatt 8160
atttttaatg gaaaataaca ttgagagatt attttccttt ttcataaaat ttcccttttt 8220
ccctccctct attctcttca ctaacattgg aaattaaaca agttttacag gctctattgt 8280
tattaaccct caaatctatt cttcagagaa tatatgatca gcctgtgttt actatgcacc 8340
tactcttata ccagaaactg tgaatacaaa tacatatatt tcctacttct ctctttaatt 8400
ggggcacaca gtcccatggt ccattctgca tttttcaaaa ttgaatataa ttgcaacacc 8460
tgataggttt tgccacttag aattctgaaa ataaatcaac tctgttctaa accttaagtt 8520
tccactatta ttgccaaact ctggactgat acaataagcc ttttaaaagg tgaatttaac 8580
acttcaccta ttatggttat ttaagtaaaa tgagttttca aatatttccc ccaggagaaa 8640
tataaaggac tatgcaaaaa tagaaggaga aaaaggttag ttagaggtcc agaaggagaa 8700
ttaaaacatg gaattgataa attcacctac tgatttatga tgttaatgag caggtaccta 8760
tacattttat ttacttgaaa acattttggc cattaactat ttctgttttc taaatacatt 8820
tgtgtttata aaattttaaa atctatatca caagacttag acatgccttt ctttgcaata 8880
aagtatatat acctttttac aaatgtaaat tttattttga aacttggcat tttctttata 8940
attcctaaga tatctttggg cacacagact acagataaat ctatttaaat caattcatca 9000
ttatcactgg tttaaatatt taatgtaacc attggaattt ttattcttat tccttcagag 9060
aattctcctt ttcttctatg tttctgactg caatacagcc cgatattgtt attccctata 9120
tcttaatgaa aagcaagctg tcagcaaaat gcatttatag tttccagatg tttaacaatc 9180
tctttcttct tttctttttt gttattattt ttatttatgt gaagttagtt agctgaggta 9240
ccaaaaaaga gacaaagaca gtattaaaaa gtgtgcataa agcacttatt tttgtacttt 9300
agtacaatgt tttatagaac tttgtgatct atctaaatat attaagtaaa attacaccat 9360
tcacttgttg ggaaaataat ctttggtttg gaagatatta acataatggg catcttagaa 9420
tcataaatca catgaaatga gagacaatgc aatattgtat aattcctgga tgatgcaatt 9480
gttttaattg aattttcaag tgccattata aagtttt 9517
<210> 6
<211> 9350
<212> DNA
<213> 智人 (homo sapiens)
<400> 6
tttgatatga cgattagagc ataacccgag tgacacgttg aattcgccat aatcaaggaa 60
accttttccg ggtggggatc tctgaaatta ctcagataac agtgctgtgc caaaaacctg 120
tggattttct ctacaaaaat tatcatgact gttatctttt tgatggaaaa gatgaagttc 180
agcgaagaac aaatctacaa cttggccaga agactgtaga ctttgccttc aaagagtgag 240
caaccctaat taacctgatt ttttgctgat aatcactctc aatggaatca aatcacaaat 300
ccggggatgg attgagcggc actcagaagg aagcagccct ccgcgcactg gtccagcgca 360
caggatatag cttggtccag gaaaatggac aaagaaaata tggtggccct ccacctggtt 420
gggatgctgc accccctgaa aggggctgtg aaatttttat tggaaaactt ccccgagacc 480
tttttgagga tgagcttata ccattatgtg aaaaaatcgg taaaatttat gaaatgagaa 540
tgatgatgga ttttaatggc aacaatagag gatatgcatt tgtaacattt tcaaataaag 600
tggaagccaa gaatgcaatc aagcaactta ataattatga aattagaaat gggcgcctct 660
taggggtttg tgccagtgtg gacaactgcc gattatttgt tgggggcatc ccaaaaacca 720
aaaagagaga agaaatctta tcggagatga aaaaggttac tgaaggtgtt gtcgatgtca 780
tcgtctaccc aagcgctgca gataaaacca aaaaccgagg ctttgccttc gtggagtatg 840
agagtcatcg agcagctgcc atggcgagga ggaaactgct accaggaaga attcagttat 900
ggggacatgg tattgcagta gactgggcag agccagaagt agaagttgat gaagatacaa 960
tgtcttcagt gaaaatccta tatgtaagaa atcttatgct gtctacctct gaagagatga 1020
ttgaaaagga attcaacaat atcaaaccag gtgctgtgga gagggtgaag aaaattcgag 1080
actatgcttt tgtgcacttc agtaaccgag aagatgcagt tgaggctatg aaagctttaa 1140
atggcaaggt gctggatggt tcccccattg aagtcaccct agcaaaacca gtggacaagg 1200
acagttatgt taggtatacc cgaggcacag gtggaagggg caccatgctg caaggagagt 1260
atacctactc tttgggccaa gtttatgatc ccaccacaac ctaccttgga gctcctgtct 1320
tctatgcccc ccagacctat gcagcaattc ccagtcttca tttcccagcc accaaaggac 1380
atctcagcaa cagagccatt atccgagccc cttctgttag aggggctgcg ggagtgagag 1440
gactgggcgg ccgtggctat ttggcataca caggcctggg tcgaggatac caggtcaaag 1500
gagacaaaag agaagacaaa ctctatgaca ttttacctgg gatggagctc accccaatga 1560
atcctgtcac attaaaaccc caaggaatta aactcgctcc ccagatatta gaagagattt 1620
gtcagaaaaa taactgggga cagccagtgt accagctgca ctctgctatt ggacaagacc 1680
aaagacagct attcttgtac aaaataacta ttcctgctct agccagccag aatcctgcaa 1740
tccacccttt cacacctcca aagctgagtg cctttgtgga tgaagcaaag acgtatgcag 1800
ccgaatacac cctgcagacc ctgggcatcc ccactgatgg aggcgatggc accatggcta 1860
ctgctgctgc tgctgctact gctttcccag gatatgctgt ccctaatgca actgcacccg 1920
tgtctgcagc ccagctcaag caagcggtaa cccttggaca agacttagca gcatatacaa 1980
cctatgaggt ctacccaact tttgcagtga ctgcccgagg ggatggatat ggcaccttct 2040
gaagatgctt ttttaaattt aagaataaga cacacaaaac tctattaaaa aaaaaaaaga 2100
aataaacctc taactcggtc cccaatgatc ataaataata tgtttcctaa agaaatgcct 2160
ttccagagac tgtatagctt ataccaatta tagaatcatg aagtaagaac gttattctga 2220
aatgaaatca aatgttaaag agccttttgt ttaacagaaa gctggagagc cactgcccca 2280
aaagttgttc ttccagtctt cctgagtgtt tggggagtat gtttacaaat cctgccaggg 2340
tgaagagaga tcttgtagct ggcaagattt gggagggatg gagcagacct gggcagtcag 2400
taataatcaa gggaagccaa gtaaactcca gagtcttacc tctggctcac agctgctttt 2460
gtgatacaca aagtcacaaa gaggaaaagg gaagggagga ggttgctttt caaaatgcat 2520
tcaccatggc tcactgtgtg gggcatgatt gcaggcctga gctcatgaaa gactgtccaa 2580
gattttgtgg tttcaacctc tcttcagcct gaaaattcca tccagtcgat ttgtcacaga 2640
tcaggatctt cctgtcccct gcagcccatg gggacttcct agaaatagat atgatatgtt 2700
gtagatgtgg ttaaaacaaa tccaggcccc attgtttatt cagctcatta gtccacacct 2760
atttttccct agaactccta ccttttccaa taatcatgcc agcatgaaat gaccttttct 2820
actttaaaat tttttgactt gttcatattg cttgattttc atcatctcag actcattttt 2880
ctcctaccta atatcataaa aaagtaaatc agatatacag aatatcattt atgatacttc 2940
ttcctttcag caaattgact gaaaagtcat tttaaagaga gaagtgcaga tttgctctca 3000
tttctttgat attgttgcag tatccacccc accatctagc aatcagagat gcttatatta 3060
acttgggatt agctttgcat tatctaaccc atttatttta aatctgccag gaaatcctct 3120
aactttcctt cctttttgtt tcagtaagta tcaggcagct tcaccatacc tgagtccttt 3180
tgtcttgaag ctgccacaga aaaatcttac agcaatcatt gctgattaga aactgtttca 3240
gacaatcagc atgggtgtta tttaccaaat tccccccaga gtcctaggcc tcttctccag 3300
aaatatctga tgatgaagtg aggggagggc aacggtgcta caaaacacgg aacagaggta 3360
aagagaaggc actactttct tgccatactt gtaaatgatt gctttgttca aacataaata 3420
atcttaagtc caacaccaaa tacctgttac tcctacatca atctcattag tggtttaaga 3480
cacagtacta gaattttcat tttttaaaat cccttggccc ttaaaaaaat ttacagaaca 3540
caaaggaaaa cataaacaca aagacatgga aaattttgtc aactccttaa tggaattctg 3600
tgatcaaaaa gcaggccaga ttctaatcaa aatcaggtaa attttaatca caatcagaag 3660
tacttgtaac atttcagttg tcctaactcc aatgagataa caaagcctcc aaggctacag 3720
ctgaaactct gaaaggccct gtgctttcta ctttacattt agcgtctaat atttcctagg 3780
acagtagttc ccaaagtagg ctgtacatta gaatctcctg gagagctttt taaatgctaa 3840
tgccaataac atatctcata aaatttacac tagaatttcc ttggatgggt gcctggcatc 3900
agtatttttt aatgatccct aggtgatttc aatgtgcacc taggtttggg aattgctata 3960
ttcttgtatt tatactctat ctctttattt cttttccttt ttatttcact tttagtaaat 4020
agaaaaatgc aattaaaaaa tcatctaagt taagacaaat agccaaatca tatttatccc 4080
ataaatagta tgaatttaaa tgtaacttac gtaggcttca aactaactct aaaaatgaga 4140
aagtaaaaca atcttgtcct aaaacaattc ttagatccaa atttacactc ccctacagat 4200
ctgcttttat tctcaaagac agtgattaca ttgacataac aaatgtccat tggggcaggc 4260
