BRPI0708344A2 - vetores adenovirais quiméricos - Google Patents

vetores adenovirais quiméricos Download PDF

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BRPI0708344A2
BRPI0708344A2 BRPI0708344-0A BRPI0708344A BRPI0708344A2 BR PI0708344 A2 BRPI0708344 A2 BR PI0708344A2 BR PI0708344 A BRPI0708344 A BR PI0708344A BR PI0708344 A2 BRPI0708344 A2 BR PI0708344A2
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tlr
nucleic acid
polypeptide
promoter
sequence
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BRPI0708344-0A
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Sean N Tucker
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Vaxart Inc
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Abstract

VETORES ADENOVIRAIS QUIMéRICOS. A presente invenção refere-se a vetores adenovirais quiméricos e métodos para uso dos vetores para induzir uma resposta imune a um anti- geno de interesse.

Description

Relatório Descritivo da Patente de Invenção para "VETORESADENOVIRAIS QUIMÉRICOS".
REFERÊNCIAS CRUZADAS A PEDIDOS DE PATENTE RELACIONADOS
O presente pedido de patente reivindica prioridade ao Pedido dePatente Provisório dos Estados Unidos N0 60/778.026, depositado em 28 defevereiro de 2006, Pedido de Patente Provisório dos Estados Unidos N060/801.645, depositado em 19 de maio de 2006, Pedido de Patente Provisó-rio dos Estados Unidos N0 60/802.992, depositado em 22 de maio de 2006,Pedido de Patente Provisório dos Estados Unidos N0 60/821.492, deposita-do em 4 de agosto de 2006, Pedido de Patente Provisório dos Estados Uni-dos N0 60/846.658, depositado em 22 de setembro de 2006, e Pedido dePatente Provisório dos Estados Unidos N0 60/848.195, depositado em 28 de- setembro de 2006), as descrições dos quais são, desse modo, incorporadaspor referência em sua totalidade para todas as propostas.
" DECLARAÇÃO AOS DIREITOS A INVENÇÃO FEITA SOB PESQUISA EDESENVOLVIMENTO FEDERALMENTE PATROCINADOS
Não aplicável.Antecedentes da Invenção
As vacinas são um meio importante para prevenir e/ou tratar um número de doenças e enfermidades (por exemplo, infecção viral, infecçãobacterial, e câncer). As vacinas baseadas em ácido nucléico têm várias van-tagens sobre vacinas de proteína ou vacinas vivas atenuadas. A introduçãode um ácido nucléico que expressa um antígeno em uma célula-alvo permiterápido desenvolvimento de vacina que gera uma resposta imune contra umantígeno de interesse. Para vacinas de proteína, um método eficaz e eficien-te de purificação de proteína necessita ser desenvolvido cada vez que umanova vacina é criada. Para vacinas vivas, um método de atenuação necessi-ta ser identificado que não cessa completamente o crescimento da patoge-nia, ainda se comprovando ser completamente seguro em seres humanos.
O desenvolvimento de metodologias de purificação e atenuação são proces-sos de consumo de tempo extremo. Em contraste, muitas vacinas baseadasem ácido nucléico podem ser fabricadas muito rapidamente usando-se asmesmas técnicas de fabricação cada vez com apenas uma mudança rápidano ácido nucléico que codifica o antígeno de interesse. A replicação incom-petente do adenovírus é um sistema de vacina baseado em ácido que é rá-pida, prognostica e não-custosamente feita em alta titulação [Polo, J.M. eDubensky1 T. W., Jr., Drug Discov Today, 7(13), 719-727 (2002)]. Contudo, aeficiência da resposta específica de antígeno em seguida a administração devetores adenovirais conhecido na técnica é baixa. Desse modo, existe umanecessidade na técnica de novos vetores adenovirais que possam ser usa-dos para induzir eficientemente uma resposta imune contra um antígeno deinteresse. A presente invenção satisfaz estas e outras necessidades.
Sumário da Invenção
A presente invenção refere-se a vetores adenovirais quiméricoscompreendendo ácidos nucléicos que codificam um polipeptídeo heterólogo,e métodos para indução de uma resposta imune contra o polipeptídeo hete-rólogo.
Uma concretização da invenção proporciona vetores de expres-são adenovirais quiméricos compreendendo um cassete de expressão com-preendendo (a) um primeiro promotor operavelmente ligado a um ácido nu-cléico que codifica um agonístico de receptor-3 (TLR-3) similar a toll; e (b)um segundo promotor operavelmente ligado a um ácido nucléico que codifi-ca um polipeptídeo heterólogo. Em algumas concretizações, o ácido nucléicoque codifica o agonístico TLR compreende uma seqüência selecionada apartir de SEQ ID Ngs: 3, 7, 8, 9, 10, 11 e 12. Em algumas concretizações, opolipeptídeo heterólogo é selecionado de um polipeptídeo envelope de HIV(por exemplo, gp41, gp120 e gp160), e polipeptídeo de gripe HA. Em algu-mas concretizações, o primeiro promotor e o segundo promotor são osmesmos. Em algumas concretizações, as primeira e segunda concretizaçõessão diferentes. Em algumas concretizações, os promotores são seleciona-dos a partir do promotor beta actinae o promotor de CVM. A invenção tam-bém proporciona composições imunogênicas compreendendo o vetor deexpressão.
Uma concretização adicional da invenção proporciona métodosde indução de uma resposta imune contra o polipeptídeo heterólogo pelaadministração de uma quantidade imunologicamente eficaz das composi-ções a um indivíduo mamífero (por exemplo, um roedor, tal como um ca-mundongo, um rato, ou porquinho-da-índia, ou um primata, tal como um chi-panzé, uma macaca rhesus, ou um ser humano). Em algumas concretiza-ções, o vetor é administrado via qualquer via não-parenteral (por exemplo,oral, intranasal e mucosalmente). Em algumas concretizações, o polipeptí-deo heterólogo é expresso em uma célula selecionada a partir de uma céluladendrítica, uma célula de microdobra, e uma célula epitelial intestinal.
Uma concretização adicional da invenção proporciona composi-I ções imunogênicas compreendendo: (a) um vetor de expressão adenoviralquimérico compreendendo um promotor operavelmente ligado a um ácidonucléico que codifica um polipeptídeo heterólogo; (b) um agonístico TLR-3(por exemplo, um dsRNA). Em algumas concretizações, o agonístico TLR-3" é codificado por um ácido nucléico. A invenção também proporciona méto-dos de indução de uma resposta imune pela administração das composiçõesa um indivíduo mamífero (por exemplo, um roedor, tal como um camundon-go, um rato, ou um porquinho-da-índia, ou um primata, tal como um chipan-zé, uma macaca rhesus, ou um humano), via qualquer via não-parenteral(por exemplo, oral, intranasal, ou mucosal).
Outra concretização da invenção proporciona um ácido nucléicoisolado compreendendo a seqüência colocada em SEQ ID Nes: 1, 2, 6, 7, 13,14, 15, 16 ou 17.
Breve Descrição dos Desenhos
A Figura 1 ilustra dados demonstrando que um vetor adenoviralquimérico da invenção (isto é, DS1), em combinação com um agonísticoTLR-3, é mais eficaz do que um vetor adenoviral padrão (isto é, rAd5) naindução de uma resposta imune específica de antígeno em seguida a distri-buição do vetor oral. A Figura 1A ilustra dados representando a titulação deanticorpo para proteína envelope de HIV (isto é, gp120) em 3 semanas emseguida a distribuição oral dos vetores adenovirais. A Figura 1B ilustram da-dos representando a titulação de anticorpo para proteína envelope de HIV(isto é, gp120) em 6 semanas em seguida a distribuição oral dos vetoresadenovirais.
A Figura 2 ilustra dados demonstrando que um vetor adenoviralquimérico da invenção (isto é, DS1b ou DS1c), em combinação com um a-gonístico TLR-3, é mais eficaz na indução de uma resposta imune específicade antígeno do que um vetor adenoviral padrão (isto é, rAd5). A Figura 2Ailustram dados representando a titulação de anti-GFP IgG em 3 semanas emseguida a distribuição oral dos vetores. A Figura 2B ilustram dados represen-tando a resposta de CD8+ célula T para GFP em 10 semanas em seguida aadministração do vetor em 0, 4 e 8 semanas. A Figura 2C ilustra dados re-presentando a titulação de anticorpo anti-HA em 3 semanas em seguida aadministração oral dos vetores.
A Figura 3 ilustra dados demonstrando que os vetores adenovi-rais quiméricos da invenção são superiores para indução de respostas imu-nes quando administrados não-parenteralmente. A Figura 3A ilustram dadosrepresentando a titulação de anticorpo anti-gp 120 3 semanas em seguida aadministração intramuscular de DS1. A Figura 3B ilustra dados representan-do a titulação de anticorpo anti-HA três semanas em seguida a administra-ção intranasal de DS 1c.
A Figura 4 ilustra dados demonstrando que os agonísticos TLR-3 Iigante expressos podem induzir ativação de células apresentando antíge-no. A Figura 4A ilustra dados representando ativação de célula dendríticapelo dsRNA ILR-3 agonístico Iucl expresso. A Figura 4B ilustra dados repre-sentando a ativação de célula dendrítica pelos dsRNA TLR-3 agonísticosIucl e m1.
A Figura 5 é uma ilustração gráfica dos vetores adenovirais qui-méricos da invenção, isto é, vetores adenovirais quiméricos compreendendoácidos nucléicos que codificam agonísticos ds RNA TLR-3.
A Figura 6 ilustra dados demonstrando que os vetores adenovi-rais quiméricos da invenção são eficazes na indução de uma resposta imuneespecífica de antígeno em seguida a distribuição oral. A Figura 6 ilustra da-dos representando titulação de anticorpo anti-gp120 3 semanas em seguidaa administração oral de um adenoviral quimérico compreendendo seqüênciade ácido nucléico que codifica o dsRNA TLR-3 agonístico Iuc1.
A Figura 7 ilustra dados demonstrando que agonísticos TLR-7/8têm eficiência pobre na indução de uma resposta imune específica de antí-geno.
A Figura 8 ilustra dados demonstrando que os vetores adenovi-rais quiméricos da invenção são eficazes na indução de uma resposta imuneespecífica de antígeno em seguida a distribuição oral. A Figura 8A ilustradados representando titulação de anticorpo anti-HA 4 semanas em seguidaa administração oral de um adenoviral quimérico compreendendo uma se-I qüéncia de ácido nucléico que codifica o dsRNA TLR-3 agonístico Iuc1.A Figura 8B ilustra dados representando a titulação de anticorpo anti-HA 4semanas ou 7 semanas em seguida a administração de um adenoviral qui-mérico compreendendo uma seqüência de ácido nucléico que codifica o ds-" RNA TLR-3 agonístico Iuc1. A Figura 8C ilustra dados representando titula-ção de anticorpo anti-HA 3 semanas em seguida a administração oral ouadministração intranasal de um adenoviral quimérico compreendendo umaseqüência de ácido nucléico que codifica o dsRNA TLR-3 agonístico Iucl.
Breve Descrição das Seqüências
SEQ ID N9:1 coloca a seqüência de nucleotídeo para o vetoradenoviral quimérico DS1.
SEQ ID Ne:2 coloca a seqüência de nucleotídeo para o vetoradenoviral quimérico DS2.
SEQ ID Ns:3 coloca uma seqüência de nucleotídeo que codificaum agonístico TLR-3.
SEQ ID Ne:4 coloca uma seqüência de nucleotídeo que codificaum agonístico TLR-3.
SEQ ID N9:5 coloca uma seqüência de nucleotídeo que codificaum agonístico TLR-3.
SEQ ID N9:6 coloca uma seqüência de nucleotídeo para um ve-tor adenoviral quimérico compreendendo um ácido nucléico que codifica HAde gripe e um ácido nucléico que codifica um agonístico TLR-3 (luc), no qualo HA de gripe e o agonístico TLR-3 estão na mesma orientação.
SEQ ID N9:7 coloca uma seqüência de nucleotídeo para um ve-tor adenoviral quimérico compreendendo um ácido nucléico que codifica HAde gripe e um ácido nucléico que codifica um agonístico TLR-3 (luc), no qualo HA de gripe e o agonístico TLR-3 estão na orientação oposta.
SEQ ID N9:8 coloca uma seqüência de nucleotídeo que codificaum agonístico RNA TLR-3 em forma de grampo de cabelo curto. Porçõescomplementares da seqüência são mostradas em letras maiúsculas e a se-qüência articuladora é mostrada em letras de caso inferiores.
SEQ ID N9:9 coloca uma seqüência de nucleotídeo que codificaum agonístico RNA TLR-3 em forma de grampo de cabelo curto (g1). Por-ções complementares da seqüência são mostradas em letras maiúsculas e aseqüência articuladora é mostrada em letras de caso inferiores.
SEQ ID Ne:10 coloca uma seqüência de nucleotídeo que codifi-"ca um agonístico RNA TLR-3 em forma de grampo de cabelo curto (luc).Porções complementares da seqüência são mostradas em letras maiúsculase a seqüência articuladora é mostrada em letras de caso inferiores.
SEQ ID N9:11 coloca uma seqüência de nucleotídeo que codifi-ca um agonístico RNA TLR-3 em forma de grampo de cabelo curto (m1).Porções complementares da seqüência são mostradas em letras maiúsculase a seqüência articuladora é mostrada em letras de caso inferiores.
SEQ ID N9:12 coloca uma seqüência de nucleotídeo que codifi-ca um agonístico RNA TLR-3 em forma de grampo de cabelo curto. Porçõescomplementares da seqüência são mostradas em letras maiúsculas e a se-qüência articuladora é mostrada em letras de caso inferiores.
SEQ ID N9:13 coloca a seqüência de nucleotídeo para o vetoradenoviral quimérico DS1c. A seqüência compreende um nucleotídeo quecodifica HA(PR8/34).
SEQ ID N9:14 coloca a seqüência de nucleotídeo para o vetoradenoviral quimérico DS2beta-luc. O vetor compreende uma seqüência quecodifica o agonístico TLR-3 Iuc sob o controle do promotor beta actin. O ve-tor também compreende locais de clonagem abertos para inserção de se-qüência(s) de ácido nucléico que codificam o antígeno de interesse.
SEQ ID Ne:15 coloca a seqüência de nucleotídeo para o vetoradenoviral quimérico DS2beta-luc. O vetor compreende uma seqüência quecodifica o agonístico TLR-3 Iuc sob o controle do promotor de CMV. O vetortambém compreende locais de clonagem abertos para inserção de seqüên-cia) de ácido nucléico que codificam o antígeno de interesse.
SEQ ID Ns:16 coloca a seqüência de nucleotídeo para o vetorpshuttle compreendendo uma seqüência de ácido nucléico que codifica oagonístico TLR-3 Iuc sob o controle do promotor de CMV e uma seqüênciade ácido nucléico que codifica HA (gripe aviária) sob o controle de um pro-motor de CMV separado.
SEQ ID Ns:17 coloca a seqüência de nucleotídeo para o vetoradenoviral quimérico ND1.1 214. O ácido nucléico que codifica o antígenoheterólogo está em um texto em negrito, e é flanqueado por um local de re-conhecimento Clal na extremidade 5', e um local de reconhecimento Not 1na extremidade 3'. A seqüência de ácido nucléico que codifica os agonísti-cos TLR-3 está em itálico, com a seqüência articuladora em negrito.
Descrição Detalhada da Invenção
I. Introdução
A presente invenção proporciona novos vetores adenoviraisquiméricos que podem ser administrados não-parenteralmente para induziruma resposta imune contra um antígeno de interesse. Os vetores adenovi-rais quiméricos da invenção compreendem um ácido nucléico que codificaum polipeptídeo heterólogo, e um ácido nucléico que codifica um agonísticoTLR-3. Os vetores adenovirais quiméricos induzem respostas imunes fortese eficazes específicas para o polipeptídeo heterólogo, particularmente quan-do aplicado via uma rota não-parenteral (por exemplo, oral, intranasal, oumucosamente).
A invenção é baseada na descoberta surpreendente que aadministração de agonísticos dsRNA TLR-3 são adjuvantes específicosquando administrados em conjunto com vetores virais. De fato, o uso dedsRNA como um adjuvante para vetores virais seria contra-intuitivo,considerando-se que a maior utilidade proposta do dsRNA mimético poli 1:0era um agente antiviral [Nemes, et aí., Proc. Soc Exp Biol Med. (1969)132:776; Schafer et aí, Nature (1970) 226:449; Fenje, et ai, Nature (1970)226:171].
II. Definições
O termo "quimérico" ou "recombinante", conforme aqui usado,com referência a, por exemplo, um ácido nucléico, proteína, ou vetor, indicaque o ácido nucléico, proteína ou vetor, foi modificado pela introdução de umácido nucléico ou proteína heteróloga, ou a alteração de um ácido nucléicoou proteína nativa. Desse modo, por exemplo, vetores quiméricos e recom-binantes incluem seqüências de ácido nucléico que não são encontradasdentro da forma nativa (não-quimérica ou não-recombinante) do vetor. Umvetor de expressão adenoviral quimérico se refere a um vetor de expressãoadenoviral compreendendo uma seqüência ácido nucléico que codifica umpolipeptídeo heterólogo.