aaatttctac tgagtctaaa aagcattcca aattctagga gcaaaagttc tgattttcct 4320
taaaatcttt gcaaataaac agcaaagggt attctggatg tcttgtcaat gcaaattagg 4380
tttgatttag agaagtttta aatttaatcg caatgaaaag attagttaat acatgaatct 4440
ttttatgaga aaaaatcatt attctggata aagtcataat tgtttgttta caatattaag 4500
agcagacacc taaacataca ataataccaa agtattgaga aaattaccac tggaacacca 4560
tctcaagtta tcacaccatt tacctcttta gagccagttt tgtataagta ggtagaagtg 4620
gttttggttt ttttgctaaa attttacttt gttttagtaa tatctaggga atactttgaa 4680
ttccattaaa ataccttcat agaaagtgtt aatgtgtcta ccatgccata tgtttatttt 4740
tactttcccc aagttaggta gatagagcaa gtcctgctac cataagttta aaattattaa 4800
gacaacgggc ttttttaaat tgctggtaga accaaaggct aattttgcat aggtttatat 4860
ttttagactt aagaaattag cacctatata ataccttcat accttctgca tcactatcaa 4920
tttttctgta atttcttatt tgaatgcttc ctaattcttt acagaaaaaa ttaaaatttg 4980
tcacccaacc aggtgataat aacaaaacaa taatttagga acatccagta aatttgaatt 5040
agttctctaa attttggtaa ttaatagctt attgataatt aaaatcagcc taatgttgct 5100
taagtaggag gaaattgatc agcaatggga ttgggtatct attttctttc ctataaaagt 5160
gctgcctctt ctcaaattgc tttatttctc tcccactgca ttagtatatc tagaacagca 5220
ccttcaactg caacaaaata taattctcct agatgactag gatatcctcc aatctggtat 5280
catgccaaac aacactatgt ttggggaaca gcacccgaaa tgctgctaaa aagctacctc 5340
atgtcaagaa aatatggatt tcaaaaaata tctggcacag tggcccatgc ctataacccc 5400
agtactttgg gaggccaagg caggaggatt gctggaggcc aggagttcaa gaccagcctg 5460
ggcaacatgg agagactccg cctctacaaa aaaaaaaaaa acaaatttaa tttaattggc 5520
cagttgtggt ggcgtgggcc tgtggtccca gctacttggg aagctaaggc aggaggattg 5580
ctggaggcct ggagggcaag gctgcagtga gccatgttca catcgctgca ctccagcctg 5640
ggtgacagag caagaccctg tctccaaaaa agcaaaaata aatatctaac aaaaaggaac 5700
ctgtttccaa accacagttt cttaactttt tcatgatgga atagaaatta aactataagt 5760
atatactgat aatagctgtg caggaaattg gtttttattt tacttaaaag tattttttag 5820
aaaaaatgtt attctgattg catagattag caaaatattg catcaatata atgttccatt 5880
tttattaatt tttgttatat tctaaatgac cgttttataa ttctgtcttg gacaactggg 5940
ccacagttag aatccacata gacagggagg ttcttaggtg tgccatttgt agaataaagg 6000
gcaatcaagt taatattcgg ggtaaatttt cattgcattc taacctatga agtttgataa 6060
agtatattat tattgaacaa ctctaacact aagatttcct aaaagtaact tacaacaaaa 6120
aatgaactat gtgctcaata ttcacataaa gtcatgatta ttctcttctt gcattcatat 6180
aaaagttccc agggggaaga aaatatatct aaaaattaga ctagaaactt ggcacttttt 6240
atgtattgta gatacacttt catatattgt aaatacatct gttaaagata aaactaagtt 6300
tctaacatag cactacaagg aaactttgga taaatatttt taaaaagaaa atgttaatag 6360
gataacttaa gattttgtat atacttattg gaagacagga agaaactagg cagtaaatat 6420
tcctacctga cgtgcaacca ttgtcaatca ggttttgtta aactgtcaaa tttgattttg 6480
aaattttagt ttgcccaaat aatatcttga aaatgctctg aattttacta gaacatattc 6540
atagaaagtg taatgtatct accaggctct atgtttgtgt ttgccaacat tagaaaaaca 6600
aagtaagttg cgctataatg agtgaaacta aggaaaatga gatttttctg actcccattc 6660
cctctcttaa aaagtaaaat atttaagctt tttttattaa aggaaaaatg ggtacagaat 6720
actctattgc cctccaaatg tccaacattt ttaaagccat gttgtccaac aatgtttata 6780
cagaaaatag aatgcatagg tttaatatag atagcaatgt atatgtaggc tcatttgtgg 6840
gagattgcaa actttatgtg cccccagttc tccttggttt tgtaggaaag ctaaaagaaa 6900
accttgtact ctcactaata atgaaattca tagccaattt agaaagggaa aataacctga 6960
aaaccaaaat acctcattca tctgaagatg cctggaataa aatatggaat tcttctgtac 7020
ctacctcccc cttacagact tttctcctat tttgagagag aaattcaaga agaagaatac 7080
agcttgttct ctttccacaa atgatacttt gtctaaggga ataggagata ccaagaaaca 7140
gtatctttaa aaaagtaagc tgcccacagg ccttcttgga gaatgaagaa tatcagcccc 7200
attcagggtt taccaatgtc tctctgaggt gacaatacat tctggttttc caggacagtc 7260
ctggcttagg tctgctgtcc ttctataaat attaacaatg atccctctta tttccaaacg 7320
tgtcccagtt tagacaacaa attatacagt gtctgccccc aacacacaca cacacacccc 7380
accatcttta tgggttgttg ttgttttctt gttgttttta attttgtaga attggctttg 7440
tcttctccaa agcagataac agcttaaact aaagagccta gctacttctt tctgactgag 7500
cagggtcata gtaaacagag aagaatggat cacttcctcc tctgaaatct ccatcaatcc 7560
actttctgtc caactatctc tctacccagc ctatttttgg tcctagtttt cctctcataa 7620
cccctgggct gtgagtcctg agttctgcct tcatatggca gagcaagcta gtcattatta 7680
tgccaggtta ggtggtgggg caagacaaaa gatagctctt ggggacactt gcttggtctg 7740
tagagatcca cagggcacta gtagggtatt agagcattta ttggtttctt tcttccttga 7800
gttgagttac ttctatccca aaacagacag gtcttacgtt aaccttcacc ttaaaaagga 7860
tattgccttt tttccttctg cttcacaaat ttgctccaac actaattccc ttgcatttga 7920
tttcatcatt atgattgttc atcaaccatt cttcacgaaa aatcctcaca tcacgtcata 7980
taaaggtttt attattttta atggaaaata acattgagag attattttcc tttttcataa 8040
aatttccctt tttccctccc tctattctct tcactaacat tggaaattaa acaagtttta 8100
caggctctat tgttattaac cctcaaatct attcttcaga gaatatatga tcagcctgtg 8160
tttactatgc acctactctt ataccagaaa ctgtgaatac aaatacatat atttcctact 8220
tctctcttta attggggcac acagtcccat ggtccattct gcatttttca aaattgaata 8280
taattgcaac acctgatagg ttttgccact tagaattctg aaaataaatc aactctgttc 8340
taaaccttaa gtttccacta ttattgccaa actctggact gatacaataa gccttttaaa 8400
aggtgaattt aacacttcac ctattatggt tatttaagta aaatgagttt tcaaatattt 8460
cccccaggag aaatataaag gactatgcaa aaatagaagg agaaaaaggt tagttagagg 8520
tccagaagga gaattaaaac atggaattga taaattcacc tactgattta tgatgttaat 8580
gagcaggtac ctatacattt tatttacttg aaaacatttt ggccattaac tatttctgtt 8640
ttctaaatac atttgtgttt ataaaatttt aaaatctata tcacaagact tagacatgcc 8700
tttctttgca ataaagtata tatacctttt tacaaatgta aattttattt tgaaacttgg 8760
cattttcttt ataattccta agatatcttt gggcacacag actacagata aatctattta 8820
aatcaattca tcattatcac tggtttaaat atttaatgta accattggaa tttttattct 8880
tattccttca gagaattctc cttttcttct atgtttctga ctgcaataca gcccgatatt 8940
gttattccct atatcttaat gaaaagcaag ctgtcagcaa aatgcattta tagtttccag 9000
atgtttaaca atctctttct tcttttcttt tttgttatta tttttattta tgtgaagtta 9060
gttagctgag gtaccaaaaa agagacaaag acagtattaa aaagtgtgca taaagcactt 9120
atttttgtac tttagtacaa tgttttatag aactttgtga tctatctaaa tatattaagt 9180
aaaattacac cattcacttg ttgggaaaat aatctttggt ttggaagata ttaacataat 9240
gggcatctta gaatcataaa tcacatgaaa tgagagacaa tgcaatattg tataattcct 9300
ggatgatgca attgttttaa ttgaattttc aagtgccatt ataaagtttt 9350
<210> 7
<211> 9400
<212> DNA
<213> 智人 (homo sapiens)
<400> 7
tttgatatga cgattagagc ataacccgag tgacacgttg aattcgccat aatcaaggaa 60
accttttccg ggtggggatc tctgaaatta ctcagataac agtgctgtgc caaaaacctg 120
tggattttct ctacaaaaat tattgagcaa ccctaattaa cctgattttt tgctgataat 180
cactctcaat ggaatcaaat cacaaatccg gggatggatt gagcggcact cagaaggaag 240
cagccctccg cgcactggtc cagcgcacag gatatagctt ggtccaggaa tttagaggtt 300
cctatagatg gaagcagtgt gtctgggcac atgcccagag ccagaagcga gcatgagcac 360
agcaattcct ggcctcaaaa aaggaaataa tgctttgcag tccatcattt tgcaaacttt 420
gctggaaaag gaaaatggac aaagaaaata tggtggccct ccacctggtt gggatgctgc 480
accccctgaa aggggctgtg aaatttttat tggaaaactt ccccgagacc tttttgagga 540
tgagcttata ccattatgtg aaaaaatcgg taaaatttat gaaatgagaa tgatgatgga 600
ttttaatggc aacaatagag gatatgcatt tgtaacattt tcaaataaag tggaagccaa 660
gaatgcaatc aagcaactta ataattatga aattagaaat gggcgcctct taggggtttg 720
tgccagtgtg gacaactgcc gattatttgt tgggggcatc ccaaaaacca aaaagagaga 780
agaaatctta tcggagatga aaaaggttac tgaaggtgtt gtcgatgtca tcgtctaccc 840
aagcgctgca gataaaacca aaaaccgagg ctttgccttc gtggagtatg agagtcatcg 900
agcagctgcc atggcgagga ggaaactgct accaggaaga attcagttat ggggacatgg 960
tattgcagta gactgggcag agccagaagt agaagttgat gaagatacaa tgtcttcagt 1020
gaaaatccta tatgtaagaa atcttatgct gtctacctct gaagagatga ttgaaaagga 1080
attcaacaat atcaaaccag gtgctgtgga gagggtgaag aaaattcgag actatgcttt 1140
tgtgcacttc agtaaccgag aagatgcagt tgaggctatg aaagctttaa atggcaaggt 1200
gctggatggt tcccccattg aagtcaccct agcaaaacca gtggacaagg acagttatgt 1260
taggtatacc cgaggcacag gtggaagggg caccatgctg caaggagagt atacctactc 1320
tttgggccaa gtttatgatc ccaccacaac ctaccttgga gctcctgtct tctatgcccc 1380
ccagacctat gcagcaattc ccagtcttca tttcccagcc accaaaggac atctcagcaa 1440
cagagccatt atccgagccc cttctgttag aggggctgcg ggagtgagag gactgggcgg 1500
ccgtggctat ttggcataca caggcctggg tcgaggatac caggtcaaag gagacaaaag 1560
agaagacaaa ctctatgaca ttttacctgg gatggagctc accccaatga atcctgtcac 1620
attaaaaccc caaggaatta aactcgctcc ccagatatta gaagagattt gtcagaaaaa 1680
taactgggga cagccagtgt accagctgca ctctgctatt ggacaagacc aaagacagct 1740
attcttgtac aaaataacta ttcctgctct agccagccag aatcctgcaa tccacccttt 1800
cacacctcca aagctgagtg cctttgtgga tgaagcaaag acgtatgcag ccgaatacac 1860
cctgcagacc ctgggcatcc ccactgatgg aggcgatggc accatggcta ctgctgctgc 1920
tgctgctact gctttcccag gatatgctgt ccctaatgca actgcacccg tgtctgcagc 1980
ccagctcaag caagcggtaa cccttggaca agacttagca gcatatacaa cctatgaggt 2040
ctacccaact tttgcagtga ctgcccgagg ggatggatat ggcaccttct gaagatgctt 2100
ttttaaattt aagaataaga cacacaaaac tctattaaaa aaaaaaaaga aataaacctc 2160
taactcggtc cccaatgatc ataaataata tgtttcctaa agaaatgcct ttccagagac 2220
tgtatagctt ataccaatta tagaatcatg aagtaagaac gttattctga aatgaaatca 2280
aatgttaaag agccttttgt ttaacagaaa gctggagagc cactgcccca aaagttgttc 2340
ttccagtctt cctgagtgtt tggggagtat gtttacaaat cctgccaggg tgaagagaga 2400
tcttgtagct ggcaagattt gggagggatg gagcagacct gggcagtcag taataatcaa 2460
gggaagccaa gtaaactcca gagtcttacc tctggctcac agctgctttt gtgatacaca 2520
aagtcacaaa gaggaaaagg gaagggagga ggttgctttt caaaatgcat tcaccatggc 2580
tcactgtgtg gggcatgatt gcaggcctga gctcatgaaa gactgtccaa gattttgtgg 2640
tttcaacctc tcttcagcct gaaaattcca tccagtcgat ttgtcacaga tcaggatctt 2700
cctgtcccct gcagcccatg gggacttcct agaaatagat atgatatgtt gtagatgtgg 2760
ttaaaacaaa tccaggcccc attgtttatt cagctcatta gtccacacct atttttccct 2820
agaactccta ccttttccaa taatcatgcc agcatgaaat gaccttttct actttaaaat 2880
tttttgactt gttcatattg cttgattttc atcatctcag actcattttt ctcctaccta 2940
atatcataaa aaagtaaatc agatatacag aatatcattt atgatacttc ttcctttcag 3000
caaattgact gaaaagtcat tttaaagaga gaagtgcaga tttgctctca tttctttgat 3060
attgttgcag tatccacccc accatctagc aatcagagat gcttatatta acttgggatt 3120
agctttgcat tatctaaccc atttatttta aatctgccag gaaatcctct aactttcctt 3180
cctttttgtt tcagtaagta tcaggcagct tcaccatacc tgagtccttt tgtcttgaag 3240
ctgccacaga aaaatcttac agcaatcatt gctgattaga aactgtttca gacaatcagc 3300
atgggtgtta tttaccaaat tccccccaga gtcctaggcc tcttctccag aaatatctga 3360
tgatgaagtg aggggagggc aacggtgcta caaaacacgg aacagaggta aagagaaggc 3420
actactttct tgccatactt gtaaatgatt gctttgttca aacataaata atcttaagtc 3480
caacaccaaa tacctgttac tcctacatca atctcattag tggtttaaga cacagtacta 3540
gaattttcat tttttaaaat cccttggccc ttaaaaaaat ttacagaaca caaaggaaaa 3600
cataaacaca aagacatgga aaattttgtc aactccttaa tggaattctg tgatcaaaaa 3660
gcaggccaga ttctaatcaa aatcaggtaa attttaatca caatcagaag tacttgtaac 3720
atttcagttg tcctaactcc aatgagataa caaagcctcc aaggctacag ctgaaactct 3780
gaaaggccct gtgctttcta ctttacattt agcgtctaat atttcctagg acagtagttc 3840
ccaaagtagg ctgtacatta gaatctcctg gagagctttt taaatgctaa tgccaataac 3900
atatctcata aaatttacac tagaatttcc ttggatgggt gcctggcatc agtatttttt 3960
aatgatccct aggtgatttc aatgtgcacc taggtttggg aattgctata ttcttgtatt 4020
tatactctat ctctttattt cttttccttt ttatttcact tttagtaaat agaaaaatgc 4080
aattaaaaaa tcatctaagt taagacaaat agccaaatca tatttatccc ataaatagta 4140
tgaatttaaa tgtaacttac gtaggcttca aactaactct aaaaatgaga aagtaaaaca 4200
atcttgtcct aaaacaattc ttagatccaa atttacactc ccctacagat ctgcttttat 4260
tctcaaagac agtgattaca ttgacataac aaatgtccat tggggcaggc aaatttctac 4320
tgagtctaaa aagcattcca aattctagga gcaaaagttc tgattttcct taaaatcttt 4380
gcaaataaac agcaaagggt attctggatg tcttgtcaat gcaaattagg tttgatttag 4440
agaagtttta aatttaatcg caatgaaaag attagttaat acatgaatct ttttatgaga 4500
aaaaatcatt attctggata aagtcataat tgtttgttta caatattaag agcagacacc 4560
taaacataca ataataccaa agtattgaga aaattaccac tggaacacca tctcaagtta 4620
tcacaccatt tacctcttta gagccagttt tgtataagta ggtagaagtg gttttggttt 4680
ttttgctaaa attttacttt gttttagtaa tatctaggga atactttgaa ttccattaaa 4740
ataccttcat agaaagtgtt aatgtgtcta ccatgccata tgtttatttt tactttcccc 4800
aagttaggta gatagagcaa gtcctgctac cataagttta aaattattaa gacaacgggc 4860
ttttttaaat tgctggtaga accaaaggct aattttgcat aggtttatat ttttagactt 4920
aagaaattag cacctatata ataccttcat accttctgca tcactatcaa tttttctgta 4980
atttcttatt tgaatgcttc ctaattcttt acagaaaaaa ttaaaatttg tcacccaacc 5040
aggtgataat aacaaaacaa taatttagga acatccagta aatttgaatt agttctctaa 5100
attttggtaa ttaatagctt attgataatt aaaatcagcc taatgttgct taagtaggag 5160
gaaattgatc agcaatggga ttgggtatct attttctttc ctataaaagt gctgcctctt 5220
ctcaaattgc tttatttctc tcccactgca ttagtatatc tagaacagca ccttcaactg 5280
caacaaaata taattctcct agatgactag gatatcctcc aatctggtat catgccaaac 5340
aacactatgt ttggggaaca gcacccgaaa tgctgctaaa aagctacctc atgtcaagaa 5400
aatatggatt tcaaaaaata tctggcacag tggcccatgc ctataacccc agtactttgg 5460
gaggccaagg caggaggatt gctggaggcc aggagttcaa gaccagcctg ggcaacatgg 5520
agagactccg cctctacaaa aaaaaaaaaa acaaatttaa tttaattggc cagttgtggt 5580
ggcgtgggcc tgtggtccca gctacttggg aagctaaggc aggaggattg ctggaggcct 5640
ggagggcaag gctgcagtga gccatgttca catcgctgca ctccagcctg ggtgacagag 5700
caagaccctg tctccaaaaa agcaaaaata aatatctaac aaaaaggaac ctgtttccaa 5760
accacagttt cttaactttt tcatgatgga atagaaatta aactataagt atatactgat 5820
aatagctgtg caggaaattg gtttttattt tacttaaaag tattttttag aaaaaatgtt 5880
attctgattg catagattag caaaatattg catcaatata atgttccatt tttattaatt 5940
tttgttatat tctaaatgac cgttttataa ttctgtcttg gacaactggg ccacagttag 6000
aatccacata gacagggagg ttcttaggtg tgccatttgt agaataaagg gcaatcaagt 6060
taatattcgg ggtaaatttt cattgcattc taacctatga agtttgataa agtatattat 6120
tattgaacaa ctctaacact aagatttcct aaaagtaact tacaacaaaa aatgaactat 6180