Um "vetor de expressão" é um constructo de ácido nucléico, ge-rado recombinante ou sinteticamente, com uma série de elementos de ácidonucléico específicos que permitem transcrição de um ácido nucléico particu-lar em uma célula hospedeira. O vetor de expressão pode ser parte de umplasmídeo, vírus, ou fragmento de ácido nucléico. Tipicamente, o vetor deexpressão inclui um ácido nucléico a ser transcrito operavelmente ligado aum promotor.
Os termos "promotor" e "seqüência de controle de expressão"são aqui usados para se referir a uma série de seqüências de controle deácido nucléico que direcionam transcrição de uma ácido nucléico. Conformeaqui usado, um promotor inclui seqüências de ácido nucléico necessáriasperto do local de partida de transcrição, tais como, no caso de um promotortipo polimerase II, um elemento TATA. Um promotor também inclui opcio-nalmente elementos intensificadores ou repressores distais, que podem es-tar localizados tanto quanto vários milhares de pares de base a partir do lo-cal de partida de transcrição. Os promotores incluem promotores constituti-vos e inducíveis. Um promotor "constitutivo" é um promotor que é ativo sobmuitas condições ambientais e de desenvolvimento. Um promotor "inducível"é um promotor que é ativo sob regulação ambiental e de desenvolvimento. Otermo "operavelmente ligado" se refere a uma ligação funcional entre umaseqüência de controle de expressão de ácido nucléico (tal como um promo-tor, uma série de locais de ligação de fator de transcrição), e uma segundaseqüência de ácido nucléico, no. qual a seqüência de controle de expressãodireciona transcrição do ácido nucléico correspondente à segunda seqüên-cia.
O termo "agonístico TLR" ou "agonístico receptor similar a Troll",conforme aqui usado, se refere a um composto que liga e estimula um re-ceptor similar a Troll, incluindo, por exemplo, TLR-2, TLR-3, TRL-6, TLR-7,ou TLR-8. Os agonísticos TLR são revistos em MacKichan, IAVI Report. 9:1-(2005) e Abreu et ai, J. Immunol, 174(8), 4453-4460 (2005). Os agonísti-cos incluem transdução de sinal em seguida a ligação a seu receptor.
O termo "agonístico TLR-3" ou "agonístico receptor 3 similar aTroll", conforme aqui usado, se refere a um composto que liga e estimula oTLR-3. Os agonísticos TLR-3 foram identificados incluindo RNA de filamentoduplo, dsRNA viralmente derivado, vários análogos quimicamente sintetiza-dos para RNA de filamento duplo incluindo ácido (poli l:C), poliinosina-policitidílico - ácido (poli A:U) poliadenílico poliuridílico e (poli l:poli C, e anti-corpos (ou reticulação de anticorpos) para TLR-3 que conduz a produção deIFN-beta [Matsumoto, M, et al., Biochem Biophys Res Commum 24:1364(2002), de Bouteiller, et ai, J Biol Chem 18:38133-45 (2005)]. Os agonísticosTLR-3 também incluem dsRNA expresso (por exemplo, dsRNA codificadopor um ácido nucléico compreendendo um seqüência colocada em SEQ IDNOS: 3, 7, 8,9, 10, 11 ou 12).
O termo "agonístico TLR-7/8" ou agonístico 7/8 receptor similara ToU", conforme aqui usado, se refere a um composto que liga e estimulaos receptores TLR-7 ou TLR-8; este receptores reconhecem vários dos mes-30 mos ligantes. Vários agonísticos TLR-7/8 foram identificados tais como umRNA viral de trançado simples, imiquimod, loxrribina, ácido poliuridílico, ouresiquimod.O termo "heterólogo" quando usado com referência a porçõesde um ácido nucléico indica que o ácido nucléico compreende duas ou maissubseqüências que não são encontradas no mesmo relacionamento uma emrelação à outra na natureza. Por exemplo, o ácido nucléico é típica e recom-binantemente produzido, tendo duas ou mais seqüências de genes não-relacionadas para produzir um novo ácido nucléico funcional, por exemplo,um promotor de uma fonte, e uma região de codificação de outra fonte. Simi-larmente, uma proteína heteróloga indica que a proteína compreende duasou mais subseqüências que não são encontradas no mesmo relacionamentouma em relação à outra na natureza (por exemplo, uma proteína de fusão).
Os termos "ácido nucléico" e "polinucleotídeo" são usados per-mutavelmente aqui para se referirem a deoxirribonucleotídeos e ribonucleo-- tídeos e polímeros destes na forma de filamento simples ou duplo. O termoenvolve ácidos nucléicos contendo análogos de nucleotídeo conhecidos, ouresíduos de estruturas principais modificadas ou ligações, que são sintéticas,que ocorrem naturalmente, e não ocorrem naturalmente, que têm proprieda-des de ligação similares como o ácido nucléico de referência, e que são me-tabolizados em uma maneira similar aos nucleotídeos de referência. Exem-plos de tais análogos incluem, sem limitação, fosforotioatos, fosforamidatos,fosfonatos de metila, fosfonatos de quiral-metila, ribonucleotídeos de 2-0-metiia, ácidos peptídeo-nucléico (PNAs).
A menos que de outro modo indicado, uma seqüência de ácidonucléico particular também envolve variantes conservativamente modifica-das desta (por exemplo, substituições de códon degeneradas) e seqüênciascomplementares, bem, como a seqüência explicitamente indicada. Especifi-camente, substituições de códon degeneradas podem ser alcançadas pelageração de seqüências nas quais a terceira posição de um ou mais (ou to-dos) códons é substituída com base de mistura e/ou resíduos de deoxinosi-na (Batzer et ai, Nucleic Acid REs. 19:5081 (1991); Ohtsuka et ai, J. Biol.Chem. 260:2605-2608 (1985); Rossolini et al., Mol. Cell. Probes 8:91-98(1994)). O termo ácido nucléico é usado permutavelmente com gene, cDNA,mRNA, oligonucleotídeo, e polinucleotídeo.Antígeno se refere a uma proteína ou parte de uma cadeia depolipeptídeo que pode ser reconhecida por receptores de célula T e/ou anti-corpos. Tipicamente, os antígenos são derivados de proteínas bacteriais,virais ou fungais.
Uma "dose ou quantidade imunologicamente eficaz" das com-posições da presente invenção é uma quantidade que induz ou modula umaresposta imune específica para o polipeptídeo heterólogo. As respostas imu-nes incluem respostas imunes humorais e respostas imunes mediadas porcélula. Uma composição imunogênica pode ser usada terapêutica ou profila-ticamente para tratar ou prevenir doença em qualquer estágio.
"Respostas imunes humorais" são mediadas por componenteslivres de célula do sangue, isto é, plasma ou soro; transferência do soro ouplasma de um indivíduo para outra imunidade de transferências.
"Respostas imunes mediadas por célula" são mediadas por Iin-focitos específicos de antígeno; transferência dos linfócitos específicos deantígeno de um indivíduo para outra imunidade de transferências.
Uma "dose terapêutica" ou "quantidade terapeuticamente eficaz"ou "quantidade eficaz" de um vetor adenoviral quimérico, ou uma composi-ção compreendendo um vetor adenoviral quimérico, é uma quantidade dovetor ou composição compreendendo o vetor que previne, alivia, abate, oureduz a severidade de sintomas de doenças e enfermidades associadas coma fonte do polipeptídeo heterólogo (por exemplo, um vírus, uma bactéria, umparasita, ou um câncer).
Anticorpo se refere a um polipeptídeo codificado por um gene deimunoglobulina ou fragmentos deste que se liga especificamente e reconhe-ce um antígeno. Os genes de imunoglobulina reconhecidos incluem genesde região constante kappa, lâmbda, alfa, gama, delta, épsilon e mu, bemcomo genes de região variável de imunoglobulina miríade. As cadeias levessão classificadas como ou kappa ou lâmbda. As cadeias pesadas são classi-ficadas como gama, mu, alfa, delta, ou épsilon, que, por sua vez, define asclasses de imunoglobulina IgG, IgM, IgA, IgD e IgE, respectivamente.
Células T se referem a uma classe particular de linfócitos queexpressam um receptor específico (receptor de célula T) codificado por umafamília de genes. Os genes de receptor de célula T reconhecidos incluemreceptores alfa, beta, delta, e gama, de loci, e os receptores de célula T(mas não universalmente) tipicamente reconhecem uma combinação deMHC mais um peptídeo curto.
Resposta imune adaptativa se refere a reconhecimento de célu-la T/de anticorpo de antígeno.
Células de apresentação de antígeno (APCs), conforme aquiusadas, se referem a células que são capazes de apresentar peptídeos imu-nogênicos ou fragmentos destes de células T para ativar ou aumentar umaresposta imune. APCs incluem células dendríticas, células B, monócito eoutras células que podem ser projetadas para serem APCs eficientes. Taiscélulas podem, mas não necessitam, serem geneticamente modificadas paraaumentar a capacidade de apresentação de antígeno, para aperfeiçoar aativação e/ou manutenção da resposta de célula T, para ter efeitos antitumorpor si, e/ou para ser imunologicamente compatível com o recebedor (isto é,halotipo HLA equiparado). APCs podem ser isolados de qualquer de umavariedade de fluidos biológicos e órgãos incluindo tutano de osso, sangueperiférico, tumor e tecidos peritumorais, e podem ser células autólogas, alo-genéicas, singenéicas ou xenogenéicas. APCs tipicamente utilizam um re-ceptor a partir do local de maior histocompatibilidade (MHC) para apresentarpolipeptídeos curtos para células T.
Adjuvante é um intensificador de resposta imune não-específica.Adjuvantes adequados incluem, por exemplo, toxina de cólera, monosfofillipídeo A (MLP), Adjuvante Completo de Freund, Adjuvante Incompleto deFreund, Quil A, e AI(OH). Os adjuvantes podem também ser aquelas subs-tâncias que causam ativação de APC e apresentação aumentada de célulasT através de moléculas de sinalização secundárias. Exemplos de receptoressimilares a Troll que reconhecem RNA de filamento duplo, flagelante bacte-rial, LPS, CpG DNA, e lipopeptídeo bacterial (Revisto recentemente em [A-breu et ai, J. Immunol, 174(8), 4453-4460 (2005)].
Os termos "polipeptídeo", "peptídeo" e "proteína" são usadospermutavelmente aqui para se referirem a um polímero de resíduos de ami-noácido. Os termos se aplicam a polímeros de aminoácido nos quais um oumais resíduos de aminoácido é um mimético químico artificial de um amino-ácido que ocorre naturalmente correspondente, bem como a polímeros deaminoácido que ocorrem naturalmente, e polímeros de aminoácido que nãoocorrem naturalmente.
O termo "aminoácido" se refere a aminoácidos que ocorrem na-turalmente e sintéticos, bem como análogos de aminoácido e miméticos deaminoácido que funcionam em uma maneira similar aos aminoácidos queocorrem naturalmente. Os aminoácidos que ocorrem naturalmente são aque-Ies codificados pelo código genético, bem como aqueles aminoácidos quesão mais tarde modificados, por exemplo, hidroxíprolina, y-carboxiglutamato,O-fofoserina. Análogos de aminoácido se referem a compostos que têm amesma estrutura quimérica básica como um aminoácido que ocorre natu-ralmente, isto é, um y carbono que é ligado a um hidrogênio, um grupo car-boxi, um grupo amino, e um grupo R, por exemplo, homoserina, norleucina,metionina sulfóxido, metionina metil sulfônio. Tais análogos têm grupos Rmodificados (por exemplo, norleucina), ou suportes de peptídeo modificados,mas retêm a mesma estrutura química básica como um aminoácido que o-corre naturalmente. Miméticos de aminoácido se referem a compostos quí-micos que têm uma estrutura que é diferente da estrutura química geral deum aminoácido, mas que funciona em uma maneira similar a um aminoácidoque ocorre naturalmente.
Os aminoácidos podem ser referidos aqui por, ou seus símbolosde três letras comumente conhecidos, ou por símbolos de uma letra reco-mendados pela IUPAC-IUB Biochemical NomencIature Commission. Os nu-cleotídeos, do mesmo modo, podem ser referidos por seus códigos de letrasimples comumente aceitos.
"Variantes conservativamente modificadas" se aplicam a ambasseqüências de aminoácido e de ácido nucléico. Com relação a seqüênciasde ácido nucléico particulares, variantes conservativamente modificadas sereferem aqueles ácidos nucléicos que codificam seqüências de aminoácidoidênticas, ou essencialmente idênticas, ou onde o ácido nucléico não codifi-ca uma seqüência de aminoácido, para seqüências essencialmente idênti-cas. Devido à degeneração do código genético, um grande número de áci-dos nucléicos funcionalmente idênticos codifica qualquer dada proteína. Porexemplo, os códons GCA, GCC1 GCG e GCU todos codificam o aminoácidoalanina. Desse modo, em toda posição onde uma alanina é especificada porum códon, o códon pode ser alterado para qualquer dos códons correspon-dentes descritos sem alterar o polipeptídeo codificado. Tais variações deácido nucléico são "variações mudas", que são uma espécie de variaçõesconservativamente modificadas. Toda seqüência de ácido nucléico aqui quecodifica um polipeptídeo também descreve toda variação muda possível doácido nucléico. Um versado no assunto reconhecerá que cada códon em um.. ácido nucléico (exceto AUG, que é ordinariamente o único códon para meti-onina, e TGG1 que é ordinariamente o único códon para triptofan), pode ser"modificado para produzir uma molécula funcionalmente idêntica. Conse-qüentemente, cada variação muda de um ácido nucléico que codifica umpolipeptídeo é implicada em cada seqüência descrita.
Como para seqüências de aminoácido, um versado reconheceráque substituições individuais, retiradas ou adições a um ácido nucléico, pep-tídeo, polipeptídeo, ou seqüência de proteína que alteram, adicionam ou reti-ra um aminoácido simples ou em uma percentagem pequena de aminoáci-dos na seqüência codificada é uma "variante conservativamente modifica-da", onde a alteração resulta na substituição de uma aminoácido com umaminoácido quimicamente similar. Tabelas de substituição conservativa pro-porcionando aminoácidos funcionalmente similares são bem-conhecidas natécnica. Tais variantes conservativamente modificadas são em adição a enão excluem variantes polimórficas, homólogos inter-espécie, e alelos dainvenção.
Os seguintes oito grupos cada contém aminoácidos que sãosubstituições conservativas para uma outra:
1) Alanina (A), Glicina (G);
2) Ácido aspártico (D), Ácido glutâmico (E);3) Aspargina (N)1 Glutmina (Q);
4) Arginina I, Lisina (K);
5) Isoleucina (I), Leucina (L)1 Metionina (Μ), Valina (V);
6) Fenilalanina (F), Tirosina (Υ), Triptofan (W);
7) Serina (S)1 Treonina (T); e
8) Cisteina (C)1 Metionina (M);
(vide, por exemplo, Creighton, Proteins (1984)).
A frase "seletivamente (ou especificamente) hidrolisa para" serefere à ligação, duplexação, ou hibridização de uma molécula somente auma seqüência de nucleotídeo particular sob condições de hibridização es-tringentes quando esta seqüência está presente em uma mistura complexa(por exemplo, DNA ou RNA celular total ou de biblioteca).
A frase "condições de hibridização estringentes" se refere acondições sob as quais uma sonda hibridizará para sua seqüência-alvo, tipi-camente em uma mistura de complexo de ácido nucléico, mas não para ou-tras seqüências. As condições estringentes são dependentes da seqüência,e serão diferentes em circunstâncias diferentes. Seqüências mais longashibridizam especificamente em temperaturas mais altas. Um guia extensivoà hibridização de ácidos nucléicos é encontrado em Tijssen, Techniques inBiochemistry and Molecular Biology-Hybridization with Nucleic Probes, "Vi-são geral de princípios de hibridização e a estratégia de ensaios de ácidonucléico" (1993). Geralmente, condições estringentes são selecionadas paraserem cerca de 5-100C mais baixas do que o ponto de fusão térmico I para aseqüência específica em um resistência iônica definida Ph. A Tm é a tempe-ratura (sob resistência iônica definida, Ph, e concentração nucléica) na qual50% das sondas complementares ao alvo hidrolisam para a seqüência-alvoem equilíbrio (à medida que as seqüências de alvo estão presentes em ex-cesso, em Tm, 50% das sondas estão ocupadas em equilíbrio). As condiçõesestringentes serão aquelas nas quais a concentração de sal é menos do quecerca de 1,0 M de íon sódio, tipicamente cerca de 0,01 a 1,0 M de concen-tração de íon sódio (ou outros sais) em pH 7,0 a 8,3, e a temperatura é pelomenos cerca de 30°C para sondas curtas (por exemplo, 10 a 50 nucleotí-deos), e pelo menos cerca de 60°C para sondas grandes (por exemplo, mai-or do que 50 nucleotídeos). As condições estringentes podem também se-rem alcançadas com a adição de agentes desestabilizantes, tal como for-mamida. Para hibridização seletiva ou específica, um sinal positivo é pelomenos duas vezes antecedente, opcionalmente 10 vezes antecedente a hi-bridização. Condições de hibridização estringentes exemplares podem serconforme se segue: 50% de formamida, e 1% de SDS1 incubando a 42°C,óu, 5xSSC, 1% de SDS, incubando a 65°C, com lavagem em 0,2xSSC, e0,1% de SDS a 65°C.