gtgctcaata ttcacataaa gtcatgatta ttctcttctt gcattcatat aaaagttccc 6240
agggggaaga aaatatatct aaaaattaga ctagaaactt ggcacttttt atgtattgta 6300
gatacacttt catatattgt aaatacatct gttaaagata aaactaagtt tctaacatag 6360
cactacaagg aaactttgga taaatatttt taaaaagaaa atgttaatag gataacttaa 6420
gattttgtat atacttattg gaagacagga agaaactagg cagtaaatat tcctacctga 6480
cgtgcaacca ttgtcaatca ggttttgtta aactgtcaaa tttgattttg aaattttagt 6540
ttgcccaaat aatatcttga aaatgctctg aattttacta gaacatattc atagaaagtg 6600
taatgtatct accaggctct atgtttgtgt ttgccaacat tagaaaaaca aagtaagttg 6660
cgctataatg agtgaaacta aggaaaatga gatttttctg actcccattc cctctcttaa 6720
aaagtaaaat atttaagctt tttttattaa aggaaaaatg ggtacagaat actctattgc 6780
cctccaaatg tccaacattt ttaaagccat gttgtccaac aatgtttata cagaaaatag 6840
aatgcatagg tttaatatag atagcaatgt atatgtaggc tcatttgtgg gagattgcaa 6900
actttatgtg cccccagttc tccttggttt tgtaggaaag ctaaaagaaa accttgtact 6960
ctcactaata atgaaattca tagccaattt agaaagggaa aataacctga aaaccaaaat 7020
acctcattca tctgaagatg cctggaataa aatatggaat tcttctgtac ctacctcccc 7080
cttacagact tttctcctat tttgagagag aaattcaaga agaagaatac agcttgttct 7140
ctttccacaa atgatacttt gtctaaggga ataggagata ccaagaaaca gtatctttaa 7200
aaaagtaagc tgcccacagg ccttcttgga gaatgaagaa tatcagcccc attcagggtt 7260
taccaatgtc tctctgaggt gacaatacat tctggttttc caggacagtc ctggcttagg 7320
tctgctgtcc ttctataaat attaacaatg atccctctta tttccaaacg tgtcccagtt 7380
tagacaacaa attatacagt gtctgccccc aacacacaca cacacacccc accatcttta 7440
tgggttgttg ttgttttctt gttgttttta attttgtaga attggctttg tcttctccaa 7500
agcagataac agcttaaact aaagagccta gctacttctt tctgactgag cagggtcata 7560
gtaaacagag aagaatggat cacttcctcc tctgaaatct ccatcaatcc actttctgtc 7620
caactatctc tctacccagc ctatttttgg tcctagtttt cctctcataa cccctgggct 7680
gtgagtcctg agttctgcct tcatatggca gagcaagcta gtcattatta tgccaggtta 7740
ggtggtgggg caagacaaaa gatagctctt ggggacactt gcttggtctg tagagatcca 7800
cagggcacta gtagggtatt agagcattta ttggtttctt tcttccttga gttgagttac 7860
ttctatccca aaacagacag gtcttacgtt aaccttcacc ttaaaaagga tattgccttt 7920
tttccttctg cttcacaaat ttgctccaac actaattccc ttgcatttga tttcatcatt 7980
atgattgttc atcaaccatt cttcacgaaa aatcctcaca tcacgtcata taaaggtttt 8040
attattttta atggaaaata acattgagag attattttcc tttttcataa aatttccctt 8100
tttccctccc tctattctct tcactaacat tggaaattaa acaagtttta caggctctat 8160
tgttattaac cctcaaatct attcttcaga gaatatatga tcagcctgtg tttactatgc 8220
acctactctt ataccagaaa ctgtgaatac aaatacatat atttcctact tctctcttta 8280
attggggcac acagtcccat ggtccattct gcatttttca aaattgaata taattgcaac 8340
acctgatagg ttttgccact tagaattctg aaaataaatc aactctgttc taaaccttaa 8400
gtttccacta ttattgccaa actctggact gatacaataa gccttttaaa aggtgaattt 8460
aacacttcac ctattatggt tatttaagta aaatgagttt tcaaatattt cccccaggag 8520
aaatataaag gactatgcaa aaatagaagg agaaaaaggt tagttagagg tccagaagga 8580
gaattaaaac atggaattga taaattcacc tactgattta tgatgttaat gagcaggtac 8640
ctatacattt tatttacttg aaaacatttt ggccattaac tatttctgtt ttctaaatac 8700
atttgtgttt ataaaatttt aaaatctata tcacaagact tagacatgcc tttctttgca 8760
ataaagtata tatacctttt tacaaatgta aattttattt tgaaacttgg cattttcttt 8820
ataattccta agatatcttt gggcacacag actacagata aatctattta aatcaattca 8880
tcattatcac tggtttaaat atttaatgta accattggaa tttttattct tattccttca 8940
gagaattctc cttttcttct atgtttctga ctgcaataca gcccgatatt gttattccct 9000
atatcttaat gaaaagcaag ctgtcagcaa aatgcattta tagtttccag atgtttaaca 9060
atctctttct tcttttcttt tttgttatta tttttattta tgtgaagtta gttagctgag 9120
gtaccaaaaa agagacaaag acagtattaa aaagtgtgca taaagcactt atttttgtac 9180
tttagtacaa tgttttatag aactttgtga tctatctaaa tatattaagt aaaattacac 9240
cattcacttg ttgggaaaat aatctttggt ttggaagata ttaacataat gggcatctta 9300
gaatcataaa tcacatgaaa tgagagacaa tgcaatattg tataattcct ggatgatgca 9360
attgttttaa ttgaattttc aagtgccatt ataaagtttt 9400
<210> 8
<211> 9221
<212> DNA
<213> 智人 (homo sapiens)
<400> 8
ataatcaagg aaaccttttc cgggtgggga tctctgaaat tactcagata acagtgctgt 60
gccaaaaacc tgtggatttt ctctacaaaa attattgagc aaccctaatt aacctgattt 120
tttgctgata atcactctca atggaatcaa atcacaaatc cggggatgga ttgagcggca 180
ctcagaagga agcagccctc cgcgcactgg tccagcgcac aggatatagc ttggtccagg 240
aaaatggaca aagaaaatat ggtggccctc cacctggttg ggatgctgca ccccctgaaa 300
ggggctgtga aatttttatt ggaaaacttc cccgagacct ttttgaggat gagcttatac 360
cattatgtga aaaaatcggt aaaatttatg aaatgagaat gatgatggat tttaatggca 420
acaatagagg atatgcattt gtaacatttt caaataaagt ggaagccaag aatgcaatca 480
agcaacttaa taattatgaa attagaaatg ggcgcctctt aggggtttgt gccagtgtgg 540
acaactgccg attatttgtt gggggcatcc caaaaaccaa aaagagagaa gaaatcttat 600
cggagatgaa aaaggttact gaaggtgttg tcgatgtcat cgtctaccca agcgctgcag 660
ataaaaccaa aaaccgaggc tttgccttcg tggagtatga gagtcatcga gcagctgcca 720
tggcgaggag gaaactgcta ccaggaagaa ttcagttatg gggacatggt attgcagtag 780
actgggcaga gccagaagta gaagttgatg aagatacaat gtcttcagtg aaaatcctat 840
atgtaagaaa tcttatgctg tctacctctg aagagatgat tgaaaaggaa ttcaacaata 900
tcaaaccagg tgctgtggag agggtgaaga aaattcgaga ctatgctttt gtgcacttca 960
gtaaccgaga agatgcagtt gaggctatga aagctttaaa tggcaaggtg ctggatggtt 1020
cccccattga agtcacccta gcaaaaccag tggacaagga cagttatgtt aggtataccc 1080
gaggcacagg tggaaggggc accatgctgc aaggagagta tacctactct ttgggccaag 1140
tttatgatcc caccacaacc taccttggag ctcctgtctt ctatgccccc cagacctatg 1200
cagcaattcc cagtcttcat ttcccagcca ccaaaggaca tctcagcaac agagccatta 1260
tccgagcccc ttctgttaga ggggctgcgg gagtgagagg actgggcggc cgtggctatt 1320
tggcatacac aggcctgggt cgaggatacc aggtcaaagg agacaaaaga gaagacaaac 1380
tctatgacat tttacctggg atggagctca ccccaatgaa tcctgtcaca ttaaaacccc 1440
aaggaattaa actcgctccc cagatattag aagagatttg tcagaaaaat aactggggac 1500
agccagtgta ccagctgcac tctgctattg gacaagacca aagacagcta ttcttgtaca 1560
aaataactat tcctgctcta gccagccaga atcctgcaat ccaccctttc acacctccaa 1620
agctgagtgc ctttgtggat gaagcaaaga cgtatgcagc cgaatacacc ctgcagaccc 1680
tgggcatccc cactgatgga ggcgatggca ccatggctac tgctgctgct gctgctactg 1740
ctttcccagg atatgctgtc cctaatgcaa ctgcacccgt gtctgcagcc cagctcaagc 1800
aagcggtaac ccttggacaa gacttagcag catatacaac ctatgaggtc tacccaactt 1860
ttgcagtgac tgcccgaggg gatggatatg gcaccttctg aagatgcttt tttaaattta 1920
agaataagac acacaaaact ctattaaaaa aaaaaaagaa ataaacctct aactcggtcc 1980
ccaatgatca taaataatat gtttcctaaa gaaatgcctt tccagagact gtatagctta 2040
taccaattat agaatcatga agtaagaacg ttattctgaa atgaaatcaa atgttaaaga 2100
gccttttgtt taacagaaag ctggagagcc actgccccaa aagttgttct tccagtcttc 2160
ctgagtgttt ggggagtatg tttacaaatc ctgccagggt gaagagagat cttgtagctg 2220
gcaagatttg ggagggatgg agcagacctg ggcagtcagt aataatcaag ggaagccaag 2280
taaactccag agtcttacct ctggctcaca gctgcttttg tgatacacaa agtcacaaag 2340
aggaaaaggg aagggaggag gttgcttttc aaaatgcatt caccatggct cactgtgtgg 2400
ggcatgattg caggcctgag ctcatgaaag actgtccaag attttgtggt ttcaacctct 2460
cttcagcctg aaaattccat ccagtcgatt tgtcacagat caggatcttc ctgtcccctg 2520
cagcccatgg ggacttccta gaaatagata tgatatgttg tagatgtggt taaaacaaat 2580
ccaggcccca ttgtttattc agctcattag tccacaccta tttttcccta gaactcctac 2640
cttttccaat aatcatgcca gcatgaaatg accttttcta ctttaaaatt ttttgacttg 2700
ttcatattgc ttgattttca tcatctcaga ctcatttttc tcctacctaa tatcataaaa 2760
aagtaaatca gatatacaga atatcattta tgatacttct tcctttcagc aaattgactg 2820
aaaagtcatt ttaaagagag aagtgcagat ttgctctcat ttctttgata ttgttgcagt 2880
atccacccca ccatctagca atcagagatg cttatattaa cttgggatta gctttgcatt 2940
atctaaccca tttattttaa atctgccagg aaatcctcta actttccttc ctttttgttt 3000
cagtaagtat caggcagctt caccatacct gagtcctttt gtcttgaagc tgccacagaa 3060
aaatcttaca gcaatcattg ctgattagaa actgtttcag acaatcagca tgggtgttat 3120
ttaccaaatt ccccccagag tcctaggcct cttctccaga aatatctgat gatgaagtga 3180
ggggagggca acggtgctac aaaacacgga acagaggtaa agagaaggca ctactttctt 3240
gccatacttg taaatgattg ctttgttcaa acataaataa tcttaagtcc aacaccaaat 3300
acctgttact cctacatcaa tctcattagt ggtttaagac acagtactag aattttcatt 3360
ttttaaaatc ccttggccct taaaaaaatt tacagaacac aaaggaaaac ataaacacaa 3420
agacatggaa aattttgtca actccttaat ggaattctgt gatcaaaaag caggccagat 3480
tctaatcaaa atcaggtaaa ttttaatcac aatcagaagt acttgtaaca tttcagttgt 3540
cctaactcca atgagataac aaagcctcca aggctacagc tgaaactctg aaaggccctg 3600
tgctttctac tttacattta gcgtctaata tttcctagga cagtagttcc caaagtaggc 3660
tgtacattag aatctcctgg agagcttttt aaatgctaat gccaataaca tatctcataa 3720
aatttacact agaatttcct tggatgggtg cctggcatca gtatttttta atgatcccta 3780
ggtgatttca atgtgcacct aggtttggga attgctatat tcttgtattt atactctatc 3840
tctttatttc ttttcctttt tatttcactt ttagtaaata gaaaaatgca attaaaaaat 3900
catctaagtt aagacaaata gccaaatcat atttatccca taaatagtat gaatttaaat 3960
gtaacttacg taggcttcaa actaactcta aaaatgagaa agtaaaacaa tcttgtccta 4020
aaacaattct tagatccaaa tttacactcc cctacagatc tgcttttatt ctcaaagaca 4080
gtgattacat tgacataaca aatgtccatt ggggcaggca aatttctact gagtctaaaa 4140
agcattccaa attctaggag caaaagttct gattttcctt aaaatctttg caaataaaca 4200
gcaaagggta ttctggatgt cttgtcaatg caaattaggt ttgatttaga gaagttttaa 4260
atttaatcgc aatgaaaaga ttagttaata catgaatctt tttatgagaa aaaatcatta 4320
ttctggataa agtcataatt gtttgtttac aatattaaga gcagacacct aaacatacaa 4380
taataccaaa gtattgagaa aattaccact ggaacaccat ctcaagttat cacaccattt 4440
acctctttag agccagtttt gtataagtag gtagaagtgg ttttggtttt tttgctaaaa 4500
ttttactttg ttttagtaat atctagggaa tactttgaat tccattaaaa taccttcata 4560
gaaagtgtta atgtgtctac catgccatat gtttattttt actttcccca agttaggtag 4620
atagagcaag tcctgctacc ataagtttaa aattattaag acaacgggct tttttaaatt 4680
gctggtagaa ccaaaggcta attttgcata ggtttatatt tttagactta agaaattagc 4740
acctatataa taccttcata ccttctgcat cactatcaat ttttctgtaa tttcttattt 4800
gaatgcttcc taattcttta cagaaaaaat taaaatttgt cacccaacca ggtgataata 4860
acaaaacaat aatttaggaa catccagtaa atttgaatta gttctctaaa ttttggtaat 4920
taatagctta ttgataatta aaatcagcct aatgttgctt aagtaggagg aaattgatca 4980
gcaatgggat tgggtatcta ttttctttcc tataaaagtg ctgcctcttc tcaaattgct 5040
ttatttctct cccactgcat tagtatatct agaacagcac cttcaactgc aacaaaatat 5100
aattctccta gatgactagg atatcctcca atctggtatc atgccaaaca acactatgtt 5160
tggggaacag cacccgaaat gctgctaaaa agctacctca tgtcaagaaa atatggattt 5220
caaaaaatat ctggcacagt ggcccatgcc tataacccca gtactttggg aggccaaggc 5280
aggaggattg ctggaggcca ggagttcaag accagcctgg gcaacatgga gagactccgc 5340
ctctacaaaa aaaaaaaaaa caaatttaat ttaattggcc agttgtggtg gcgtgggcct 5400
gtggtcccag ctacttggga agctaaggca ggaggattgc tggaggcctg gagggcaagg 5460
ctgcagtgag ccatgttcac atcgctgcac tccagcctgg gtgacagagc aagaccctgt 5520
ctccaaaaaa gcaaaaataa atatctaaca aaaaggaacc tgtttccaaa ccacagtttc 5580
ttaacttttt catgatggaa tagaaattaa actataagta tatactgata atagctgtgc 5640
aggaaattgg tttttatttt acttaaaagt attttttaga aaaaatgtta ttctgattgc 5700
atagattagc aaaatattgc atcaatataa tgttccattt ttattaattt ttgttatatt 5760
ctaaatgacc gttttataat tctgtcttgg acaactgggc cacagttaga atccacatag 5820
acagggaggt tcttaggtgt gccatttgta gaataaaggg caatcaagtt aatattcggg 5880
gtaaattttc attgcattct aacctatgaa gtttgataaa gtatattatt attgaacaac 5940
tctaacacta agatttccta aaagtaactt acaacaaaaa atgaactatg tgctcaatat 6000
tcacataaag tcatgattat tctcttcttg cattcatata aaagttccca gggggaagaa 6060
aatatatcta aaaattagac tagaaacttg gcacttttta tgtattgtag atacactttc 6120
atatattgta aatacatctg ttaaagataa aactaagttt ctaacatagc actacaagga 6180
aactttggat aaatattttt aaaaagaaaa tgttaatagg ataacttaag attttgtata 6240
tacttattgg aagacaggaa gaaactaggc agtaaatatt cctacctgac gtgcaaccat 6300
tgtcaatcag gttttgttaa actgtcaaat ttgattttga aattttagtt tgcccaaata 6360
atatcttgaa aatgctctga attttactag aacatattca tagaaagtgt aatgtatcta 6420
ccaggctcta tgtttgtgtt tgccaacatt agaaaaacaa agtaagttgc gctataatga 6480
gtgaaactaa ggaaaatgag atttttctga ctcccattcc ctctcttaaa aagtaaaata 6540
tttaagcttt ttttattaaa ggaaaaatgg gtacagaata ctctattgcc ctccaaatgt 6600
ccaacatttt taaagccatg ttgtccaaca atgtttatac agaaaataga atgcataggt 6660
ttaatataga tagcaatgta tatgtaggct catttgtggg agattgcaaa ctttatgtgc 6720
ccccagttct ccttggtttt gtaggaaagc taaaagaaaa ccttgtactc tcactaataa 6780
tgaaattcat agccaattta gaaagggaaa ataacctgaa aaccaaaata cctcattcat 6840
ctgaagatgc ctggaataaa atatggaatt cttctgtacc tacctccccc ttacagactt 6900
ttctcctatt ttgagagaga aattcaagaa gaagaataca gcttgttctc tttccacaaa 6960
tgatactttg tctaagggaa taggagatac caagaaacag tatctttaaa aaagtaagct 7020
gcccacaggc cttcttggag aatgaagaat atcagcccca ttcagggttt accaatgtct 7080
ctctgaggtg acaatacatt ctggttttcc aggacagtcc tggcttaggt ctgctgtcct 7140
tctataaata ttaacaatga tccctcttat ttccaaacgt gtcccagttt agacaacaaa 7200
ttatacagtg tctgccccca acacacacac acacacccca ccatctttat gggttgttgt 7260
tgttttcttg ttgtttttaa ttttgtagaa ttggctttgt cttctccaaa gcagataaca 7320
gcttaaacta aagagcctag ctacttcttt ctgactgagc agggtcatag taaacagaga 7380
agaatggatc acttcctcct ctgaaatctc catcaatcca ctttctgtcc aactatctct 7440
ctacccagcc tatttttggt cctagttttc ctctcataac ccctgggctg tgagtcctga 7500
gttctgcctt catatggcag agcaagctag tcattattat gccaggttag gtggtggggc 7560
aagacaaaag atagctcttg gggacacttg cttggtctgt agagatccac agggcactag 7620
tagggtatta gagcatttat tggtttcttt cttccttgag ttgagttact tctatcccaa 7680
aacagacagg tcttacgtta accttcacct taaaaaggat attgcctttt ttccttctgc 7740
ttcacaaatt tgctccaaca ctaattccct tgcatttgat ttcatcatta tgattgttca 7800
tcaaccattc ttcacgaaaa atcctcacat cacgtcatat aaaggtttta ttatttttaa 7860
tggaaaataa cattgagaga ttattttcct ttttcataaa atttcccttt ttccctccct 7920
ctattctctt cactaacatt ggaaattaaa caagttttac aggctctatt gttattaacc 7980
ctcaaatcta ttcttcagag aatatatgat cagcctgtgt ttactatgca cctactctta 8040