Os ácidos nucléicos que não hidrolisam um ao outro sob condi-ções estringentes são ainda substancialmente idênticos se os polipeptídeosque eles codificam são substancialmente idênticos. Isto ocorre, por exemplo,quando uma cópia de um ácido nucléico é criada usando-se a degeneraçãode códon máxima permitida pelo código genético. Em tais casos, os ácidos" nucléicos tipicamente hibridizam sob condições de hibridização moderada-mente estringentes. "Condições de hibridização moderadamente estringen-tes" exemplares incluem uma hibridização em um tampão de 40% de for-mamida, 1M de NaCIl 1% de SDS a 37°C, e uma lavagem em 1XSSC a45°C. Uma hibridização positiva é pelo menos duas vezes antecedente. A-queles versados na técnica reconhecerão prontamente que hibridização al-ternativa e condições de lavagem podem ser utilizadas para proporcionarcondições de estringência similares.
"Anticorpo" se refere a um polipeptídeo compreendendo umaregião de estrutura de um gene de imunoglobulina ou fragmentos deste queliga especificamente e reconhece um antígeno. Os genes de imunoglobulinareconhecidos incluem genes de região constante kappa, lâmbda, alfa, gama,delta, épsilon, e mu, bem como os genes de região variável de imunoglobuli-na miríades. As cadeias leves são classificadas como, ou kappa ou lâmbda.As cadeias pesadas são classificadas como gama, mu, alfa, delta ou épsilon,que, por sua vez, definem as classes de imunoglobulina, IgG, IgM, IgA, IgD eIgE, respectivamente.
Uma unidade estrutural (anticorpo) de imunoglobulina exemplarcompreende um tetrâmero. Cada tetrâmero é composto de dois pares idênti-cos de cadeias de polipeptídeo, cada par tendo uma cadeia "leve" (cerca de25 kDa) e uma cadeia "pesada" (cerca de 50-70 kDa). O terminal N de cadacadeia define uma região variável de cerca de 100 a 110 ou mais aminoáci-dos principalmente responsáveis pelo reconhecimento do antígeno. Os ter-mos cadeia leve variável (Vl) e cadeia pesada variável (Vh) se referem à-quelas cadeias leves e pesadas, respectivamente.
A frase "ligar especificamente (ou seletivamente)" a um anticor-po ou "especificamente (ou seletivamente) imunorreativo com", quando sereferindo a uma proteína ou peptídeo, se refere a um reação de ligação queé determinativa da presença da proteína em uma população heterogênea deproteínas e outras biologias. Desse modo, sob condições de imunoensaiodesignadas, os anticorpos especificados se ligam a um proteína particularpelo menos duas vezes de fundo e não se liga substancialmente em umaquantidade significante a outras proteínas presentes na amostra. Ligaçõesespecíficas a um anticorpo sob tais condições podem requerer um anticorpoque é selecionado para sua especificidade para uma proteína particular. Porexemplo, anticorpos policlonais ocorridos de proteínas de fusão podem serselecionados para obter somente aqueles anticorpos policlonais que sãoespecificamente imunorreativos com proteína de fusão, e não com compo-nentes individuais das proteínas de fusão. Esta seleção pode ser alcançadapela subtração de anticorpos que reagem em cruzamento com os antígenosindividuais. Uma variedade de formato de imunoensaio pode ser usada paraselecionar anticorpos especificamente imunorreativos com uma proteína par-ticular. Por exemplo, imunoensaios ELISA de fase sólida são rotineiramenteusados para selecionar anticorpos especificamente imunorreativos com umaproteína (vide, por exemplo, Harlow & Lane, Antibodies, A Laboratory Manu-al (1988), para uma descrição de formatos de imunoensaio, e condições quepodem ser usadas para determinar imunorreatividade específica). Tipica-mente uma reação específica ou seletiva será pelo menos duas vezes sinalou ruído de fundo, mais tipicamente mais do que 10 a 100 vezes de fundo.
Os polinucleotídeos podem compreender uma seqüência nativa(isto é, uma seqüência endógena que codifica um polipeptídeo individual, oudsRNA, ou uma porção deste), ou pode compreender uma variante de talseqüência. As variantes de polinucleotídeo podem conter uma ou mais subs-tituições, retiradas, e/ou inserções, tais que a atividade biológica do polipep-tídeo codificado não é diminuída, relativo a um polipeptídeo compreendendoantígenos nativos. As variantes de polinucleotídeo podem conter uma oumais substituições, adições, retiradas, e/ou inserções, tal que a atividade deagonístico de TLR-3 do dsRNA codificado não é diminuída, relativa a umdsRNA que não contém substituições, adições, retiradas, e/ou inserções. Asvariantes preferivelmente exibem pelo menos cerca de 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99%, para uma seqüência de polinucleotídeo que codifica um polipep-. tídeo nativo ou uma porção deste, ou para um seqüência de polinucleotídeoque codifica um dsRNA com atividade agonística de TLR-3.
Os termos "idêntico" ou "identidade" por cento, no contexto dedois ou mais ácidos nucléicos (por exemplo, um dsRNA que é um agonísticode TLR-3), ou seqüências de polipeptídeo, se referem a duas ou mais se-qüências ou subseqüências que são as mesmas, ou têm uma percentagemespecificada de resíduos de aminoácido ou nucleotídeos que são as mes-mas (isto é, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, 99%, ou mais identidade sobre uma regi-ão especificada), quando comparada e alinhada para correspondência má-xima sobre uma janela de comparação, ou região designada conforme me-dida usando um dos seguintes algoritmos de comparação de seqüência, oupor alinhamento manual e inspeção visual. Tais seqüências são, em segui-da, referidas para serem "substancialmente idênticas". Esta definição tam-bém se refere ao cumprimento de uma seqüência de um teste. Opcional-mente, a identidade existe sobre uma região que é pelo menos 10 a cercade 100, cerca de 20 a cerca de 75, cerca de 30 a cerca de 50 aminoácidos ou nucleotídeos de comprimento.
Para comparação de seqüência, tipicamente uma seqüência agecomo uma seqüência de referência, a cujas seqüências de teste são compa-radas. Quando se usa um algoritmo de comparação de seqüência, as se-qüências de teste e de referência são admitidas em um computador, coor-denadas de subseqüência são designadas, se necessário, e parâmetros deprograma de algoritmo de seqüência são designados. O algoritmo de com-paração de seqüência em seguida calcula a percentagem de identidades deseqüência para as seqüências de teste relativo à seqüência de referência,baseado nos parâmetros do programa.
Uma "janela de comparação", conforme aqui usado, inclui refe-rência a um segmento de qualquer um do número de posições contíguas decerca de 10 a cerca de 500, cerca de 25 a cerca de 200, 50 a cerca de 150,em que um seqüência pode ser comparada a uma seqüência de referênciado mesmo número de posições contíguas após as duas seqüências seremotimamente alinhadas. Os métodos de alinhamento de seqüência para com-paração são bem-conhecidos na técnica. O alinhamento ótimo de seqüên-cias para comparação pode ser conduzido, por exemplo, pelo algoritmo dehomologia local de Smith & Waterman, Adv. Appi Math. 2:482 (1981), peloalgoritmo de alinhamento de homologia de Needleman & Wunsch, J. Mol.Biol. 48:443 (1970), pela pesquisa para método de similaridade de Pearson& Lipman, Proc. Nat'l. Acad. Sei. USA. 85-2444 (1988), por implementaçõescomputadorizadas destes algoritmos (GAP, BESTFIT, FASTA, e TFASTA noWisconsin Genetics Software Package, Genetics Computer Group, 575 Sci-ence Dr., Madison, Wl), ou por alinhamento manual e inspeção visual (vide,por exemplo, Current Protocols in Molecular Biology (Ausubel et ai, eds.1995 suplemento)).
Um exemplo de um algoritmo útil é PILEUP. PILEUP cria um ali-nhamento de seqüência múltiplo de um grupo de seqüências relacionadasusando alinhamentos em pares progressivos para mostrar relacionamento epercentagem de identidade de seqüência. Ele também assinala uma árvoreou dendograma mostrando os relacionamentos de agrupamento usados pa-ra criar o alinhamento. PILEUP usa uma simplificação do método de alinha-mento progressivo de Feng & Doolittle, J. Moi Evol. 35:351-360 (1987). Ométodo usado é similar ao método descrito por Higgins & Sharp, CABIOS5:15-153 (1989). O programa pode alinhar até 300 seqüências, cada uma deum comprimento máximo de 5.000 nucleotídeos ou aminoácidos. O proce-dimento de alinhamento múltiplo começa com o alinhamento de par das du-as seqüências mais similares, produzindo um grupo de duas seqüências ali- nhadas. Este grupo é, em seguida, alinhado à próxima seqüência mais rela-cionada, ou grupo de seqüências alinhadas. Dois grupos de seqüências sãoalinhados por uma extensão simples do alinhamento de par de duas se-qüências individuais. O alinhamento final é alcançado por uma série de ali-nhamentos de par progressivo. O programa é operado pela designação deseqüências específicas e suas coordenadas de aminoácido ou nucleotídeopara regiões de comparação de seqüência, e pela designação dos parâme-tros do programa. Usando-se PILEUP, uma seqüência de referência é com-_ parada a outras seqüências de teste para determinar a percentagem do re-lacionamento de identidade de seqüência usando-se os seguintes parâme- tros: peso de intervalo padrão (3.00), peso de comprimento de intervalo pa-drão (0.10), e folgas terminais pesadas. PILEUP pode ser obtido a partir deacondicionamento de software de análise de seqüência de GCG1 por exem-plo, versão 7.0 (Devereaux etal., Nuc. Acids Res. 12:387-395 (1984).
Outro exemplo de algoritmo que é adequado para determinarpercentagem de identidade de seqüência e similaridade de seqüência são osalgoritmos BLAST e BLAST 2.0, que são descritos em Altschul et aí., Nuc.Acids Res. 25:3389-3402 (1977) e Atschul et ai., J. Mol. BioL 215:403-410(1990), respectivamente. O software para realização de análise de BLAST épublicamente disponível através do Centro Nacional de Informação de Bio-tecnologia (http://www.ncbi.n1 m.nih.gov/). Este algoritmo envolve primeiroidentificação de pares de seqüência de alta classificação (HSPs) por identifi-cação de palavras curtas de comprimento W na seqüência de consulta, queou se equipara ou satisfaz alguma contagem T de limite de valor positivoquando alinhada com uma palavra do mesmo comprimento em uma se-qüência de base de dados. T é referido como o limite de contagem de pala-vra vizinha (Altschul et ai, supra). Estes ataques de palavra vizinha inicialagem como sementes para iniciação de pesquisas para encontrar HSPsmais longos contendo-as. Os ataques de palavra são extendidos em ambasas direções ao longo de cada seqüência tanto quanto a contagem de ali-nhamento cumulativo pode ser aumentada. Contagens cumulativas são cal-culadas usando, para seqüências de nucleotídeo, os parâmetros M (conta-gem de recompensa de um par de resíduo de equiparação; sempre >0) e N(contagem de penalidade para resíduos de desequiparação; sempre <0).Para seqüências de aminoácido, uma matriz de classificação é usada paracalcular a contagem cumulativa. A extensão dos ataques de palavra em ca-da direção é cessada quando: a contagem de alinhamento cumulativo decli-na pela quantidade X de seu valor máximo alcançado; a contagem cumulati-va vai à zero ou abaixo, devido ao acúmulo de um ou mais alinhamentos deresíduo de classificação negativa; ou a extremidade de sua seqüência é al-cançada. Os parâmetros de algoritmo BLAST W, T e X determinam à sensi-bilidade e velocidade do alinhamento. O programa BLAST (para seqüênciasde nucleotídeo) usa como padrão um comprimento de palavra (W) de 11,uma expansão (E) ou 10, M=5, N=4, e uma comparação de ambas as resis-tências. Para seqüência de aminoácido, o programa BLASTP usa como pa-drão um comprimento de palavra de 3, e expressão (E) de 10, e alinhamen-tos de matriz de classificação BLOSUM62 (B) (vide Henikoff & Henikoff,Proc. Nati Acad. Sei. USA 89:10915 (1989) de 50, expectativa (E) de 10,M=5, N=4, e uma comparação de ambas resistências.
O algoritmo BLAST também realiza uma análise estatística dasimilaridade entre duas seqüências (vide, por exemplo, Karlin & Altschul,Proc. Nat'! Acad. Sei. USA 90:5873-5787 (1993). Uma medida de similarida-de provida pelo algoritmo BLAST é a menor probabilidade de soma (P(N))1que proporciona uma indicação da probabilidade pela qual uma equiparaçãoentre duas seqüências de nucleotídeo ou aminoácido ocorreria por chance.Por exemplo, um ácido nucléico é considerado similar a uma seqüência dereferência se a probabilidade de soma menor em uma comparação do ácidonucléico de teste para o ácido nucléico de referência é menor do que 0,2,mais preferivelmente menor do que 0,0,1 e, mais preferivelmente, menor doque cerca de 0,001.III. Composições da Presente Invenção
A invenção proporciona composições compreendendo vetoresadenovirais quiméricos. Em algumas concretizações, os vetores adenoviraisquiméricos da invenção compreendem um primeiro promotor operavelmenteligado a um ácido nucléico que codifica um polipeptídeo heterólogo, e umsegundo promotor operavelmente ligado a um ácido nucléico que codificaum agonístico TLR-3. Os primeiro e segundo promotores podem ser osmesmos ou diferentes. Em algumas concretizações, os primeiro e segundopromotores são independentemente selecionados de: o promotor beta acti-nae o promotor de CMV.
Em algumas concretizações, o vetor adenoviral quimérico com-preende o genoma adenoviral (menos o genes E1 e E3), e um ácido nucléi-co que codifica um gene que ativa IRF-3 e outras moléculas de sinalização ajusante de TLR-3. O vetor quimérico pode ser administrado a uma célula queexpressa gene Ad's, E1 tal que adenovírus recombinante (rAd) é produzidopela célula. Este rAd pode ser colhido e é capaz de uma etapa simples deinfecção que distribuirá a composição transgênica para outra célula dentrode um mamífero de modo a induzir respostas imunes ao polipeptídeo heteró-logo.
A. Vetores Adenovirais Adequados
Em algumas concretizações, o vetor adenoviral é adenovírus 5,incluindo, por exemplo, Ad5 com retiradas das regiões E1/E3, e Ad5 comuma retirada da região E4. Outros vetores adenovirais adequados incluemcepas 2, cepas oralmente testadas 4 e 7, adenovírus entéricos 40 e 41, eoutras cepas (por exemplo, Ad34) que são suficientes para distribuição deum antígeno e indução de uma resposta imune adaptativa ao antígenotransgene [Lubeck et ai, Proc Natl Acad Sci USA, 86(17), 6763-6767 (1989);Shen et al., J. Virol, 75(9), 4297-4307 (2001); Bailey et ai, Virology, 202(2),695-706 (1994)]. Em algumas concretizações, o vetor adenoviral é um vetoradenoviral incompetente de replicação, vivo (tais como rAd5 retirado E1 eE3), vetor adenoviral atenuado e vivo (tais como vírus de retirada E1B55K),ou um vetor adenoviral vivo com uma replicação tipo selvagem.As seqüências de controle transcricionais e translacionais nosvetores de expressão a serem usadas na transformação de células verte-bradas in vivo podem ser providas por fontes virais. Por exemplo, promoto-res comumente usados e intensificadores são derivados, por exemplo, debeta actin, adenovírus, vírus simian (SV40), e citomegalovírus humano(CMV). Por exemplo, vetores que permitem expressão de proteínas sob adireção do promotor de CMV, promotor anterior SV40, promotor posteriorSV40, promotor metalotionein, promotor de vírus de tumor mamário de muri-na, promotor de vírus de sarcoma de Rous, promotor transdutor, ou outrospromotores mostrados eficazes para expressão em células mamíferas, sãoadequados. Promotor genômico viral adicional, seqüências de controle e/oude sinal podem ser usadas, provido que tais seqüências de controle sãocompatíveis com a célula hospedeira escolhida.
B. Polipeptídeos Heterólogos
Os ácidos nucléicos que codificam polipeptídeos heterólogosadequados podem ser derivados de antígenos, tais como, por exemplo, an-tígenos virais, antígenos bacteriais, antígenos de câncer, antígenos fungais,ou antígenos parasitas.
Os antígenos virais podem ser derivados de, por exemplo, vírusde imunodeficiência humana (por exemplo, gag (p55 e p160), pol, env(gp120 e gp41), conforme colocado em Shiver et al., Nature 415(6869):331(2002); as seqüências genômicas de HIV colocadas nos Acessos no Bancode Gene N95 EF363127; EF363126; EF363125; EF363124; EF363123;EF363122; EF192592; e EF192591; as seqüências gag de HIV colocadasnos Acessos no Banco de Gene Ngs EF396891; EF396890; EF396889;EF396888; EF396887; EF396886; EF396885; EF396884; EF396883;EF396882; EF396882; EF396881; EF396880; EF396879; EF396878;EF396877; EF396876; EF39687; EF396874; EF396873; e EF396872; asseqüências pol de HIV colocadas nos Acessos no Banco de Gene NesEF396810; EF396809; EF396808; EF396807; EF396806; EF396805;EF396804; EF396803; EF396802; EF396801; EF396800; EF396799;EF396798; EF396797; EF396796; EF396795; EF396794; EF396793;EF396792; e EF396791; e as seqüências env de HIV colocadas nos Aces-sos no Banco de Gene Nss 9: EF367234; EF367233; EF367232; EF367231;EF367230; EF367229; EF367228; EF367227; EF367226; EF367225;EF367224 e EF367223, vírus papilloma humano (por exemplo, proteína L1capsid, conforme descrita em, por exemplo, Donnelly et al., J Infect Dis.173:314 (1996), e as seqüências colocadas nos Acessos no Banco de GeneNss EF362755; EF362754; NC_001694; NC_001693; NC_001691;NC_001690; NC_005134; NC_001458; NC_001457; NC_001354;NC_001352; NC_001526; e X94164), vírus Epstein Barr, vírus simplex dherpes, vírus da herpes humano, rinovírus, cocksackievírus, enterovírus,hepatite A, B, C e E (por exemplo, antígeno de superfície de hepatite B con-forme descrito em, por exemplo, Lubeck et al, PNAS USA 86:6763 (1989), e- as seqüências colocadas nos Acessos no Banco de Gene N°s AB236481;AB236471; AB206501; AB206489; AB206487; AB221788; AB221777;AB221773; AR933671; AR933670; AB236514; AB236513; AB236512;AB236511; AB236510; AB236509; AB236508; AB236507); hepatite C NS5(vide, por exemplo, Acessos no Banco de Gene N°s X59609; DQ911563;S71627; S70787; S70786; S70341; S6220; S70790; S70789; S70788; eAB204642)), vírus mumps, vírus rubella, vírus measles, poliovírus, vírussmallpox, vírus rabies, e vírus Variella-zoster. O antígeno da gripe inclui, porexemplo, hemaglutinin (HA), proteína matriz 1 (M1), e nucleoproteína (NP)(vide, por exemplo, Donnelly, et al, Vaccine 15:865 (1997) e as seqüênciasde HA de gripe colocadas no Acesso no Banco de Genes N9s AB294219;AB294217; AB294215; AB294213; EF102944; EF102943; EF102942;EF102941; EF102940; EF102939; EF102938; EF102937; EF102936;EF102935; EF102934; EF102933; DQ643982; DQ464354; CY019432;CY019424; CY019416; CY019408; CY019400; CY019392; CY019384;CY019376; CY019368; CY019360; CY019352; EF124794; EF110519;EF110518; EF165066; EF165065; EF165064; e EF165063; as seqüênciasde M1 de gripe colocadas nos Acessos no Banco de Gene Nes AB292791;CY019980; CY019972; CY019964; CY019956; CY019948; CY019940;CY019628; CY019652; CY019644; CY019932; CY019924; CY019916;CY019908; CY019900; CY019892; CY019884; CY019876; CY019868;CY019860; e as seqüências de NP de gripe colocadas nos Acessos no Ban-co de Gene Nss AB292790; CY019461; CY019974; CY019966; CY019958;CY019950; CY019942; CY019630; CY019654; CY019934; CY019926;CY019918; CY019910; CY019902; CY019894; CY019886; CY019878;CY019870; e CY019862.
Antígenos virais adequados também incluem, por exemplo, pro-teínas não-estruturais virais. O termo "Proteína não-estrutural viral", confor-me aqui usado, se refere a proteínas codificadas por ácido nucléico viral quenão codifica para polipeptídeos estruturais, tais como aqueles que produzemcapsid ou a proteína que circunda um vírus. As proteínas não-estruturaisincluem aquelas que promovem replicação de ácido nucléico viral e expres-são de gene viral tais como, por exemplo, proteínas não-estruturais , 2, 3 e 4(NS1, NS2, NS3 e NS4, respectivamente) de encefalite Eqüina Venezuelana(VEE), EEE, ou vírus Semiliki Forest [Dubensky et ai, J Virol, 70(1), 508-519(1996); Petrakova et al J Virol 2005 79(12): 7595-608; Patente dos EstadosUnidos Nss 5.185.440; 5.739.026; 6.566.093; e 5.814.482. Vários exemplosrepresentativos de alfavírus adequados incluem Aura (ATCC VR-368), vírusBebaru (ATCC VR-600, ATCC VR-1240), Cabassou (Acesso no Banco deGenes Nes AF398387, ATCC VR-922), vírus chikungunya (ATCC VR-64,ATCC VR-1241), vírus de encefalomielite eqüina do oeste (Acesso no Bancode Genes Ngs AY705241, AY705240, ATCC VR-65, ATCC VR-1242), FortMorgan (ATCC VR-924), vírus Getah (ATCC VR-369, ATCC VR-1243), Kyz-ylagach (ATCC VR-927), Mayaro (ATCC VR-66), vírus Mayaro (ATCC VR-1277), Middleburg (ATCC VR-370), vírus Mucambo (ATCC VR-580, ATCCVR-1244), Ndumu (ATCC VR-371), vírus Pixuna (ATCC VR-372, ATCC VR-1245), vírus Ross River (ATCC VR-373), ATCC VR-1246), Semliki Forest(Acesso no Banco de Genes Nss AJ251359, ATCC VR-67, ATCC VR-1247),vírus Sindbis (Acesso no Banco de Genes Nes J02363, ATCC VR-68, ATCCVR-1248), Tonate (ATCC VR-925), Triniti (ATCC VR-469), Una (ATCC VR-374), encefalomielite eqüina venezuelana (ATCC VR-69), vírus de encefalo-mielite eqüina venezuelana (Acesso no Banco de Genes Nss AY986475,ΑΥ973944, NC 001449, ATCC VR-923), ATCC VR-1250, ATCC VR-1249,ATCC VR-532), encefalomielite eqüina do oeste (ATCC VR-70, ATCC VR-1251, ATCC VR-622, ATCC VR-1252), Whatoroa (ATCC VR-926), e Y-62-33(ATCC VR-375).
Os antígenos bacteriais podem ser derivados de, por exemplo,Staphylococcus aureus, Staphylococcus epidermis, Helieobacter pylori, S-treptoeoeeus bovis, Streptococcus pyogenes, Streptoeoceus pneumoniae,Listeria monoeytogenes, Myeobaeterium tubereulosis, Myeobaeterium leprae,Corynebaeterium diphtheriae, Borrelia burgdorfi, Bacillus anthraeis, Baeilluseereus, Clostridium botulinum, Clostridium diffieile, salmonella typhi, Vibrioehloerae, Haemophilus influenza, Bordetella pertussis, Yersinia pestis, Neis-seria gonorrhoeae, Treponema pallidum, Myeoplasm sp., Nisseria ransdueerLegionella pneumophila, Riekettsia typhi, Chlamydia traehomatis, e Shigel-Ia dysenteriae, Vibrio eholera (por exemplo, Cholera toxin subunidade B con-forme colocada no Acesso no Banco de Genes N9S U25679; A09803;EF158842; X76391; AF390572; eholera toxin-pilus co-regulado (TCP), con-forme descrito em Wu et ai, Infeetion and Immunity Vol 69(12):7695 (2001),e conforme colocado no Acesso no Banco de Gene Nss NC_002505 e A-E004169); Helicobaeter pylorii (VacA, conforme colocado no Acesso no Ban-co de Gene N98 AY848858; AF042737; AF042736; AF042735; AF042734;NC_000921; CagA, conforme colocado no Acesso no Banco de Gene NesAF043490; AF043489; AF043488; AF043487; NAP conforme colocado noAcesso no Banco de Gene Nss AF284121; AF284120; AF284119AF284118; AF284117; AF284116; AB045143; AB045142; AF227081AF227080; AF227079; AF227078; AF227077; AF227076; AF227075AF227074; Hsp ou catalase, conforme colocado no Acesso no Banco deGene Nes NC_000921; urease, conforme colocado no Acesso no Banco deGene Nss AM417610; AM417609; AM417608; AM417607; AM417606;AM417605; AM417604; AM417603; AM417602; AM417601; e AM417600;antígenos de E. co//', conforme colocado no Acesso no Banco de Gene NesNC_000913; U00096; NC_002655; BA000007; AE014075; incluindo antíge-nos finbrial de E. eoli conforme colocado no Acesso no Banco de Gene NqsΑΒ214865; ΑΒ214864; ΑΒ214863; ΑΒ214862; enteroxina instável a calorconforme colocado no Acesso no Banco de Gene Ngs X83966; V00275;X83966; J01646; V00275; M35581; M17873; M17874; K01995; M61015;M178894; M17101; K00433.
Antígenos de parasita podem ser derivados de, por exemplo,Giardia lamblia, Leishmania sp., Trypanosoma sp., Trichomonas sp., Plas-modium sl. (por exemplo, antígenos de proteína de superfície P. falciparum,tais como seqüências pfs25, conforme colocado no Acesso no Banco deGene Nss XM_001347551; AF193769; AF179423; AF154117; e AF030628,seqüências pfs28, conforme colocado no Acesso no Banco de Gene NssL25843, seqüências pfs45, conforme colocado no Acesso no Banco de GeneNes EF158081; EF158079; EF158078; EF158076; EF158075; e EF158085,seqüências pfs84, pfs48/45, conforme colocadas no Acesso no Banco de
Gene Ngs AF356146
AF356141AF356134AF356128
AF356139AF356133
AF356145AF356138AF356132
AF356143AF356136AF356130
AF356142AF356135AF356129
AF356144AF356137AF356131
AF356127; seqüências pfs 230, conforme colocadas no Acessono Banco de Gene Nss NC_000910; XM_001349564; AE001393; L22219;L08135; e AF269242, antígenos P. virax, tais como seqüências Pvs25, con-forme colocadas no Acesso no Banco de Gene Nss DQ641509; DQ641508;DQ641507; AY639971; AY639970; AY639969; AY639968; AY639967;AY639966; e AY639965; e seqüências Pvs28, conforme colocadas no Aces-so no Banco de Gene Nes AB033364; AB033363; AB033362; AB033361ΑΒ033360; AB033359; AB033358; AB033357; AB033356; AB033355ΑΒ033354; AB033353; AB033352; AB033351; AB033350; AB033349AB033348; AB033347; AB033346; e AB033345), Schistosoma sp., Myco-bacterium tuberculosis (por exemplo, seqüências Ag85, conforme colocadasno Acesso no Banco de Gene Nes AX253506; AX253504; AX253502; eAX211309; MPT64, ESAT-6, CFP10, R8307, MTB-32 MTB-39, CSP, LSA-1,30 LSA-3, EXP1, SSP1, SSP-2, SALSA, STARP, GLURP, MSP-1, MSP-2,MSP-3, MSP-4, MSP-5, MSP-8, MSP-9, AMA-1, proteína de membrana inte-gral tipo 1, RESA, EBA-175, e seqüências DBA conforme colocadas no A-cesso no Banco de Gene Nes BX842572; BX842573; BX842574; BX842575;BX842576; BX842577; BX842578; BX842579; BX842580; BX842581;BX842582; BX842583; BX842584; e NC_000962, seqüências HSP65, con-forme colocadas no Acesso no Banco de Gene Ngs AY299175; AY299174;AY299144; AF547886; e AF547885).
Antígenos de câncer incluem, por exemplo, antígenos expres-sos, por exemplo, em câncer de cólon, câncer de estômago, câncer pan-creático, câncer de pulmão, câncer de ovário, câncer de próstata, câncer deseio, câncer de pele (por exemplo, melanoma), leucemia, linfoma, ou mielo-ma, antígenos de câncer exemplares incluem, por exemplo, HPV L1, HPVL2, HPV E1, HPV E2, fosfatase alcalina placental, AFP, BRCA1, Her2/neu,CA 15-3, CA 19-9, CA-125, CEA, Hcg, ativador de plasminogêneo tipo uro-quinase (Upa), inibidor de ativador de plasminogêneo.
Antígenos fungais podem ser derivados de, por exemplo, Tineapedis, Tinea corporus, Tinea crusis, Tinea unguium, Cladoporium carionii,Coccidioides immitis, Cândida sp., Aspergillus fumigatus, e Pneumocytis ca-rínii.
Os ácidos nucléicos que codificam polipeptídeos imunogênicossão tipicamente produzidos por métodos de DNA recombinante (vide, porexemplo, Ausubel, et ai, ed. (2001) Current Protocols in Molecular Biology).Por exemplo, as seqüências de DNA que codificam o polipeptídeo imunogê-nico podem ser montadas de fragmentos de cDNA e Iigantes de oligonucleo-tídeo curtos, ou de uma série de oligonucleotídeos, ou amplificadas de cDNAusando iniciadores apropriados para proporcionar um gene sintético que écapaz de ser inserido em um vetor de expressão recombinante (isto é, umvetor de plasmídeo, ou um vetor viral), e expresso em uma unidade transcri-cional recombinante. Uma vez que o ácido nucléico que codifica um polipep-tídeo imunogênico é produzido, ele pode ser inserido em um vetor de ex-pressão recombinante que é adequado para expressão in vivo ou ex-vivo.
Os vetores de expressão recombinantes contêm uma seqüênciade DNA que codifica um polipeptídeo imunogênico operavelmente ligado aelementos regulatórios transcricionais ou translacionais adequados deriva-dos de genes de mamíferos ou virais. Tais elementos regulatórios incluemum promotor transcricional, uma seqüência operadora opcional para contro-lar transcrição, uma seqüência que codifica locais de ligação ribossomal demRNA adequados, e seqüências que controlam a terminação de transcriçãoe translação. Uma origem de replicação e um marcador selecionável parafacilitar reconhecimento de transformantes podem adicionalmente seremincorporados. Os genes utilizados nos vetores de expressão recombinantespodem ser divididos entre mais do que um vírus, tal que os produtos de geneestão em dois vetores diferentes, e os vetores são usados para co-transdução para proporcionar todos os produtos de gene em trans. Existemrazões que dividem os produtos de gene, tais como limitações de tamanhopara inserção, ou toxicidade dos produtos de gene combinados para as li-nhas de célula produzirem vírus.
C. AqonisticoS TLR
De acordo com os métodos da invenção, os agoníticos TLR sãousados para aumentar a resposta imune ao polipeptídeo heterólogo. Em al-gumas concretizações, os agoníticos TLR-3 aqui descritos podem ser distri-buídos simultaneamente com o vetor de expressão que codifica um antígenode interesse, ou distribuídos separadamente (isto é, temporariamente ouespacilmente) a partir do vetor de expressão que codifica um antígeno deinteresse. Por exemplo, o vetor de expressão pode ser administrado via umavia não-paralela (por exemplo, oralmente, intranasalmente, ou mucosamen-te), enquanto o agonístico TLR é distribuído por uma via parenteral (porexemplo, intramuscular, intraperitoneal, ou subcutaneamente).
1. Aaonísticos TLR
Em uma concretização preferida da presente invenção, um ago-nítico TLR-3 é usado para estimular reconhecimento imune de um antígenode interesse. Os agonísticos TLR-3 incluem, por exemplo, RNA em forma degrampo de cabelo curto, RNA viralmente derivado, segmentos curtos deRNA que podem formar filamentos duplos, ou RNA em forma de grampo decabelo curto, e RNA de interferência curto (siRNA). Em uma concretizaçãoda invenção, o agonístico TLR-3 é dsRNA viralmente derivado, tal como, porexemplo, um ds-RNA derivado de um vírus Sindbis, ou intermediários viraisde dsRNA [Alexopoulou et ai, Nature 413:732-8(2001). Em algumas concre-tizações, o agonístico TLR-3 é um RNA em forma de grampo de cabelo cur-to. Seqüências de RNA em forma de grampo de cabelo curto tipicamentecompreendem duas seqüências complementares unidas por uma seqüêncialigante. A seqüência Iigante particular não é um aspecto crítico da invenção.Qualquer seqüência ligante apropriada pode ser usada, considerando-seque ela não interfira com a ligação das duas seqüências complementarespara formar um dsRNA.
Em algumas concretizações, o RNA em forma de grampo decabelo curto compreende uma seqüência colocada em SEQ ID Nss: 3, 4, 5,8, 9, 10, 11 ou 12, uma seqüência com identidade substancial para uma se-qüência colocada em SEQ ID Nes: 3, 4, 5, 8, 9,10, 11 ou 12, ou uma variante" de uma seqüência colocada em SEQ ID Nss: 3, 4, 5, 8, 9, 10, 11 ou 12. Emcertas concretizações, dsRNA que é um agonístico TLR-3 que não codificaum polipeptídeo particular, mas produz uma citoquina pró-inflamatória (porexemplo, IL-6, IL-8, TLF-alfa, IFN-alfa, IFN-beta) quando contactado comuma célula respondedora (por exemplo, uma célula dendrítica, um célulamononuclear de sangue periférico, ou um macrófago) in vitro, ou in-vivo. Emalguns casos, o ácido nucléico que codifica o agonístico TLR-3 (por exem-plo, um dsRNA expresso) e o vetor adenoviral quimérico compreendendo umácido nucléico que codifica um antígeno heterólogo são administrados namesma formulação. Em outros casos, Em alguns casos, o ácido nucléicoque codifica o agonístico TLR-3 e o vetor adenoviral quimérico compreen-dendo um ácido nucléico que codifica um polipeptídeo heterólogo são admi-nistrados em formulações diferentes. Quando o ácido nucléico que codifica oagonístico TLR-3 e o vetor adenoviral quimérico compreendendo um ácidonucléico que codifica um antígeno heterólogo são administrados em formu-lações diferentes, sua administração pode ser simultânea ou seqüencial. Porexemplo, o ácido nucléico que codifica o agonístico TLR-3 pode ser adminis-trado primeiro, seguido pelo vetor adenoviral quimérico (por exemplo, 1,2,4,8, 12, 16, 20 ou 24 horas, 2, 4, 6, 8 ou 10 dias mais tarde). Alternativamente,o vetor adenoviral pode ser administrado primeiro, seguido pelo ácido nu-cléico que codifica o agonístico TLR-3 (por exemplo, 1, 2, 4, 8, 12, 16, 20 ou24 horas, 2, 4, 6, 8 ou 10 dias mais tarde). Em algumas concretizações, oácido nucléico que codifica o agonístico TLR-3 e o ácido nucléico que codifi-ca o antígeno heterólogo estão sob o controle do mesmo promotor. Em ou-tras concretizações, o ácido nucléico que codifica o agonístico TLR-3 e oácido nucléico que codifica o antígeno heterólogo estão sob o controle depromotores diferentes.