taccagaaac tgtgaataca aatacatata tttcctactt ctctctttaa ttggggcaca 8100
cagtcccatg gtccattctg catttttcaa aattgaatat aattgcaaca cctgataggt 8160
tttgccactt agaattctga aaataaatca actctgttct aaaccttaag tttccactat 8220
tattgccaaa ctctggactg atacaataag ccttttaaaa ggtgaattta acacttcacc 8280
tattatggtt atttaagtaa aatgagtttt caaatatttc ccccaggaga aatataaagg 8340
actatgcaaa aatagaagga gaaaaaggtt agttagaggt ccagaaggag aattaaaaca 8400
tggaattgat aaattcacct actgatttat gatgttaatg agcaggtacc tatacatttt 8460
atttacttga aaacattttg gccattaact atttctgttt tctaaataca tttgtgttta 8520
taaaatttta aaatctatat cacaagactt agacatgcct ttctttgcaa taaagtatat 8580
ataccttttt acaaatgtaa attttatttt gaaacttggc attttcttta taattcctaa 8640
gatatctttg ggcacacaga ctacagataa atctatttaa atcaattcat cattatcact 8700
ggtttaaata tttaatgtaa ccattggaat ttttattctt attccttcag agaattctcc 8760
ttttcttcta tgtttctgac tgcaatacag cccgatattg ttattcccta tatcttaatg 8820
aaaagcaagc tgtcagcaaa atgcatttat agtttccaga tgtttaacaa tctctttctt 8880
cttttctttt ttgttattat ttttatttat gtgaagttag ttagctgagg taccaaaaaa 8940
gagacaaaga cagtattaaa aagtgtgcat aaagcactta tttttgtact ttagtacaat 9000
gttttataga actttgtgat ctatctaaat atattaagta aaattacacc attcacttgt 9060
tgggaaaata atctttggtt tggaagatat taacataatg ggcatcttag aatcataaat 9120
cacatgaaat gagagacaat gcaatattgt ataattcctg gatgatgcaa ttgttttaat 9180
tgaattttca agtgccatta taaagtttta aaaattatca a 9221
<210> 9
<211> 2211
<212> DNA
<213> 智人 (homo sapiens)
<400> 9
tttgatatga cgattagagc ataacccgag tgacacgttg aattcgccat aatcaaggaa 60
accttttccg ggtggggatc tctgaaatta ctcagtgagc aaccctaatt aacctgattt 120
tttgctgata atcactctca atggaatcaa atcacaaatc cggggatgga ttgagcggca 180
ctcagaagga agcagccctc cgcgcactgg tccagcgcac aggatatagc ttggtccagg 240
aatttagagg ttcctataga tggaagcagt gtgtctgggc acatgcccag agccagaagc 300
gagcatgagc acagcaattc ctggcctcaa aaaaggaaat aatgctttgc agtccatcat 360
tttgcaaact ttgctggaaa aggaaaatgg acaaagaaaa tatggtggcc ctccacctgg 420
ttgggatgct gcaccccctg aaaggggctg tgaaattttt attggaaaac ttccccgaga 480
cctttttgag gatgagctta taccattatg tgaaaaaatc ggtaaaattt atgaaatgag 540
aatgatgatg gattttaatg gcaacaatag aggatatgca tttgtaacat tttcaaataa 600
agtggaagcc aagaatgcaa tcaagcaact taataattat gaaattagaa atgggcgcct 660
cttaggggtt tgtgccagtg tggacaactg ccgattattt gttgggggca tcccaaaaac 720
caaaaagaga gaagaaatct tatcggagat gaaaaaggtt actgaaggtg ttgtcgatgt 780
catcgtctac ccaagcgctg cagataaaac caaaaaccga ggctttgcct tcgtggagta 840
tgagagtcat cgagcagctg ccatggcgag gaggaaactg ctaccaggaa gaattcagtt 900
atggggacat ggtattgcag tagactgggc agagccagaa gtagaagttg atgaagatac 960
aatgtcttca gtgaaaatcc tatatgtaag aaatcttatg ctgtctacct ctgaagagat 1020
gattgaaaag gaattcaaca atatcaaacc aggtgctgtg gagagggtga agaaaattcg 1080
agactatgct tttgtgcact tcagtaaccg agaagatgca gttgaggcta tgaaagcttt 1140
aaatggcaag gtgctggatg gttcccccat tgaagtcacc ctagcaaaac cagtggacaa 1200
ggacagttat gttaggtata cccgaggcac aggtggaagg ggcaccatgc tgcaaggaga 1260
gtatacctac tctttgggcc aagtttatga tcccaccaca acctaccttg gagctcctgt 1320
cttctatgcc ccccagacct atgcagcaat tcccagtctt catttcccag ccaccaaagg 1380
acatctcagc aacagagcca ttatccgagc cccttctgtt agaggggctg cgggagtgag 1440
aggactgggc ggccgtggct atttggcata cacaggcctg ggtcgaggat accaggtcaa 1500
aggagacaaa agagaagaca aactctatga cattttacct gggatggagc tcaccccaat 1560
gaatcctgtc acattaaaac cccaaggaat taaactcgct ccccagatat tagaagagat 1620
ttgtcagaaa aataactggg gacagccagt gtaccagctg cactctgcta ttggacaaga 1680
ccaaagacag ctattcttgt acaaaataac tattcctgct ctagccagcc agaatcctgc 1740
aatccaccct ttcacacctc caaagctgag tgcctttgtg gatgaagcaa agacgtatgc 1800
agccgaatac accctgcaga ccctgggcat ccccactgat ggaggcgatg gcaccatggc 1860
tactgctgct gctgctgcta ctgctttccc aggatatgct gtccctaatg caactgcacc 1920
cgtgtctgca gcccagctca agcaagcggt aacccttgga caagacttag cagcatatac 1980
aacctatgag gtctacccaa cttttgcagt gactgcccga ggggatggat atggcacctt 2040
ctgaagatgc ttttttaaat ttaagaataa gacacacaaa actctattaa aaaaaaaaaa 2100
gaaataaacc tctaactcgg tccccaatga tcataaataa tatgtttcct aaagaaatgc 2160
ctttccagag actgtatagc ttataccaat tatagaatca tgaagtaaga a 2211
<210> 10
<211> 1997
<212> DNA
<213> 智人 (homo sapiens)
<400> 10
tgagcaaccc taattaacct gattttttgc tgataatcac tctcaatgga atcaaatcac 60
aaatccgggg atggattgag cggcactcag aaggaagcag ccctccgcgc actggtccag 120
cgcacaggat atagcttggt ccaggaaaat ggacaaagaa aatatggtgg ccctccacct 180
ggttgggatg ctgcaccccc tgaaaggggc tgtgaaattt ttattggaaa acttccccga 240
gacctttttg aggatgagct tataccatta tgtgaaaaaa tcggtaaaat ttatgaaatg 300
agaatgatga tggattttaa tggcaacaat agaggatatg catttgtaac attttcaaat 360
aaagtggaag ccaagaatgc aatcaagcaa cttaataatt atgaaattag aaatgggcgc 420
ctcttagggg tttgtgccag tgtggacaac tgccgattat ttgttggggg catcccaaaa 480
accaaaaaga gagaagaaat cttatcggag atgaaaaagg ttactgaagg tgttgtcgat 540
gtcatcgtct acccaagcgc tgcagataaa accaaaaacc gaggctttgc cttcgtggag 600
tatgagagtc atcgagcagc tgccatggcg aggaggaaac tgctaccagg aagaattcag 660
ttatggggac atggtattgc agtagactgg gcagagccag aagtagaagt tgatgaagat 720
acaatgtctt cagtgaaaat cctatatgta agaaatctta tgctgtctac ctctgaagag 780
atgattgaaa aggaattcaa caatatcaaa ccaggtgctg tggagagggt gaagaaaatt 840
cgagactatg cttttgtgca cttcagtaac cgagaagatg cagttgaggc tatgaaagct 900
ttaaatggca aggtgctgga tggttccccc attgaagtca ccctagcaaa accagtggac 960
aaggacagtt atgttaggta tacccgaggc acaggtggaa ggggcaccat gctgcaagga 1020
gagtatacct actctttggg ccaagtttat gatcccacca caacctacct tggagctcct 1080
gtcttctatg ccccccagac ctatgcagca attcccagtc ttcatttccc agccaccaaa 1140
ggacatctca gcaacagagc cattatccga gccccttctg ttagagaaat ttacatgaat 1200
gtacctgtag gggctgcggg agtgagagga ctgggcggcc gtggctattt ggcatacaca 1260
ggcctgggtc gaggatacca ggtcaaagga gacaaaagag aagacaaact ctatgacatt 1320
ttacctggga tggagctcac cccaatgaat cctgtcacat taaaacccca aggaattaaa 1380
ctcgctcccc agatattaga agagatttgt cagaaaaata actggggaca gccagtgtac 1440
cagctgcact ctgctattgg acaagaccaa agacagctat tcttgtacaa aataactatt 1500
cctgctctag ccagccagaa tcctgcaatc caccctttca cacctccaaa gctgagtgcc 1560
tttgtggatg aagcaaagac gtatgcagcc gaatacaccc tgcagaccct gggcatcccc 1620
actgatggag gcgatggcac catggctact gctgctgctg ctgctactgc tttcccagga 1680
tatgctgtcc ctaatgcaac tgcacccgtg tctgcagccc agctcaagca agcggtaacc 1740
cttggacaag acttagcagc atatacaacc tatgaggtct acccaacttt tgcagtgact 1800
gcccgagggg atggatatgg caccttctga agatgctttt ttaaatttaa gaataagaca 1860
cacaaaactc tattaaaaaa aaaaaagaaa taaacctcta actcggtccc caatgatcat 1920
aaataatatg tttcctaaag aaatgccttt ccagagactg tatagcttat accaattata 1980
gaatcatgaa gtaagaa 1997
<210> 11
<211> 885
<212> DNA
<213> 智人 (homo sapiens)
<400> 11
tttgatatga cgattagagc ataacccgag tgacacgttg aattcgccat aatcaaggaa 60
accttttccg ggtggggatc tctgaaatta ctcagataac agtgctgtgc caaaaacctg 120