Sete análogos quimicamente sintetizados para RNA de filamen-to duplo são comercialmente disponíveis. Estes incluem poliinosina ácidopolicitidílico (poli l:C), ácido poliadenílico:poliuridílico (poli A:U), e poli IrpoliC. Anticorpos (ou reticulação de anticorpos) para TLR-3 podem tambémconduzir a IFN-beta, ou produção de citoquina pró-inflamatória [Matsumotoetal, Biochem. Biophys. Res. Commun. 24:1364(2002), de Bouteiller et al, J.Biol. Chem. 18:38133-45 (2005). Segmentos de siRNA comercialmente dis-poníveis de qualquer seqüência podem também serem obtidos através defontes, tal como Invitrogen.
2. Aaonísticos TLR7/8
Em algumas concretizações, os agonísticos TLR são agonísti-cos TLR7/8. Ligantes TRL7/8 são tipicamente RNA derivado viralmente defilamento duplo. Devido aos receptores serem expressos em compartimen-tos intracelulares, tais como o endossoma, nem todos os segmentos curtosde RNA dispararão a cascata de sinalização de TLR7/8 porque eles necessi-tam alcançar o compartimento correto. Alguns Iigantes que foram mostradosnão disparar esta adição exógena são ácido poliuridílico, resiquimod, e imi-quimod [Westwood, et al., Vaccine 24:1736-1745(2006)].
IV. Composições Farmacêuticas
Composições farmacêuticas compreendendo os vetores aquidescritos podem também conter outros compostos, que podem ser biologi-camente ativos ou inativos. Polipeptídeos podem, mas não necessitam, se-rem conjugados a outras macromoléculas conforme descrito, por exemplo,nas Patentes dos Estados Unidos Nps 4.372.945 e 4.474.757. As composi-ções farmacêuticas podem geralmente serem usadas para proposta profiláti-ca e terapêutica. As composições farmacêuticas podem ser compostas demétodos para proteger contra degradação do estômago, tal que o vetor ade-noviral quimérico administrado pode alcançar as localizações desejadas.
Para o ambiente oral, vários destes são disponíveis, incluindo os sistemasde liberação Eudragit e TimeCIock, bem como outros métodos especifica-mente designados para adenovírus [Lubeck et ai., Proc Natl Acad Sci USA,86(17), 6763-6767 (1989); Chourasia e Jain, J. Pharm. Sei, 6(1), 33-66(2003)]. Existem também vários métodos já descritos para microencapsula-mento de DNA e fármacos para distribuição oral (vide, por exemplo, Publica-ção de Patente dos Estados Unidos Ns 2004043952). Em algumas concreti-zações, o sistema Eudragit será usado para distribuir o vetor adenoviral qui-mérico ao intestino delgado inferior. Contudo, a distribuição para outros Io-cais do intestino delgado deve também operar.
Conforme notado acima, os vetores adenovirais quiméricos nainvenção podem ser distribuídos usando-se quaisquer sistemas de distribui-ção conhecidos àqueles versados na técnica. Numerosas técnicas de distri-buição de gene são bem-conhecidas na técnica, tais como aquelas descritaspor Rolland (1998) Crit. Rev. Therap. Drug Carrier Systems 15:143-198, ereferências aqui citadas.
Será aparente que composições imunogênicas podem contersais farmaceuticamente aceitáveis dos polinucleotídeos que codificam ospolipeptídeos heterólogos (por exemplo, polipeptídeos imunogênicos). Taissais podem ser preparados de bases não-tóxicas farmaceuticamente aceitá-veis, incluindo bases orgânicas (por exemplo, sais de aminas primária, se-cundária e terciária, e aminoácidos básicos), e bases inorgânicas (por e-xemplo, sais de sódio, potássio, lítio, amônia, cálcio e magnésio). Algunsexemplos particulares de sais incluem solução salina tamponada por fosfato,e solução salina para injeção.
Qualquer veículo adequado conhecido àqueles versados na téc-nica pode ser empregado nas composições farmacêuticas desta invenção.Veículos adequados incluem, por exemplo, água, solução salina, álcool, umagordura, um cera, um tampão, um veículo sólido, tais como manitol, lactose,amido, estearato de magnésio, sacarina de sódio, talco, celulose, glicose,sacarose, e carbonato de magnésio, ou microesferas biodegradáveis (porexemplo, polilactto poliglicolato). Microesferas biodegradáveis adequadassão descritas, por exemplo, nas Patentes dos Estados Unidos Nss 4.897.268;5.075.109; 5.928.647; 5.811.128; 5.820.883. O polipeptídeo imunogênicoe/ou vírus veículo podem ser encapsulados dentro da microesfera biodegra-dável, ou associados com a superfície da microesfera.
Tais composições podem também compreender tampões (porexemplo, solução salina tamponada neutra, ou solução salina tamponadapor fosfato), carboidratos (por exemplo, glicose, manose, sacarose e dextra-nos), manitol, proteínas, polipeptídeos ou aminoácidos, tais como glicina,antioxidantes, bacteriostats, agentes quelatantes, tais como EDTA ou gluta-tionina, adjuvãntes (por exemplo, hidróxido de alumínio), solutos que tornama formulação isotônica, hipotônica ou fracamente hipertônica com o sanguede um recipiente, agentes de suspensão, agentes de espessamento e/ouconservantes. Alternativamente, as composições da presente invenção po-dem ser formuladas como um liofilisato. Os compostos podem também serencapsulados dentro dos Iipossomas usando-se tecnologia bem-conhecida.
Em algumas concretizações da presente invenção, as composi-ções compreendem adicionalmente um adjuvante. Adjuvãntes adequadosincluem, por exemplo, os compostos de lipídeos e não-lipídeos, cholera toxin(CT), CT subunidade B, CT derivativo CTK63, enterotoxina instável a calorde E. coli (LT), derivado de LT LTK63, AI(OH)3, e ácidos orgânicos poliiôni-cos conforme descritos em, por exemplo, WO 04/020592, Anderson e Cro-wle, Infect Immun. 31(1):413-418 (1981), Roterman et ai, J. Physioi Phar-macol., 44(3):212-32 (1993), Arora e Crowle, J. Reticuloendothel. 24(3):271-86(1978), e Crowle e May, Infect. Immun. 38(3):932-7 (1982)). Ácidos orgâ-nicos poliiônicos adequados incluem, por exemplo, 6,6'-[3,3'-dimetil[1,1'-bifenil]-4,4'-diil]bis(azo)bis[ácido 4-amino-5-hidróxi-1,3-naftaleno-dissulfônico](Evans Blue) e 3,3'-[1,1'bifenil]-4,4'-diilbis(azo)bis[ácido 4-amino-1-naftalenossulfônico] (Congo Red). Será apreciado por aqueles ver-sados na técnica que os ácidos orgânicos poliiônicos podem ser usados pa-ra qualquer método de vacinação genética em conjunto com qualquer tipo deadministração.
Outros adjuvantes adequados incluem imunomoduladores tópi-cos, tais como, membros da família imidazoquinolina, tais como, por exem-plo, imidaquimod e resiquimod (vide, por exemplo, Hengge et al., Lancet Irt-fect. Dis. 1(3):189-98 (2001). Agonísticos TLR-3 expressos (por exemplo,dsRNA) e agonísticos TLR-7 (por exemplo, ssRNA), podem também seremusados com a invenção.
Adjuvantes adequados adicionais são comercialmente disponí-veis como, por exemplo, adjuvantes baseado em alum adicionais (por exem-plo, Alhydrogel, Rehydragel, fosfato de alumínio, Algammulin); adjuvantesbaseado em óleo (Adjuvante Incompleto e Adjuvante Completo de Freund(Difco Laboratories, Detroit, Mich), Specol, RIBI, TiterMax, Montanide ISA 50ou Seppic MONTANIDE ISA 720); adjuvantes baseados em copolímero debloco não-iônico, citoquinas (por exemplo, GM-CSF ou Flat3 ligante); Adju-vante Merck 65 (Merck and Company, Inc., Rahway, N.J.); AS-2 (SmithKIineBeecham, Philadelphia, Pa); sais de cálcio, ferro ou zinco; uma suspensãoinsolúvel de tirosina acilatada; açúcares acilatados; polissacarídeos cationi-camente ou anionicamente derivatizados; polifosfozenos; microesferas bio-degradáveis; monofosforil lipídeo A e Quil A. Citoquinas, tais como GM-CFSou interleukin-2, -7, ou -12, são também adjuvantes adequados. Hemocia-nins (por exemplo, hemocianin de lapa) e hemoeritrins podem também se-rem usados na invenção. Adjuvante de polissacarídeo tais como, por exem-plo, chitin, chitosan, e chitin deacetilado são também adequados como adju-vantes. Outros adjuvantes adequados incluem muramil dipeptídeo (MDP, Nacetilmuramil L alanil D isoglutamina) peptidoglicans bacteriais e seus deri-vados (por exemplo, threonil-MDP, e MTPPE). BCG e esqueleto de paredede célula de BCG (CWS) podem também serem usados como adjuvantes nainvenção, com ou sem trehalose dimicolato. Trehalose dimicolato pode serusado (vide, por exemplo, Patentes dos Estados Unidos Ns 4.579.945). En-dotoxins detoxificados são também úteis como adjuvantes apenas, ou emcombinação com outros adjuvantes (vide, por exemplo, Patente dos EstadosUnidos Nss 4.866.034; 4.435.386; 4.505.899; 4.436.727; 4.436.728;4.505.900; e 4.520.019. Os saponins QS21, QS17, QS7 são também úteiscomo adjuvantes (vide, por exemplo, Patente dos Estados Unidos Nss5.057.540; EP 0362 279; WO 96/33739; e WO 96/11711). Outros adjuvantesadequados incluem Montanide ISA 720 (Seppic, França), SAF (Chiron Calif,United States), ISCOMS (CSL), MF-59 (Chiron), a série SBAS de adjuvantes(por exemplo, SBAS-2, SBAS-4 ou SBAS-6 ou variantes destes, disponíveisde SmithKIine Beecham, Rixensart, Bélgica), Detox, Hamilton, Mont.), e RC-529 (Corixa, Hamilton, Mont).
Superantígenos são também contemplados para uso como ad-juvantes na presente invenção. Superantígenos incluem Staphylococcus e-xoproteínas, tais como α, β, γ e Δ enterotoxins de S.aureus e S. epidermidis,e a, β, γ e Δ exotoxins E. coli. Staphylococcus enterotoxins comum são co-nhecidos como staphyloeoceal entetotoxin A (SEA) e staphyloeoeeal entero-toxin B (SEB), com enterotoxins através de E (SEE) sendo descritas (Rott etal., 1992). Streptoeoeeus pyogenes B (SEB), Clostridium perfringes entero-toxin (Bowness et al., 1992), proteína associada a membrana citoplástmica(CAP) de S. pyogenes (Sato et al., 1994) e toxin de síndrome de choquetérmico 1 (TSST 1) de S. aureus (Schwab et al., 1993) são superantígenosúteis adicionais.
Dentro das composições farmacêuticas aqui providas, a compo-sição adjuvante pode ser designada para induzir, por exemplo, uma respostaimune predominantemente do tipo Th1 ou Th2. Altos níveis de citoquinastipo Th1 (por exemplo, IFN-gama, TNF-alfa, IL-2 e IL-3) tendem a favorecera indução de respostas imunes mediadas de célula para um antígeno admi-nistrado. Em contraste, altos níveis de citoquinas tipo Th2 (por exemplo, IL-4, IL-5, IL-6 e IL-10) tendem a favorecer a indução de repostas imunes hu-morais. Seguindo distribuição oral de uma composição compreendendo umpolipeptídeo imunogênico conforme provido aqui, uma resposta imune queinclui respostas tipo Th1 e Th2 será tipicamente induzida.
As composições aqui descritas podem ser administradas comoparte de uma formulação de liberação sustentada (isto é, uma formulação talcomo uma cápsula ou esponja que efetua uma liberação lenta de compostoem seguida a administração). Tais formulações podem geralmente ser pre-paradas usando-se tecnologias conhecidas (vide, por exemplo, Coombes etal (1996) Vaccine 14:1429-1438). Formulações de liberação sustentada po-dem conter um polipeptídeo, polinucleotídeo ou anticorpo disperso em umamatriz transportadora, e/ou contidas dentro de um reservatório circundadopor uma membrana de controle de taxa.
Os veículos para uso dentro de tais formulações são biocompa-tíveis, e podem ser biodegradáveis; preferivelmente as formulações propor-cionam um nível relativamente constante de liberação de componente ativo.
Tais veículos incluem micropartículas de poli(lactídeo-co-glicolídeo), bemcomo poliacrilato, látex, amido, celulose e dextrano. Outros veículos de libe-ração retardada incluem biovetores supramoleculares, que compreendemum núcleo hidrofílico não-líquido (por exemplo, um polissacarídeo reticuladoou oligossacarídeo) e, opcionalmente, uma camada externa compreendendoum composto anfifílico (vide, por exemplo, W094/20078; W094/23701 eW096/06638). A quantidade de composto ativo contida dentro de uma for-mulação de liberação sustentada depende do local de implantação, da taxae da duração esperada de liberação e da natureza da condição a ser tratadaou prevenida.
As composições farmacêuticas podem ser apresentadas em re-cipientes de dose única ou de dose múltipla, tais como ampolas vedadas oufrascos. Tais recipientes são preferivelmente hermeticamente vedados parapreservar a esterilidade da formulação até uso. Em geral, formulações po-dem ser armazenadas como suspensões, soluções ou emulsões em veícu-los oleosos ou aquosos. Alternativamente, uma composição farmacêuticapode ser armazenada por uma condição secada por armazenamento reque-rendo somente a adição de um veículo liquido estéril imediatamente antesdo uso.
V. Usos Terapêuticos da Invenção
Um aspecto da presente invenção envolve o uso das composi-ções imunogênicas aqui descritas para induzir uma resposta imune especifi-ca de antígeno de um indivíduo ou paciente com uma doença tal como, porexemplo, uma infecção viral, infecção bacterial, uma infecção parasítica,uma infecção fungai, ou câncer. Conforme aqui usado, um "indivíduo" ou um"paciente" se refere a qualquer animal de sangue quente, tal como, por e-xemplo, um roedor, um felino, um canino, ou um primata, preferivelmente umser humano. As composições imunogênicas podem ser usadas em qualquerestagio da doença, isto é, no pré-cancer, câncer, ou estados metastáticos,ou para prevenir doença. Por exemplo, as composições aqui descritas po- dem ser usadas para tratar uma doença viral, tal como HIV, ou hepatite, ou aI prevenção ou tratamento de câncer. Dentro de tais métodos as composiçõesfarmacêuticas são tipicamente administradas a um paciente. O paciente po-de ou não pode ser afligido com a doença ou enfermidade (por exemplo,uma infecção viral, uma infecção bacterial, ou câncer). Conseqüentemente,as composições farmacêuticas acima podem ser usadas para prevenir, o de-senvolvimento de uma doença ou enfermidade (por exemplo, uma infecçãoviral, uma infecção bacterial ou câncer), ou tratar um paciente afligido com adoença ou enfermidade (por exemplo, uma infecção viral, uma infecção bac-terial ou câncer). A doença ou enfermidade pode ser diagnosticada usando-se critérios geralmente aceitos na técnica. Por exemplo, a infecção viral po-de ser diagnosticada pela medição da titulação viral em uma amostra do pa-ciente, a infecção bacterial pode ser diagnosticada pela detecção da bactériaem uma amostra do paciente, e o câncer pode ser diagnosticado pela detec-ção da presença de um tumor maligno. As composições farmacêuticas po-dem ser administradas, ou antes, ou, em seguida a remoção cirúrgica detumores primários e/ou tratamento, tal como administração de radioterapiaou fármacos quimioterapêuticos convencionais.
A imunoterapia é tipicamente imunoterapia ativa, em que o tra-tamento ocorre na estimulação in vivo do sistema imune hospedeiro endó-geno para reagir contra, por exemplo, tumores ou células bacterial ou viral-mente infectadas, com a administração de agentes de modificação de res-posta imune (composições compreendendo ácidos nucléicos que codificampolipeptídeos imunogênicos conforme aqui providos).
A freqüência de administração das composições profiláticas outerapêuticas aqui descritas, bem como a dosagem, variará de indivíduo paraindivíduo, e pode ser prontamente estabelecida usando-se técnicas padrão.Freqüentemente entre 1 e 10 doses podem ser administradas sobre üm pe-ríodo de 51 semanas. Tipicamente 3 doses são administradas, em intervalosde um mês, mais tipicamente 2-3 doses são administradas todo 2-3 meses,é possível que os intervalos sejam mais de uma vez por ano para certas te-rapias. Vacinações em grupo podem ser dadas periodicamente em seguida.Protocolos alternados podem ser apropriados para pacientes individuais edoenças e enfermidades particulares. Uma dose adequada é uma quantida-de de um composto que, quando administrada conforme descrito acima, écapaz de promover, por exemplo, uma resposta imune antitumor, antiviral ouantibacterial, e é pelo menos 10-50% do nível basal (isto é, não tratado). Talresposta pode ser monitorada pela medição dos anticorpos antitumor em umpaciente, ou por geração dependente de vacina de células T citolíticas capa-zes de matar, por exemplo, as células tumorais do paciente, as células vi-ralmente infectadas do paciente, ou as células bacterialmente infectadas dopaciente in vitro. Tais vacinas devem também serem capazes de causar umaresposta imune que conduz a um efeito clínico aperfeiçoado (por exemplo,remissões mais freqüentes, sobrevivência livre de doença completa ou par-cial ou mais longa) em pacientes vacinados, conforme comparado a pacien-tes não vacinados. Tipicamente a quantidade das titulações virais estará en-tre 1,0 X 104 pfu/animal e 1,0 X 1015 pfu/animal. Os tamanhos da dose a-dequados variarão com o tamanho do paciente, mas tipicamente variará decerca d 0,01 ml a cerca de 10 ml, mais tipicamente de cerca de 0,025 ml acerca de 7,5 ml, mais tipicamente de cerca de 0,05 ml a cerca de 5 ml.Aqueles versados na técnica apreciarão que o tamanho da dose pode serajustado baseado no paciente particular, ou na doença particular ou enfer-midade sendo tratada. Para a administração oral, o vetor adenoviral quiméri-co pode ser convenientemente formulado em uma pílula.
Em geral, uma dosagem apropriada e regime de tratamentoproporciona o(s) composto(s) em uma quantidade suficiente para proporcio-nar benefício terapêutico e/ou profilático. Tal resposta pode ser monitoradapelo estabelecimento de um efeito clínico aperfeiçoado (por exemplo, remis-sões mais freqüentes, sobrevivência livre de doença completa ou parcial oumais longa) em pacientes tratados, conforme comparado a pacientes nãotratados. Tais respostas imunes podem geralmente serem avaliadas usando-se proliferação padrão, citotoxicidade ou ensaios de citoquina descritos aci-ma, que podem ser realizados usando-se amostras obtidas de um pacienteantes e após tratamento.
Por exemplo, a detecção de imunocomplexos formados entrepolipeptídeos imunogênicos e anticorpos no fluido corpóreo que são especí-ficos para polipeptídeos imunogênicos, pode ser usada para monitorar a efi-ciência de terapia, que envolve um polipeptídeo inunogênico particular, parauma doença Ou enfermidade em que o polipeptídeo inumogênico é associa-do. As amostras de fluido corpóreo tomadas de um indivíduo antes e subse-qüente a iniciação de terapia podem ser analisadas para os imunocomplexospelas metodologias descritas acima. Brevemente, o número de imunocom-plexos detectado em ambas as amostras é comparado. Uma mudança subs-tancial no número de imunocomplexos na segunda amostra (iniciação depós-terapia), relativa à primeira amostra (pré-terapia), reflete terapia bem-sucedida.
A. Administração das Composições da Presente Invenção
De acordo com os métodos da presente invenção, uma compo-sição compreendendo o vetor adenoviral quimérico é administrada por qual-quer via não-parenteral (por exemplo, oral, intranasal ou mucosalmente via,por exemplo, a vagina, pulmões, glândulas salivares, cavidades nasais, in-testino delgado, cólon, reto, amídala, ou emplastros de Peyer). A composi-ção pode ser administrada sozinha, ou com um adjuvante conforme descritoacima. Em algumas concretizações, os adjuvantes são codificados por umaseqüência de ácido nucléico (por exemplo, um ácido nucléico que codificaIL-2, GM-CSF, IL-12, ou flagellin bacterial). Em algumas concretizações dapresente invenção, o adjuvante é administrado ao mesmo tempo, conformea composição. Em outras concretizações da presente invenção, o adjuvanteé administrado após a composição, por exemplo, 6, 12, 18, 24, 36, 48, 60 ou72 horas após administração da composição.
B. Detecção de uma Resposta Imune a Antíqenos de Interesse
Uma resposta imune ao polipeptídeo heterólogo pode ser detec-tada usando-se qualquer meio conhecido na técnica, incluindo, por exemplo,detecção de ativação específica de células T CD4+ ou CD8+, ou pela detec-ção da presença de anticorpos que se ligam especificamente ao polipeptídeo.
A ativação específica de células T CD4+ou CD8+associada comuma resposta imune mediada por mucosal, humoral ou célula, pode ser de-tectada em uma variedade de modos. Os métodos de detecção de ativaçãode célula T específica incluem, mas não estão limitados a, detecção da proli-feração de células T, a produção de citoquinas (por exemplo, linfoquinas), oua geração de atividade citolítica (isto é, geração de células T citotóxicas es-pecíficas para o polipeptídeo imunogênico). Para células T CD4+, um métodopreferido para detecção de ativação de célula T específica é a detecção daproliferação de células T. Para células T CD4+, um método preferido paradetecção de ativação de célula T específica é a detecção da proliferação decélulas T. Para células T CD8+, um método preferido para detecção de ati-vação de célula T específica é a detecção da geração de atividade citolíticausando-se ensaios de liberação de 51Cr (vide, por exemplo, Brossat e Be-van, Blood 90(4): 1594-1599 (1997) e Lenz et ai, J. Exp. Med. 192(8):1135-1142(2000)).
A detecção da proliferação de células T pode ser efetuada poruma variedade de técnicas conhecidas. Por exemplo, a proliferação de célu-la T pode ser detectada pela medição da taxa de síntese de DNA. As célulasque foram estimuladas a proliferarem exibem uma taxa aumentada de sín-tese de DNA. Um modo típico de medir a taxa de síntese de DNA é, porexemplo, por culturas de pulso-etiquetamento de células T com timidina triti-atada, um precursor de nucleosídeo que é incorporado em um DNA recen-temente sintetizado. A quantidade de timidina tritiatada incorporada pode serdeterminada usando-se um espectrofotomedidor de cintilação líquida. Outrosmodos para detectar proliferação de célula T incluem medição do aumentona produção de interleukin-2(IL-2), fluxo de Ca2+, ou percepção de corante,tal como 3-(4,5-dimetiltiazol-2-il))-2,5-difeniltetrazolium. Alternativamente, asíntese de Iinfoquinas (por exemplo, interferon-gama) pode ser medida, ou onúmero relativo de células T que pode responder ao polipeptídeo imunogê-nico pode ser quantificado.
As respostas imunes de anticorpo (Respostas imunes humoraisaka ou respostas de célula B), incluindo respostas de anticorpo mucosal,podem ser detectadas usando-se imunoensaios conhecidos na técnica [Tuc-ker et ai, Mol. Therapy, 8, 392-399 (2003); Tucker et ai, Vaccine, 22, 2500-2504 (2004)]. Imunoensaios adequados incluem a técnica de imunoensaiode intercalamento de anticorpo monoclonal duplo de David et al (Patente dosEstados Unidos N2 4.376.110); ensaios de intercalamento de anticorpo mo·noclonal-policlonal (Wide et al., em Kirkham e Hunter, eds., Radioimmune-assay Methods, E e S. Livingstone, Edinburgh (1970)); o método de " wes-tern blot" de Gordon et al. (Patente dos Estados Unidos Ne 4.452.901); imu-noprecipitação de Iigante etiquetado (Brown et al (1980) J.-BioL Chem.255:4980-4983); ensaios imunoabsorventes ligado por enzima (ELISA) con-forme descrito, por exemplo, por Raines et àl. (1982) J. Biol. Chem.257:5154-5160; técnicas imunocitoquímicas, incluindo o uso de fluorocromos(Brooks etal. (1980) Clin. Exp. Immunol. 39:477); e neutralização de ativida-de (Bowen-Pope etal. (1984) Proc. Natl. Acad. Sei. USA 81:2396-2400). Emadição aos imunoensaios descritos acima, um número de outros imunoen-saios são disponíveis, incluindo aqueles descritos nas Patentes dos EstadosUnidos Ngs 3.817.827; 3.850.752; 3.901.654; 3.935.074; 3.984.533;3.996.345; 4.034.074; e 4.098.876.
Exemplos
Os seguintes exemplos são pretendidos para ilustrarem, masnão limitarem a presente invenção.
Exemplo 1: Construção de um Vetor Adenoviral Quimérico (DSI)
Para demonstrar que agonistas TLR-3 podem aperfeiçoar res-postas imunes adaptativas a antígenos expressos de interesse, vários veto-res adenovirais quiméricos diferentes foram construídos, que compreendemseqüências de ácido nucléico que codificam vários antígenos diferentes deinteresse. Neste exemplo, o ácido nucléico que codifica gp 120 (a partir doPrograma de Reagente de Referência NIH AIDS) foi colocado sob controlede um promotor de CMV com um pequeno intron imediatamente a montantedo códon de partida no vetor de lançadeira (pShuttle, Qbiogene). Uma caldapoli A de bGH foi colocada a jusante do ácido nucléico que codifica gp120.
A seqüência de vetor é colocada em SEQ ID Ns:1. A recombinação homólo-ga com o vetor pAd (Qbiogene) foi realizada para gerar um vetor capaz deproduzir Ad recombinante (E1/E2 retirado), que contém o ácido nucléico quecodifica gp120. DSI foi gerado pela transferência do constructo de expressãopAd-CMV-gp120 nova em 293 células. As titulações foram medidas por mé-todos padrões.
Exemplo 2: DSI (vetor mais aqonístico TLR-3) é superior a rAd5 padrão paraindução de uma resposta imune específica de antíqeno
Para determinar se a adição de agonístico TLR-3 podia aperfei-çoar respostas imunes adaptativas, 10x107 PFU de ou rAd-CMV-gp120 mais5 ug/ml de poli l:C (DSI), ou rAd-CMV-gap-120 somente (rAd5), foram admi-nistrados a animais por administração oral nas semanas 0 e 3. Ambos osvetores expressam HIV gp120 sob controle do promotor de CVM e usamadenovírus tipo 5 retirado de recombinante E1/E3. Titulações de anticorpo agp120 foram medidas no plasma 3 e 6 semanas após a administração inicialpor anti-gp120 IgG ELISA, conforme descrito em Tucker, et ai, MoL Ther8:392 (2004)). Conforme mostrado na Figura 1, DSI se portou significante-mente melhor do que rAd5 na indução de respostas de anticorpo para gp120ambos em 3 e 6 semanas pós administração oral inicial. Em particular, a titu-lação de anticorpo média para gp120 foi 100 vezes melhor com o grupo DSIdo que com o grupo rAd5 na semana 6. Parece também que o grupo DSI foiagrupado por re-administração na semana 4 em que a titulação média au-mentou mais do que 20 vezes entre as semanas 3 e 6 onde o grupo rAd5mostrou somente um leve aumento na titulação de anticorpo média. Os re-sultados demonstraram que a adição de um agonístico TLR-3 pode aperfei-çoar grandemente respostas de anticorpo mediadas por Ad5 a antígenos deinteresse em seguida a administração oral de um vetor adenovírus quiméricocompreendendo um ácido nucléico que codifica o antígeno de interesse.
Como um controle positivo para o ensaio, soro de um animal injetado subcu-taneamente com gp120 mais Adjuvante Completo de Freund foi tambémmedido no anti-gp120 ELISA na semana 3. Os animais não-tratados e ani-mais administrados com o análogo dsRNA somente (dsRNA) serviram comocontroles negativo e antecedentes respectivamente para a ELISA. Cadagrupo contém 6 animais.
I Exemplo 3: Construção de Um Segundo Vetor Adenoviral Quimérico (DSIb)e um Terceiro Vetor Adenoviral Quimérico (DS1c)
Um ácido nucléico que codifica proteína fluorescente verde(GFP) foi inserido em pShuttle-CMV (Qbiogene) usando-se digestões de en-zima de restrição padrão. O plasmídeo pShuttleCMV-GFP foi combinado porrecombinação.homóloga com o vetor pAd(Qbiogene), conforme descrito an-tes, de modo a gerar um vetor capaz de produzir recombinante Ad(E1/E3retirado) compreendendo uma seqüência de ácido nucléico que codificaGFP. Um ácido nucléico que codifica hemaglutinin (HA) de gripe A/PR/8/34foi clonado e colocado no vetor pShuttle-CMV (Qbiogene) (SEQ ID Ne: 13). Oplasmídeo pShuttleCVM-HA (PR/8) foi combinado por recombinação homó-loga com o vetor pAd(Qbiogene), conforme descrito antes, de modo a gerarum vetor capaz de produzir recombinante Ad(E1/E3 retirado) compreenden-do uma seqüência de ácido nucléico que codifica HA. O recombinante Ad foigerado por transfecção do novo constructo de expressão de pAd-CMV-GFPe pAd-CMV-HA em 239 células. As titulações foram medidas por métodospadrões.
Exemplo 4: DSIB (Ad-CMV-GFP mais agonístico LTR-3) e DS1c (Ad-CMV-HA mais agonístico TLR-3) é superior a rAd5 padrão para indução de umaresposta imune específica de antígeno.
1,0x107 PFU de ou Ad-CMV-GFP mais 5 ug/ml de poli l:C(DS1b), ou Ad-CMV-GFP (rAd5), foram administrados a animais por admi-nistração oral na semana 0. Ambos os vírus expressam o GFP sob controledo promotor de CVM e usam adenovírus tipo 5 retirado de recombinanteE1/E3. Titulações de anticorpo para GFP foram medidas no plasma 3 sema-nas após a administração de vírus inicial por anti-GFP IgG ELISA. Conformemostrado na Figura 2, o grupo DS 1b se portou significantemente melhor doque rAd5 na indução de respostas de anticorpo para GFP em 3 semanaspós administração oral inicial.
As respostas de célula T CD8+ para GFP foram medidas por tra-tamento de manchamento de esplenócitos. Os animais foram vacinados nassemanas 0, 4, 8, e os baços foram colhidos na semana 10. Os esplenócitosforam manchados com CD8-FITC, e o tetrâmero que reconhece o epítopeimunodominante para GFP em Balb/c camundongos. Os resultados mostramque administração oral do vetor DS1b foi estatisticamente melhor do que rAdsozinho na indução de células CD8 de tetrâmero (Figura 2b).
1,0x107 PFU de ou Ad-CMV-HA mais 5 ug/ml de poli l:C (DS1c),ou Ad-CMV-HA (rAd5), foram administrados a animais por administraçãooral na semana 0. Ambos os vírus expressam HA sob controle do promotorde CVM e usam adenovírus tipo 5 retirado de recombinante E1/E3. Titula-ções de anticorpo para HA foram medidas no plasma 3 semanas após aadministração de vírus inicial por anti-PR8/34 IgG ELISA. O procedimentopara medição de respostas de anticorpo é similar àquele descrito antes, coma exceção que as placas de ELISA foram revestidas com 5 ug/ml de IisatoA/PR8/34 total (Advanced Biotechnology Incorporated, Gaithersburg, MD).Conforme mostrado na Figura 2C, o grupo DS1c se portou significantementemelhor (aproximadamente 100 vezes melhor) do que rAd5 na indução derespostas de anticorpo para gripe em 3 semanas pós administração oral ini-cial. Os resultados destes estudos demonstraram também que a aproxima-ção de usar-se agonístico TLR-3 junto com um vetor adenoviral recombinan-te quimérico pode ser geralmente aplicada a antígenos heterólogos diferen-tes múltiplos, com um aperfeiçoamento de 100 vezes na titulação de anticorpo.Exemplo 5: As Vias Não-Parenterais de Distribuição São Superiores a ViasParenterais
A distribuição intramuscular foi testada por injeção diretamentede 1,0x107 pfu de pAd-CMV-gp120 (DS10+/-poli l:C em 5 ug/ml nos quadrí-cepes de animais. Titulações de IgG de soro de plasma para GFP forammedidas conforme descrito acima. Cada grupo continha 6 animais. Confor-me mostrado na Figura 3A, titulações de anticorpo significantes em gp120foram observadas em 3 semanas pós administração no grupo com agonísti-co TLR-3 (i.m. rAd+PI). (Figura 3A).
A administração intranasal foi testada por administração de 20 ulde 1,1x106 pfu de DS1c+/5 ug/ml de poli l:C na cavidade nasal de camun-dongos. Os camundongos foram levemente anestesiados com isofluranoantes da administração do vírus formulado em solução salina estéril. Os re-sultados mostram que o rAd-CMV-HA mais poli l:C (DS1c) tinham titulaçõesde anticorpo levemente mais altas comparadas a animais dado o padrãorAd-CMV-HA. Os resultados são plotados como animais individuais para osgrupos DS1c (N=6) e rAd (N=5). Animais não-tratados (N=4) são usadospara controles negativos.
Exemplo 6: Construção de um aqonístico TLR-3 expresso.