tggattttct ctacaaaaat tatcatgact gttatctttt tgatggaaaa gatgaagttc 180
agcgaagaac aaatctacaa cttggccaga agactgtaga ctttgccttc aaagagtgag 240
caaccctaat taacctgatt ttttgctgat aatcactctc aatggaatca aatcacaaat 300
ccggggatgg attgagcggc actcagaagg aagcagccct ccgcgcactg gtccagcgca 360
caggatatag cttggtccag gaaaatggac aaagaaaata tggtggccct ccacctggtt 420
gggatgctgc accccctgaa aggggctgtg aaatttttat tggaaaactt ccccgagacc 480
tttttgagga tgagcttata ccattatgtg aaaaaatcgg taaaatttat gaaatgagaa 540
tgatgatgga ttttaatggc aacaatagag gatatgcatt tgtaacattt tcaaataaag 600
tggaagccaa gaatgcaatc aagcaactta ataattatga aattagaaat gggcgcctct 660
taggggtttg tgccagtgtg gacaactgcc gattatttgt tgggggcatc ccaaaaacca 720
aaaagagaga agaaatctta tcggagatga aaaaggttac tgaaggtgtt gtcgatgtca 780
tcgtctaccc aagcgctgca gataaaacca aaaaccgagg ctttgccttc gtggagtatg 840
agagtcatcg agcagctgcc atggcgagga ggaaactgct accag 885
<210> 12
<211> 19
<212> DNA
<213> 智人 (homo sapiens)
<400> 12
guggacaacu gccgauuau 19
<210> 13
<211> 19
<212> DNA
<213> 智人 (homo sapiens)
<400> 13
cugaaggugu ugucgaugu 19
<210> 14
<211> 19
<212> DNA
<213> 智人 (homo sapiens)
<400> 14
caacagagcc auuauccga 19
<210> 15
<211> 19
<212> DNA
<213> 智人 (homo sapiens)
<400> 15
agacguaugc agccgaaua 19
<210> 16
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 16
ugguuuacau gucgacuaa 19
<210> 17
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 17
gcacuucgcu ucaccucug 19
<210> 18
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 18
ccgtgtgcac ttcgcttca 19
<210> 19
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 19
gcacagcttg gaggcttga 19
<210> 20
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 20
catggagacc accgtgaacg ccc 23
Claims (32)
1.一种A1CF(APOBEC1互补因子)抑制剂，其在乙型肝炎病毒(HBV)感染的治疗中使用。
2.根据权利要求1所述使用的A1CF抑制剂，其中所述HBV感染是慢性感染。
3.根据权利要求1或2所述使用的A1CF抑制剂，其中所述A1CF抑制剂能够减少HBV感染细胞中的cccDNA(共价闭合环状DNA)的量。
4.根据权利要求1至3中任一项所述使用的A1CF抑制剂，其中所述抑制剂为长度为12个至60个核苷酸的核酸分子，所述核酸分子包含与哺乳动物A1CF靶序列，特别是人A1CF靶序列至少95％互补，诸如完全互补的、长度为至少12个核苷酸的连续核苷酸序列，并且所述抑制剂能够减少A1CF mRNA在表达所述A1CF mRNA的细胞中的表达。
5.根据权利要求1至4中任一项所述使用的A1CF抑制剂，其中所述抑制剂选自由单链反义寡核苷酸、siRNA和shRNA组成的组。
6.根据权利要求1至5中任一项所述使用的A1CF抑制剂，其中哺乳动物A1CF靶序列选自由以下项组成的组：SEQ ID NO:1、SEQ ID NO:4、SEQ IDNO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10和SEQ ID NO:11。
7.根据权利要求4至6中任一项所述使用的A1CF抑制剂，其中所述连续核苷酸序列与SEQ ID NO:1和SEQ ID NO:2的靶序列至少98％互补，诸如完全互补。
8.根据权利要求3至7中任一项所述使用的A1CF抑制剂，其中所述HBV感染细胞中的cccDNA的量减少至少60％。
9.根据权利要求4至7中任一项所述使用的A1CF抑制剂，其中所述A1CF mRNA减少至少60％。
10.一种长度为12个至30个核苷酸的核酸分子，其包含与哺乳动物A1CF靶序列，特别是人A1CF靶序列90％互补、诸如完全互补的、至少12个核苷酸的连续核苷酸序列，其中所述核酸分子能够抑制A1CF mRNA的表达。
11.根据权利要求10所述的核酸分子，其中所述连续核苷酸序列与选自由以下项组成的组的序列完全互补：SEQ ID NO:1、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10和SEQ ID NO:11。
12.根据权利要求10或11所述的核酸分子，其中所述核酸分子包含长度为12个至25个，诸如16个至20个核苷酸的连续核苷酸序列。
13.根据权利要求10至12中任一项所述的核酸分子，其中所述核酸分子是RNAi分子，诸如双链siRNA或shRNA。
14.根据权利要求10至12中任一项所述的核酸分子，其中所述核酸分子为单链反义寡核苷酸。
15.根据权利要求14所述的核酸分子，其中所述单链反义寡核苷酸能够募集RNA酶H。
16.根据权利要求10至15中任一项所述的核酸分子，其中所述核酸分子包含一个或多个2'糖修饰的核苷。
17.根据权利要求16所述的核酸分子，其中所述一个或多个2'糖修饰的核苷独立地选自由以下项组成的组：2'-O-烷基-RNA、2'-O-甲基-RNA、2'-烷氧基-RNA、2'-O-甲氧基乙基-RNA、2'-氨基-DNA、2'-氟-DNA、阿糖核酸(ANA)、2'-氟-ANA和LNA核苷。
18.根据权利要求16或17中任一项所述的核酸分子，其中所述一个或多个2'糖修饰的核苷为LNA核苷。
19.根据权利要求10至18中任一项所述的核酸分子，其中所述连续核苷酸序列包含至少一个硫代磷酸酯核苷间键。
20.根据权利要求19所述的核酸分子，其中所述连续核苷酸序列内的所有核苷间键均为硫代磷酸酯核苷间键。
21.根据权利要求10至20中任一项所述的核酸分子，其中所述核酸分子或其连续核苷酸序列包含式5'-F-G-F'-3'的间隔聚体(gapmer)，其中区域F和F'独立地包含1个至4个2'糖修饰的核苷，并且G为能够募集RNA酶H的介于6个与18个之间的核苷的区域，诸如包含介于6个与18个之间的DNA核苷的区域。
22.一种缀合物化合物，其包含根据权利要求10至21中任一项所述的核酸分子，以及共价连接至所述核酸分子的至少一个缀合物部分。
23.根据权利要求22所述的缀合物化合物，其中所述缀合物部分是或包含GalNAc部分，诸如三价GalNAc部分，例如选自图1中的三价GalNAc部分中的一者或多者的GalNAc部分。
24.根据权利要求22或23所述的缀合物化合物，其中所述缀合物化合物包含由2个至5个连接的核苷构成的包含至少两个连续的磷酸二酯键的生理上不稳定的接头，其中所述生理上不稳定的接头共价结合在所述核酸分子的5'或3'末端处。
25.一种根据权利要求10至21中任一项所述的核酸分子或根据权利要求22至24中任一项所述的缀合物化合物的药用盐。
26.一种药物组合物，其包含根据权利要求10至21中任一项所述的核酸分子、根据权利要求22至24中任一项所述的缀合物化合物或根据权利要求25所述的药用盐，以及药用赋形剂。
27.一种用于在表达A1CF的靶细胞中抑制A1CF表达的体内或体外方法，所述方法包括向所述细胞施用有效量的根据权利要求10至21中任一项所述的核酸分子、根据权利要求22至24中任一项所述的缀合物化合物、根据权利要求25所述的药用盐或根据权利要求26所述的药物组合物。
28.一种用于治疗疾病的方法，其包括向患有或易患疾病的受试者施用治疗或预防有效量的根据权利要求10至21中任一项所述的核酸分子、根据权利要求22至24中任一项所述的缀合物化合物、根据权利要求25所述的药用盐或根据权利要求26所述的药物组合物。
29.根据权利要求28所述的方法，其中所述疾病是乙型肝炎病毒(HBV)感染，诸如慢性HBV感染。
30.根据权利要求10至21中任一项所述的核酸分子、根据权利要求22至24中任一项所述的缀合物化合物、根据权利要求25所述的药用盐或根据权利要求26所述的药物组合物，其在药物中使用。
31.根据权利要求10至21中任一项所述的核酸分子、根据权利要求22至24中任一项所述的缀合物化合物、根据权利要求25所述的药用盐或根据权利要求26所述的药物组合物，其在乙型肝炎病毒(HBV)感染，诸如慢性HBV感染的治疗中使用。
32.根据权利要求10至21中任一项所述的核酸分子、根据权利要求22至24中任一项所述的缀合物化合物、根据权利要求25所述的药用盐或根据权利要求26所述的药物组合物用于制备药物的用途，所述药物用于乙型肝炎病毒(HBV)感染，诸如慢性HBV感染的治疗。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP20192212.7 | 2020-08-21 | ||
| EP20192212 | 2020-08-21 | ||
| PCT/EP2021/072985 WO2022038211A2 (en) | 2020-08-21 | 2021-08-19 | Use of a1cf inhibitors for treating hepatitis b virus infection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116157522A true CN116157522A (zh) | 2023-05-23 |
Family
ID=72193368
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202180051604.7A Pending CN116157522A (zh) | 2020-08-21 | 2021-08-19 | A1cf抑制剂用于治疗乙型肝炎病毒感染的用途 |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US20230257748A1 (zh) |
| EP (1) | EP4200419A2 (zh) |
| JP (1) | JP2023538630A (zh) |
| CN (1) | CN116157522A (zh) |
| WO (1) | WO2022038211A2 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR128558A1 (es) * | 2022-02-21 | 2024-05-22 | Hoffmann La Roche | Oligonucleótido antisentido |
Family Cites Families (48)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3756313B2 (ja) | 1997-03-07 | 2006-03-15 | 武 今西 | 新規ビシクロヌクレオシド及びオリゴヌクレオチド類縁体 |
| EP2253639A1 (en) | 1997-09-12 | 2010-11-24 | Exiqon A/S | Bi- and tri-cyclic nucleoside, nucleotide and oligonucleoide analogues |
| ID30093A (id) | 1999-02-12 | 2001-11-01 | Sankyo Co | Analog-analog nukleosida dan oligonukleotida baru |
| EP1178999B1 (en) | 1999-05-04 | 2007-03-14 | Santaris Pharma A/S | L-ribo-lna analogues |
| US6617442B1 (en) | 1999-09-30 | 2003-09-09 | Isis Pharmaceuticals, Inc. | Human Rnase H1 and oligonucleotide compositions thereof |
| EP2752488B1 (en) | 2002-11-18 | 2020-02-12 | Roche Innovation Center Copenhagen A/S | Antisense design |
| DK1606406T4 (da) | 2003-03-21 | 2013-12-16 | Santaris Pharma As | Short Interfering RNA (siRNA) Analogues |
| SI2270162T1 (sl) | 2003-06-12 | 2019-03-29 | Alnylam Pharmaceuticals Inc. | Konzervirana HBV in HCV zaporedja uporabna za utišanje genov |
| WO2007031091A2 (en) | 2005-09-15 | 2007-03-22 | Santaris Pharma A/S | Rna antagonist compounds for the modulation of p21 ras expression |
| AU2007211080B9 (en) | 2006-01-27 | 2012-05-03 | Isis Pharmaceuticals, Inc. | 6-modified bicyclic nucleic acid analogs |
| AU2007209481B2 (en) | 2006-01-27 | 2012-01-12 | Roche Innovation Center Copenhagen A/S | LNA modified phosphorothiolated oligonucleotides |