Um segmento curto de 45 bp de DNA foi sintetizado por ordena-ção de oligos de DNA que quando recozidos juntos formam um segmento de45 bp designado para produzir um grampo de cabelo de RNA de filamentoduplo (GAAACGATATGGGCTGAATACGGATCCGTATTCAGCCCATATCGTTTC) (SEQID NQ:10). Este segmento curto (denominado Iucl) foi clonado no plasmídeopSK contendo o promotor beta actinahumano e uma cauda A poli BGH. Esteplasmídeo é denominado pSklucl.
Exemplo 7: As funções pSK-luc1 em culturas de célula dendrítica similars apoli l:C, os efeitos de poli l:C e rAd são aditivos.
Para determinar se o agonístico TLR-3 expresso do Exemplo 6acima pode funcionar como um indutor de citoquinas pró-inflamatórias e ma-turação de célula dendrítica similares a poli l:C Iigante de TLR-3, um agonís-tico dsTLR-3 expresso foi testado em culturas de célula dendrítica. Tutanosde osso de fêmures de camundongos Balb/c foram cultivados com Iigante ftl-3 (200 ng/m), 5% de soro, em meio DMEM de modo a produzir culturas decélula dendrítica primária. Cinco dias após as culturas de tutano de ossoprimária serem assentadas, 293 células foram transfectadas com, ou pSk-Iuc1, pSK-beta 2 (um segmento longo de beta galactosidase que forma umgrampo de cabelo de 200 bp), ou pcDNA3 (vetor de expressão vazio). No dia6, as células transfectadas foram tratadas por irradiação UV (20 segundos a40 kUcm2) para causar apoptose, e estas células foram dadas para as célu-las dendríticas. Ou poli l:C (1 ug/ml), rAd (1 pfu/célula), rAd + poli IrC1 células transfectadas pSK-luc1, células transfectadas pSK-bera2, ou células trans-fectadas pcDNA3, foram dados para as células dendríticas, e cultivadas du-rante toda a noite. Conforme mostrado na Figura 4A, células transfectadaspSK-luc1 podem aperfeiçoar significantemente ativação de célula dendríticaconforme medida pelo camundongo IL-6 ELISA. Os resultados deste expe-rimento também mostram que a combinação de rAd mais Iigante de TLR-3(poli l:C) juntos pode aperfeiçoar grandemente a atividade da célula dendríti-ca.
Ligantes adicionais também foram testados. O agonístico TLR-3colocado em SEQ ID Ns: 11 (ml) também forma um grampo de cabelo de ds-RNA de aproximadamente o mesmo tamanho como Iucl. Estes foram pro-duzidos por sobreposição de oligonucleotídeos e recozimento dos mesmosjuntos antes de clonagem no vetor pSK sob controle do promotor beta acti-nahumano. Os vetores foram transfectados em 293 células e dados às célu-las dendríticas primárias, conforme descrito antes. Conforme mostrado naFigura 4B, estes Iigantes adicionais podem ativar células dendríticas simila-res àquelas do Iigante Iucl (Figura 4B).
Exemplo 8: Construção de um Quarto Vetor Adenoviral Quimérico (DS2) evetores de clonagem rápida (DS2beta-luc e DS2C-luc).
Um ácido nucléico que codifica gp120 (do Programa de Reagen-te de Pesquisa e Referência de NIH AIDS) foi colocado sob controle de umpromotor de CVM com um pequeno intron imediatamente a montante do có-don de partida no vetor de lançadeira (pShuttleCMV, Qbiogene). Uma caudaA poli A de bGH foi colocada a jusante do ácido nucléico que codifica gp120.O agonístico dsRNA TLR-3 Iucl sob o controle do promotor beta actinahu-mano e poli A (descrito no exemplo 5 acima) foi inserido no vetor gp120 p-Shuttle, tal que ambos o ácido nucléico que codifica gp120 e o ácido nucléi-co que codifica agonístico TLR-3 estavam contidos em um vetor simples sobo controle de dois promotores separados. A orientação da expressão do áci-do nucléico que codifica o antígeno de interresse e a expressão do agonísti-co TLR-3 é ilustrada na Figura 5.
Dois vetores de lançadeira genéricos denominados DS2beta-luc(SEQ ID N9:14) e DS2-luc (SEQ ID Ng: 15) foram também construídos tal queácido nucléico que codifica qualquer antígeno de interesse podia ser inse-rido sob o promotor de CMV e, ou o promotor beta actinahumano ou o pro-motor de CMV, é usado para acionar expressão de um agonístico dsRNATLR-3. Em particular, o vetor DS2-luc tem um local Kpn 1 único que um áci-do nucléico que codifica um antígeno de interesse pode facilmente ser clo-nado. A proposta destes vetores é produzir construção de vetor subseqüentemais fácil porque um ácido nucléico que codifica qualquer antígeno de inte-resse podia ser inserido no local de clonagem para manufaturar rapidamenteum vetor capaz de induzir anticorpo e respostas de célula T contra o antíge-no de interesse. Recombinação homóloga de DS2 com o vetor pAd (Qbio-gene) foi realizada como antes de modo a gerar um vetor capaz de produzirrecombinante Ad (E1/E3 retirado) que continha um ácido nucléico que codifi-ca GFP e um ácido nucléico que codifica o agonístico dsRNA LR-3 Iuc1.
O recombinante Ad foi gerado por transfecção do novo constructo de ex-pressão de pAd-betaactin-luc1-CMV-gp120 em 293 células. As titulaçõesforam medidas por métodos padrões.
Exemplo 9: Indução de uma reposta imune específica de antígeno em se-guida a distribuição oral de DS2.
1,0x107 PFU de, ou pAd-CMV-gp120 mais o agonístico TLR-3Iucl (DS2), ou pAd-CMV-gp120 (rAd5), foram administrados a animais poradministração oral na semana. Ambos os vírus expressam gp120 sob con-trole do promotor de CVM e usam adenovírus tipo 5 retirado de recombinan-te E1/E3. Titulações de anticorpo para gp120 foram medidas no plasma 3semanas após a administração de vírus por anti-gp120 IgG ELISA. O proto-colo ELISA foi descrito antes (Tucker, et al, Mol. Therapy 8:392 (2004)). Osresultados demonstraram que DS2 pode induzir aproximadamente um aper-feiçoamento de 2 Iog na titulação de anticorpos para gp120, o antígeno hete-rólogo usado no experimento. O vetor DS2 compreende uma seqüência deácido nucléico que codifica expressão de gp120 e uma seqüência de ácidonucléico que codifica expressão de um agonístico dsRNA TLR03. Como umcontrole positivo para o ensaio, soro de dois animais injetados subcutanea-mente com 10 microgramas de proteína de gp120 mais Adjuvante Completode Freund, foi também medido no anti-gp120 ELISA. Os animais não-tratados serviram como controles negativos para ELISA. Cada grupo conti-nha 6 animais. Os resultados são ilustrados na Figura 6.Exemplo 10: Indução de um resposta imune específica de antígeno em se-guida a distribuição oral de DS3.
1,0x107 PFU de, ou pAd-CMV-HA de gripe (de A/PFI/8/34) maiso ácido poliuridílico Iigante TLR7/8 (DS3), ou pAd-CMV-HA (rAd5), foramadministrados a animais por administração oral na semana 0. Ambos os ví-rus expressam HA de gripe sob controle do promotor de CVM e usam ade-novírus tipo 5 retirado de recombinante E1/E3. Titulações de anticorpo paraHA foram medidas no plasma 3 semanas após a administração de vírus porHA de anti-gripe IgG ELISA. Cada grupo continha 6 animais. Os resultadossão ilustrados na Figura 7.
Exemplo 11: Construção de um quinto, sexto e sétimo vetor adenoviral qui-mérico para, e (DS2b, DS2b e ND1.1 214).
O gene de HA de gripe (A/lndo/5/2005) foi sintetizado por Cel-Tek (Nashville, TN), e colocado no vetor pShuttleCMV (Qbiogene) que tinhaum promotor de CMV com um pequeno intron imediatamente a montante docódon de partida no vetor de lançadeira. O Iucl DNA com promotor beta ac-tinahumano e poli A (descrito no exemplo 5) foram colocados no vetor a ju-sante do antígeno, na orientação mostrada na figura 5 para DS2b. A se-qüência de Iuc 1 é (gaaacgatatgggctgaatacggatccgtattcagcccatatcgtttc)(SEQ ID NQ:10), e o vetor pShuttle completado é colocado em SEQ ID NQ:6.
Uma orientação alternativa de Iucl com promotor em um vetor de lançadeiraé descrita como SEQ ID Ne:7, e é designada DS2b-for. Nós também construímos outro vetor pShuttle (denominado DS2bC-HA) (SEQ ID Ne:16) quecompreende dois promotores separados que acionam expressão do agonís-tico TLR-3 Iuc1 e HA de gripe acima descrito. A recombinação homólogacom o vetor pAd (Qbiogene) foi realizada como antes de modo a gerar veto-res capazes de produzir recombinante Ad (E1/E3 retirado) que continha oácido nucléico que codifica HA e o agonístico TLR-3 Iucl sob promotoresseparados. O recombinante Ad foi gerado por transfecção do novo construc-to pAd em 293 células. As titulações foram medidas por métodos padrões.
O vetor pAD completado contendo DS2C-luc foi denominado ND1.1 214 edepositado no depósito de patente ATCC em 22 de fevereiro de 2007 (Ma-nassus, VA). A seqüência de ácido nucléico deste vetor adenoviral quiméricoé colocada em SEQ ID N9:17. O ácido nucléico que codifica o antígeno hete-rólogo está no texto em negrito, e é flanqueado por um local de reconheci-mento Cla I na extremidade 5', e um local de reconhecimento Not I na ex-tremidade 3'. A seqüência de ácido nucléico que codifica os agonísticosTLR-3 está em itálico, com a seqüência Iigadora em negrito. Uma seqüênciade ácido nucléico que codifica qualquer antígeno de interesse, e uma se-qüência de ácido nucléico que codifica qualquer agonístico TLR-3 expresso,podem ser inseridas no vetor adenoviral quimérico.
Exemplo 12: Indução de uma resposta imune específica de antígeno em se-guida a distribuição oral de DS2b.
1,0x107 PFU de, ou pAd-CMV-HA mais os agonísticos TLR-3Iucl na orientação reversa (DS2b-for), ou orientação de avanço (DS2b), oupAd-CMV-HA (rAd5), foram administrados a animais por administração oralna semana 0. Estes vírus expressam HA de gripe de antígeno sob controledo promotor de CVM, e usam adenovírus tipo 5 retirado de recombinanteE1/E3. Titulações de anticorpo para HA foram medidas no plasma 3 sema-nas após a administração de vírus por HA de anti-HA IgG ELISA. Os resul-tados demonstraram que o vetor DS2b induziu respostas de anticorpo paraproteína HA maior do que o vetor rAd padrão (rAd5). O vetor DS2b contémrAd5 que expressa HA1 bem como expressa um agonístico de receptor 3similar a toll (TLR-3), um grampo de cabelo de RNA de filamento duplo, de-monstrando que o uso do Iigante de dsRNA pode aperfeiçoar respostas imu-nes adaptativas a antígenos de interesse. Conforme mostrado na Figura 8Ae Figura 6, dsRNA expresso pode aperfeiçoar respostas imunes adaptativasa antígenos heterólogos diferentes múltiplos. Os animais não-tratados servi-ram como controle negativo para ELISA. Cada grupo continha 6 animais.
Os vetores na orientação oposta (DS2for) foram examinados pa-ra respostas de anticorpo em seguida, ou a administração oral, ou intramus-cular de 1 ,OxIO7 pfu de vírus por animal nas semanas 0 e 5. As respostas deanticorpo para HA foram medidas nas semanas 4 e 7 pós administração ini-cial. Conforme mostrado na Figura 8B, o vetor de orientação oposta podetambém induzir respostas de anticorpo substanciais para antígenos heteró-logos. Os vetores DS1b e DSIbfor induzem respostas similares para HA noponto de tempo de semana 4. Significantemente, o efeito de agrupamentoda resposta de anticorpo foi demonstrado com o vetor DSIfor1 e mostrouque doses múltiplas podiam ser usadas para aumentar as respostas de anti-corpo ao antígeno heterólogo. Outro exemplo de potencial da aproximaçãode vetor adenoviral quimérico foi demonstrado também. O vetor ND1. 1 214foi dado a animais por administração oral (1,0 χ IO7 pfu) ou intranasal (3x106pfu), e as respostas de anticorpo ao antígeno heterólogo foram medidas nasemana 3. Conforme mostrado na Figura 8C, respostas de anticorpo subs-tanciais para HA foram medidas em seguida a administração oral, bem alémdos valores típicos de uma administração oral simples de vetor rAd.