| ES2556128T3 (es) | 2006-03-23 | 2016-01-13 | Roche Innovation Center Copenhagen A/S | ARN interfiriente pequeño internamente segmentado |
| ES2389737T3 (es) | 2006-05-11 | 2012-10-31 | Isis Pharmaceuticals, Inc. | Análogos de ácidos nucleicos bicíclicos modificados en 5' |
| US7666854B2 (en) | 2006-05-11 | 2010-02-23 | Isis Pharmaceuticals, Inc. | Bis-modified bicyclic nucleic acid analogs |
| US20090075925A1 (en) * | 2006-11-16 | 2009-03-19 | Smith Harold C | Methods and Compositions Related to APOBEC-1 Expression |
| EP2170917B1 (en) | 2007-05-30 | 2012-06-27 | Isis Pharmaceuticals, Inc. | N-substituted-aminomethylene bridged bicyclic nucleic acid analogs |
| EP2173760B2 (en) | 2007-06-08 | 2015-11-04 | Isis Pharmaceuticals, Inc. | Carbocyclic bicyclic nucleic acid analogs |
| DK2176280T4 (en) | 2007-07-05 | 2015-07-20 | Isis Pharmaceuticals Inc | 6-Disubstituerede bicykliske nukleinsyreanaloge |
| WO2009067647A1 (en) | 2007-11-21 | 2009-05-28 | Isis Pharmaceuticals, Inc. | Carbocyclic alpha-l-bicyclic nucleic acid analogs |
| WO2010036698A1 (en) | 2008-09-24 | 2010-04-01 | Isis Pharmaceuticals, Inc. | Substituted alpha-l-bicyclic nucleosides |
| US20100249214A1 (en) | 2009-02-11 | 2010-09-30 | Dicerna Pharmaceuticals | Multiplex dicer substrate rna interference molecules having joining sequences |
| CA3151965A1 (en) | 2008-12-18 | 2010-07-15 | Dicerna Pharmaceuticals, Inc. | Extended dicer substrate agents and methods for the specific inhibition of gene expression |
| WO2011017521A2 (en) | 2009-08-06 | 2011-02-10 | Isis Pharmaceuticals, Inc. | Bicyclic cyclohexose nucleic acid analogs |
| EP2580228B1 (en) | 2010-06-08 | 2016-03-23 | Ionis Pharmaceuticals, Inc. | Substituted 2'-amino and 2'-thio-bicyclic nucleosides and oligomeric compounds prepared therefrom |
| CN108676800B (zh) * | 2010-08-17 | 2022-11-11 | 瑟纳治疗公司 | 使用短干扰核酸(siNA)的乙型肝炎病毒(HBV)基因表达的RNA干扰介导的抑制 |
| LT3124610T (lt) | 2010-10-28 | 2019-08-12 | Benitec Biopharma Limited | Hbv gydymas |
| LT3505528T (lt) | 2011-04-21 | 2021-04-26 | Glaxo Group Limited | Hepatito b viruso (hbv) raiškos moduliacija |
| ES2690538T3 (es) * | 2011-06-30 | 2018-11-21 | Arrowhead Pharmaceuticals, Inc. | Composiciones y métodos para inhibir la expresión génica del virus de la hepatitis B |
| US9752142B2 (en) | 2011-08-11 | 2017-09-05 | Ionis Pharmaceuticals, Inc. | Gapped oligomeric compounds comprising 5′-modified deoxyribonucleosides in the gap and uses thereof |
| US9221864B2 (en) | 2012-04-09 | 2015-12-29 | Isis Pharmaceuticals, Inc. | Tricyclic nucleic acid analogs |
| WO2013159109A1 (en) | 2012-04-20 | 2013-10-24 | Isis Pharmaceuticals, Inc. | Modulation of hepatitis b virus (hbv) expression |
| AU2013267209B2 (en) * | 2012-06-01 | 2017-02-02 | Baruch S. Blumberg Institute | Modulation of hepatitis B virus cccDNA transcription |
| CN104884618A (zh) | 2012-11-15 | 2015-09-02 | 罗氏创新中心哥本哈根有限公司 | 寡核苷酸缀合物 |
| RU2650510C2 (ru) | 2013-05-01 | 2018-04-16 | Ионис Фармасьютикалз, Инк. | Композиции и способы модулирования экспрессии аполипопротеина c-iii |
| EP3591054A1 (en) | 2013-06-27 | 2020-01-08 | Roche Innovation Center Copenhagen A/S | Antisense oligomers and conjugates targeting pcsk9 |
| JP6546161B2 (ja) * | 2013-10-04 | 2019-07-17 | ノバルティス アーゲー | Ｂ型肝炎ウイルスを治療するための有機化合物 |
| WO2015113922A1 (en) | 2014-01-30 | 2015-08-06 | Roche Innovation Center Copenhagen A/S | Poly oligomer compound with biocleavable conjugates |
| GB201408623D0 (en) | 2014-05-15 | 2014-07-02 | Santaris Pharma As | Oligomers and oligomer conjugates |
| US20170327524A1 (en) | 2014-10-10 | 2017-11-16 | Hoffmann-La Roche, Inc. | Galnac phosphoramidites, nucleic acid conjugates thereof and their use |
| US10781445B2 (en) | 2015-03-11 | 2020-09-22 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Decoy oligonucleotides for the treatment of diseases |
| CA2996722A1 (en) | 2015-07-17 | 2017-01-26 | Arcturus Therapeutics, Inc. | Compositions and agents against hepatitis b virus and uses thereof |
| KR101771309B1 (ko) * | 2015-07-24 | 2017-08-24 | 재단법인 목암생명과학연구소 | B형 간염 바이러스의 ｃｃｃＤＮＡ 형성 억제용 약학 조성물 |
| WO2017027350A2 (en) | 2015-08-07 | 2017-02-16 | Arrowhead Pharmaceuticals, Inc. | Rnai therapy for hepatitis b virus infection |
| KR102468177B1 (ko) | 2016-04-14 | 2022-11-16 | 에프. 호프만-라 로슈 아게 | 트리틸-모노-GalNAc 화합물 및 이의 용도 |
| MA45496A (fr) | 2016-06-17 | 2019-04-24 | Hoffmann La Roche | Molécules d'acide nucléique pour la réduction de l'arnm de padd5 ou pad7 pour le traitement d'une infection par l'hépatite b |
| CA3043637A1 (en) * | 2016-11-11 | 2018-05-17 | Janssen Biopharma, Inc. | Oligonucleotide targeting strategy for hbv cccdna |
| JP7288852B2 (ja) | 2016-11-23 | 2023-06-08 | アルニラム・ファーマシューティカルズ・インコーポレーテッド | オフターゲット効果が低下した修飾ｒｎａ剤 |
| JP7515400B2 (ja) * | 2018-04-05 | 2024-07-12 | エフ． ホフマン－ラ ロシュ アーゲー | Ｂ型肝炎ウイルス感染を治療するためのｆｕｂｐ１阻害剤の使用 |
-
2021
- 2021-08-19 CN CN202180051604.7A patent/CN116157522A/zh active Pending
- 2021-08-19 WO PCT/EP2021/072985 patent/WO2022038211A2/en unknown
- 2021-08-19 EP EP21765633.9A patent/EP4200419A2/en active Pending
- 2021-08-19 JP JP2023512305A patent/JP2023538630A/ja active Pending
-
2023
- 2023-02-17 US US18/171,130 patent/US20230257748A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JP2023538630A (ja) | 2023-09-08 |
| US20230257748A1 (en) | 2023-08-17 |
| WO2022038211A3 (en) | 2022-04-28 |
| WO2022038211A2 (en) | 2022-02-24 |
| EP4200419A2 (en) | 2023-06-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2021204244B2 (en) | Conjugated antisense compounds and their use | |
| AU2020203573B2 (en) | Oligonucleotides for inducing paternal UBE3A expression | |
| KR20200140805A (ko) | Camk2d 안티센스 올리고뉴클레오티드 및 그의 용도 | |
| KR20210138587A (ko) | 개선된 면역요법을 위한 조합 유전자 표적 | |
| KR102236784B1 (ko) | 성장 호르몬 수용체의 조절인자 | |
| KR20150064210A (ko) | 안드로겐 수용체 발현의 조절 | |
| AU2013262700A1 (en) | Compositions and methods for modulating hemoglobin gene family expression | |
| AU2021203300B2 (en) | Nucleic acid molecule for reduction of PAPD5 and PAPD7 mRNA for treating hepatitis B infection | |
| KR20200102553A (ko) | 성장 호르몬 수용체 발현을 조절하기 위한 조성물 및 방법 | |
| KR20230034198A (ko) | 종양 침윤 림프구의 활성화 및 확장 방법 | |
| CN101151371B (zh) | 治疗中的逆转录转座子抑制 | |
| KR20230043914A (ko) | App 발현을 감소시키기 위한 화합물 및 방법 | |
| KR20210144822A (ko) | Ube3a-ats를 조절하기 위한 화합물 및 방법 | |
| CN116157522A (zh) | A1cf抑制剂用于治疗乙型肝炎病毒感染的用途 | |
| KR20230048052A (ko) | Scn2a를 조절하는 화합물 및 방법 | |
| KR20230005933A (ko) | Atxn1을 조정하는 화합물 및 방법 | |
| KR102642320B1 (ko) | 항암제에 대한 내성 진단용 조성물 | |
| TW202305132A (zh) | 用於抑制α-突觸核蛋白表達之反義寡核苷酸 | |
| CN111556894A (zh) | 用于调控gsk3b表达的寡核苷酸 | |
| TW202424191A (zh) | 用於降低PAPD5及PAPD7 mRNA以治療B型肝炎感染之核酸分子 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40091303 Country of ref document: HK |