Todas as publicações, publicações de patente, patentes, pedi-dos de Nqs de Acesso no Banco de Genes citados neste relatório descritivosão aqui incorporados por referência em sua totalidade para todas as pro-postas como se cada publicação individual, publicação de patente, ou paten-tes, fossem especificamente e individualmente indicadas para serem incor-porados por referência.Listagem de Seqüência Informal
SEQ ID NO:1 (DSl)
taacatcatc aataatatac cttattttgg attgaagcça atatgataatgagggggtgg agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtgacgtagtagt gtggcggaag tgtgatgttg caagtgtggc ggaacacatgtaagcgacgg atgtggcaaa agtgacgttt ttggtgtgcg ccggtgtacacaggaagtga caattttcgc gcggttttag gcggatgttg tagtaaatttgggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataagaggaagtgaaa
tctgaataattttgtgttactcatagcgcgtaatactggtaccgcggccgcctcgagtctag
agatCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGXT.TTCCC
AGTCACGACGTTGTAAAACGACGGCCAGTGAATTGTAAT ACGACT CACTÁTAGGGCGAATTG
GGTACTGGCCAcagagcttggcccattgcatacgttgtatccatatcataatatgtacattt
atattggctcatgtccaacattaccgccatgttgacattgattattgactagttattaatag
taatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataacttac
ggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgt
atgttcccatagtaacgccaatagggactttccattgacgtcaatgggtggagtatttacgg
taaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgt
caatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggàctttccta
cttggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggcagtac
atcaatgggcgtggatagcggtttgactcacggggatttccaagtctccaccccattgacgt
caatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccg
ccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtctatataagcagagctcgt
ttagtgaaccgtcagatcgcctggagacgccatccacgctgttttgacctccatàgaagaca
ccgggaccgatccagcctgactctagCctAGCTCtgaagttggtggtgaggccctgggcagg
ttggtatcaaggttacaagacaggtttaaggagaccaatagaaactgggcatgtggagacag
agaagactcttgggtttctgataggcactgactctctctgcctattggtctattttcccacc
cttaggctgctggtctgagcctagGAGATCTCTCGAGGTCGACGGTATAGCTTCTAGAGATC
CCTCGACCTCGAGATCCATTGTGCTCTAAAGGAGATACCCGGCCAGACACCCTCACCTGCGG
TGCCCAGCTGCCCAGGCTGAGGCAAGAGAAGGCCAGAAACCATGCCCATGGGGTCTCTGCAA
CCGCTGGCCACCTTGTACCTGCTGGGGATGCTGGTCGCTTCCGTGCTAGCTGÍGGAGAAGCT
GTGGGTGACTGTATACTATGGGGTGCCTGTGTGGAAGGAGGCCACCACCACCCTGTTCTGTG
CCTCTGATGCCAAGGCCTATGACACTGAGGTCCACAATGTCTGGGCCACCCATGCCTGTGTG
CCCACTGACCCCAACCCTCAGGAGGTGGTGCTGGAGAATGTGACTGAGCACTTCAACATGTG
GAAGAACAACATGGTGGAGCAGATGCAGGAGGACATCATCAGCCTGTGGGACCAGAGCCTGA
AGCCCTGTGTGAAGCTGACCCCCCTGTGTGTGACCCTGAACTGCAAGGATGTGAATGCCACC
AACACCACCAATGACTCTGAGGGCACTATGGAGAGGGGTGAGATCAAGAACTGCAGCTTCAA
CATCACCACCAGCATCAGGGATGAGGTGCAGAAGGAGTATGCCCTGTTCTACAAGCTGGATG
TGGTGCCCATTGACAACAACAACACCAGCTACAGGCTGATCAGCTGTGACACCTCTGTGATC
ACCCAGGCCTGCCCCAAGATCAGCTTTGAGCCCATCCCCATCCACTACTGTGCCCCTGCTGG
CTTTGCCATCCTGAAGTGCAATGACAAGACCTTCAATGGCAAAGGCCCTTGCAAGAATGTGA
GCACTGTGCAGTGCACTCATGGCATCAGGCCTGTGGTGAGCACCCAGCTGCTGCTGAATGGC
AGCCTGGCTGAGGAGGAGGTGGTGATCAGGTCTGACAACTTCACCAACAATGCCAAGACCAT
CATTGTGCAGC
TGAAGGAGTCTGTGGAGATCAACTGCACCAGGCCCAACAACAACACCAGGAAGAGCATTCAC
ATTGGCCCTGGCAGGGCCTTCTACACCACTGGGGAGATCATTGGGGACATCAGGCAGG
CCCACTGCAACATCAGCAGGGCCAAGTGGAATGACACCCTGAAGCAGATTGTGATCAAGCTG
AGGGAGCAGTTTGAGAACAAGACCATTGTGTTCAATCACAGCTCTGGTGGTGATCCTGAGAT
TGTGATGCACAGCTTCAACTGTGGTGGTGAGTTCTTCTACTGCAACAGCACCCAGCTGTTCA
ACAGCACCTGGAACAACAACACTGAGGGCAGCAACAACACTGAGGGCAACACCATCACCCTGCCTTGCAGGATCAAGCAGATCATCAACATGTGGCAGGAGGTGGGCAAGGCCATGTATGCTCCTCCCATCAGGGGCCAGATCAGGTGCAGCAGCAACATCACTGGCCTGCTGCTGACCAGGGATGGTGGCATCAATGAGAATGGCACTGAGATTTTCAGGCCTGGTGGTGGGGACATGAGGGACAACTGGAGGTCTGAGCTGTACAAGTACAAGGTGGTGAAGATTGAGCCCCTTGGTGTGGCTCCCACCAAGGCTAAGCGCAGGGTGGTGCAGAGGGAGAAGcgcgctgtgggctgaggatccCGAGGGTGAGTGCTCCTGCCTGGACGCATCCCGGCTATGCAGCCCCAGTCCAGGGCAGCAAGGCAGGCCCCGTCTGCCTGTTCACCCGGAGCCTCTGCCCGCCCCACTCATGCTCAGGGAGAGGGTCTTCTGGCTTTTTCCCAGGCTCTGGGCAGGCACAGGCTAGGTGCCCCTAACCCAGGCCCTGCACACAaaggggcaggtgctgggctcagacctgccaagagccatatccgggaggaccctgcccctgacCTAAGCCCACCCCAAAGGCCAAACTCTCCACTCCCTCAGCTCGGACACCTTCTCTCCTCCCAGATTCCAGTAACTCCCAATCTTCTCTCTGCAGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCeCAGGTAAGCCAGCCCAGGCCTCGCCCTCCAGCTCAAGGCGGGACAGGTGCCCTAGAGTAGCCTGCATCCAGGGACAGGCCCCAGCCGGGTGCTGACACGTCCACCTCCATCTCTTCCTCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCÇAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCGGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGTGGGACCCGTGGGGTGCGAGGGCCACATGGACAGAGGGCGGCTCGGCCCACCCTCTGCCCTGAGAGTGACCGCTGTACCAACCTCTGTCCTACAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGXGGACAAGAGCAGGTGGCAGCAGGGGAAÇGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGAGTGCGACGGCCGCAGGTAAGCCAGCCCAGGCCTCGCGCTCCAGCTCAAGGCGGGACAGGTGCCCTAGAGTAGCCTGCATCCAGGGACAGGCCCCAGCCGGGTGGTGACACGTCCACCTCCATCTCTTCCTCAGGTCTGCCCGGGTGGCATCCCTGTGACCCCTCCCCAGTGCCTCTCCTGGCCCTGGAAGTTGCCACTCCAGTGCCCACCAGCCTTGTCCTAATAAAATTAAGTtgcatcattttgtctgactaggtgtccttctataatattatggggtggaggggggtggtatgGAGCAAGGGGÇCCAAGTTAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAAACTCATCAATGTATCTTATCATGTCTGgatctggg cgtggttaag
421 ggtgggaaag aatatataag gtgggggtct tatgtagttttgtatctgtt ttgcagcagc
481 cgccgccgcc atgagcacca actcgtttga tggaagcattgtgagctcat atttgacaac
541 gcgcatgccc ccatgggccg gggtgcgtca gaatgtgatgggctccagca ttgatggtcg
601 ccccgtcctg cccgcaaact ctactacctt gacctacgagaccgtgtctg gaacgccgtt
661 ggagactgca gcctccgccg ccgcttcagc cgctgcagccaccgcccgcg ggattgtgac
721 tgactttgct ttcctgagcc cgcttgcaag· cagtgcagcttcccgttcat ccgcccgcga
781 tgacaagttg acggctcttt tggcacaatt ggattctttgacccgggaac ttaatgtcgt
841 ttctcagcag ctgttggatc tgcgccagca ggtttctgccctgaaggctt cctcccctcc
901 caatgcggtt taaaacataa ataaaaaacc agactctgtttggatttgga tcaagcaagt961 gtcttgctgt ctttatttag gggttttgcg cgcgcggtaggcccgggacc agcggtctcg
1021 gtcgttgagg gtcctgtgta ttttttccag gacgtggtaa
aggtgactct ggatgttcag
1081 atacatgggc ataagcccgt ctctggggtg gaggtagcaccactgcagag cttcatgctg
1141 cggggtggtg ttgtagatga tccagtcgta gcaggagcgctgggcgtggt gcctaaaaat
1201 gtctttcagt agcaagctga ttgccagggg caggcccttggtgtaagtgt ttacaaagcg
1261 gttaagctgg gatgggtgca tacgtgggga tatgagatgcatcttggact gtatttttag
1321 gttggctatg ttcccagcca tatccctccg gggattcatg
ttgtgcagaa ccaccagcac
. 1381 agtgtatccg gtgcacttgg gaaatttgtc atgtagcttagaaggaaatg cgtggaagaa
1441 cttggagacg cccttgtgac ctccaagatt ttccatgcattcgtccataa tgatggcaat
1501 gggcccacgg gcggcggcct gggcgaagat atttctgggatcactaacgt catagttgtg
1561 ttccaçfgatg agatcgtcat aggccatttt tacaaagcgcgggcggaggg tgccagactg
1621 cggtataatg gttccatccg gcccaggggc gtagttaccctcacagattt gcatttccca
1681 cgctttgagt tcagatgggg ggatcatgtc tacctgcggggcgatgaaga aaacggtttc
1741 cggggtaggg gagatcagct gggaagaaag caggttcctgagcagctgcg acttaccgca
1801 gccggtgggc ccgtaaatca cacctattac cgggtgcaactggtagttaa gagagctgca
18 61 gctgccgtca tccctgagca ggggggccac ttcgttaagcatgtccctga ctcgcatgtt
1921 ttccctgacc aaatccgcca gaaggcgctc gccgcccagcgatagcagtt cttgcaagga
1981 agcaaagttt ttcaacggtt tgagaccgtc cgccgtaggcatgcttttga gcgtttgacc
2041 aagcagttcc aggcggtccc acagctcggt cacctgctctacggcatctc gatccagcat
2101 atctcctcgt ttcgcgggtt ggggcggctt tcgctgtacggcagtagtcg gtgctcgtcc
2161 agacgggcca gggtcatgtc tttccacggg cgcagggtcctcgtcagcgt agtctgggtc
2221 acggtgaagg ggtgcgctcc gggctgcgcg ctggccagggtgcgcttgag gctggtcctg
2281 ctggtgctga agcÇctgccg gtcttcgccc tgcgcgtcggccaggtagca tttgaccatg
2341 gtgtcatãgt ccagcccctc cgcggcgtgg cccttggcgcgcagcttgcc cttggaggag
2401 gcgccgcacg aggggcagtg cagacttttg agggcgtagagcttgggcgc gagaaatacc24 61 gattccgggg agtaggcatc cgcgccgcag gccccgcagacggtctcgca ttccacgagc
2521 caggtgagct ctggccgttc ggggtcaaaa accaggtttcccccatgctt tttgatgcgt
2581 ttcttacctc tggtttccat gagccggtgt ccacgctcggtgacgaaaag gctgtccgtg
2641 tccccgtata cagacttgag agggagttta aacgaattcaatagcttgtt gcatgggcgg
2701 cgatataaaa tgcaaggtgc tgctcaaaaa atcaggcaaagcctcgcgca aaaaagaaag
27 61 cacatcgtag tcatgctcat gcagataaag gcaggtaagctccggaacca ccacagaaaa
2821 agacaccatt tttctctcaa acatgtctgc gggtttctgcataaacacaa aataaaataa
2881 caaaaaaaca tttaaacatt agaagcctgt cttacaacaggaaaaacaac ccttataagc
2941 ataagacgga ctacggccat gccggcgtga ccgtaaaaaaactggtcacc gtgattaaaa
3001 agcaccaccg acagctcctc ggtcatgtcc ggagtcataatgtaagactc ggtaaacaca
3061 tcaggttgat tcatcggtca gtgctaaaaa gcgacegaaatagcccgggg gaatacatac
3121 ccgcaggcgt ágagacaaca ttacagcccc cataggaggtataacaaaat taataggaga
3181 gaaaaacaca taaacacctg aaaaaccctc ctgcctaggcaaaatagcac cctcccgctc
3241 cagaacaaca tacagcgctt cacagcggca gcctaacagtcagccttacc agtaaaaaag
3301 aaaacctatt aaaaaaacac cactcgacac ggcaccagctcaatcagtca cagtgtaaaa
3361 aagggccaag tgcagagcga gtatatatag gactaaaaaatgacgtaacg gttaaagtcc
3421 acaaaaaaca cccagaaaac cgcacgcgaa cctacgcccagaaacgaaag ccaaaaaacc
3481 cacaacttcc tcaaatcgtc acttccgttt tcccacgttacgtaacttcc cattttaaga
3541 aaactacaat tcccaacaca tacaagttac tccgccctaaaacctacgtc acccgccccg
3601 ttcccacgcc ccgcgccacg tcacaaactc caccccctcattatcatatt ggcttcaatc
3661 caaaataagg tatattattg atgatgttaa ttaacatgcatggatecata tgcggtgtga
3721 aataccgcac agatgcgtaa ggagaaaata ccgcatcaggcgctcttccg cttcctcgct
3781 cactgactcg ctgcgctcgg tcgttcggct gcggcgagcggtatcagctc actcaaaggc
3841 ggtaatacgg ttatccacag aatcagggga taacgcaggaaagaacatgt gagcaaaagg
3901 ccagcaaaag gccaggaacc gtaaaaaggc cgcgttgctggcgtttttcc ataggctccg3961 cccccctgac gagcatcaca aaaatcgacg ctcaagtcagaggtggcgaa acccgacagg
4021 actataaaga taccaggcgt ttccccctgg aagctccctcgtgcgctctc ctgttccgac
4081 cctgccgctt accggatacc tgtccgcctt tctcccttcgggaagcgtgg cgctttctca
4141 tagctcacgc tgtaggtatc tcagttcggt gtaggtcgttcgctccaagc tgggctgtgt
4201 gcacgaaccc cccgttcagc ccgaccgctg cgccttatccggtaactatc gtcttgagtc
4261 caacccggta agacacgact tatcgccact ggcagcagccactggtaaca ggattagcag
4321 agcgaggtat gtaggcggtg ctacagagtt cttgaagtggtggcctaact acggctacac
4381 tagaaggaca gtatttggta tctgcgctct gctgaagccagttaccttcg gaaaaagagt
4441 tggtagctct tgatccggca aacaaaccac cgctggtagcggtggttttt ttgtttgcaa
4 501 gcagcagatt acgcgcagaa aaaaaggatc tcaagaagatcctttgatct tttctacggg
4561 gtctgacgct cagtggaacg aaaactcacg ttaagggattttggtcatga gattatcaaa
4621 aaggatcttc acctagatcc ttttaaatta aaaatgaagttttaaatcaa tctaaagtat
4681 atatgagtaa acttggtctg acagttacca atgcttaatcagtgaggcac ctatctcagc
4741 gatctgtcta tttcgttcat ccatagttgc ctgactccccgtcgtgtaga taactacgat
4801 acgggagggc ttaccatctg gccccagtgc tgcaatgataccgcgagacc cacgctcacc
4861 ggctccagat ttatcagcaa taaaccagcc agccggaagggccgagcgca gaagtggtcc
4 921 tgcaacttta tccgcctcca tccagtctat taattgttgccgggaagcta gagtaagtag
4981 ttcgccagtt aatagtttgc gcaacgttgt tgccattgctgcagccatga gattatcaaa
5041 aaggatcttc acctagatcc ttttcacgta gaaagccagtccgcagaaac ggtgctgacc
5101 ccggatgaat gtcagctact gggctatctg gacaagggaaaacgcaagcg caaagagaaa
5161 gcaggtagct tgcagtgggc ttacatggcg atagctagactgggcggttt tatggacagc
5221 aagcgaaccg gaattgccag ctggggcgcc ctctggtaaggttgggaagc cctgcaaagt
5281 aaactggatg gctttctcgc cgccaaggat ctgatggcgcaggggatcaa gctctgatca
5341 agagacagga tgaggatcgt ttcgcatgat tgaacaagatggattgcacg caggttctcc
5401 ggccgcttgg gtggagaggc tattcggcta tgactgggcacaacagacaa tcggctgctc5461 tgatgccgcc gtgttccggc tgtcagcgca ggggcgcccg
gttctttttg tcaagaccga
5521 cctgtccggt gccctgaatg aactgcaaga cgaggcagcg
cggctatcgt ggctggccac
5581 gacgggcgtt ccttgcgcag ctgtgctcga cgttgtcact
gaagcgggaa gggactggct
5641 gctattgggc gaagtgccgg ggcaggatct cctgtcatct
caccttgctc ctgccgagaa
5701 agtatccatc atggctgatg caatgcggcg gctgcatacg
Cttgatccgg ctacctgccc
5761 attcgaccac caagcgaaac atcgcatcga gcgagcacgt
actcggatgg aagccggtct
5821 tgtcgatcag gatgatctgg acgaagagca tcaggggctc
gcgccagccg aactgttcgc
5881 caggctcaag gcgagcatgc ccgacggcga ggatctcgtc
gtgacccatg gcgatgcctg
5941 cttgccgaat atcatggtgg aaaatggccg cttttctgga
ttcatcgact gtggccggct
6001 gggtgtggcg gaccgctatc aggacatagc gttggctacc
cgtgatattg ctgaagagct
6061 tggcggcgaa tgggctgacc gcttcctcgt gctttacggt
atcgccgctc ccgattcgca
6121 gcgcatcgcc ttctatcgcc ttcttgacga gttcttctga
attttgttaa aatttttgtt
6181 aaatcagctc attttttaac caataggccg aaatcggcaa
catcccttat aaatcaaaag
6241 aatagaccgc gatagggttg agtgttgttc cagtttggaa
caagagtcca ctattaaaga
6301 acgtggactc caacgtcaaa gggcgaaaaa ccgtctatca
gggcgatggc ccactacgtg
6361 aaccatcacc caaatcaagt tttttgcggt cgaggtgccg
taaagctcta aatcggaacc
6421 ctaaagggag cccccgattt agagcttgac ggggaaagcc
ggcgaacgtg gcgagaaagg
6481 aagggaagaa agcgaaagga gcgggcgcta gggcgctggc
aagtgtagcg gtcacgctgc
6541 gcgtaaccac cacacccgcg cgcttaatgc gccgctacag
ggcgcgtcca ttcgccattc
6601 aggatcgaat taattcttaa t
SEQ ID: 2 (Seqüência de vetor DS2)
taacatcatc aataatatac cttattttgg attgaagcca atatgataatgagggggtgg agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtgacgtagtagt gtggcggaag tgtgatgttg caagtgtggc ggaacacatgtaagcgacgg atgtggcaaa agtgacgttt ttggtgtgcg ccggtgtacacaggaagtga caattttcgc gcggttttag gcggatgttg tagtaaatttgggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataagaggaaqtqaaa tctgaataat tttgtgttac tcatagcgcg
taatact GCTAGAga tCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTGTAATACGACTCACTA
TAGGGCGAATTGGGTACTGGCÇAcagagcttggcccattgcatacgttgtatccatatcata
atatgtacatttatattggctcatgtccaacattaccgccatgttgacattgattattgact
agttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgt
tacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgt
caataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtg
gagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgcç
ccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttat
gggactttcctacttggcagtacatctacgta-ttagtcatcgctattaocatggtgatgcgg;
ttttggcagtacatçaatgggcgtggatagcggtttgactcacggggatttccaagtctcca
ccccattgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtc
gtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggt ctatata
agcagagctcgtttagtgaaccgtcagatcgcctggagacgccatccacgctgttttgacct
ccatagaagacaccgggaccgatccagcctgactctagCctAGCTCtgaagttggtggtgag
gccctgggcaggttggtatcaaggttacaagacaggtttaaggagaccaatagaaactgggc
atgtggagacagagaagactcttgggtttctgataggcactgactctctctgcctattggtc
tattttcccacccttaggctgctggtctgagcctagGAGArcrcTCGAGGTCGACGGTAarCS
ATCGGTACAGCTTCTAGAGATCCCTCGACCTCGAGATCCATTGTGCTCTAAAGGAGATACCC
GGCCAGACACCCTCACCTGCGGTGCCCAGCTGCCCAGGCTGAGGCAAGAGAAGGCCAGAAAC
CATGCCCATGGGGTCTCTGCAACCGCTGGCGACCTTGTACCTGCTGGGGATGCTGGTCGCTT
CCGTGCTAGCTGTGGAGAAGCTGTGGGTGACTGTATACTATGGGGTGCCTGTGTGGAAGGAG
GCCACCACCACCCTGTTCTGTGCCTCTGATGCCAAGGCCTATGACACTGAGGTCCACAATGT
CTGGGCCACCCATGCCTGTGTGCCCACTGACCCCAACCCTCAGGAGGTGGXGCTGGAGAATG
TGACTGAGCACTTCAACATGTGGAAGAACAACATGGTGGAGCAGATGCAGGAGGACATCATC
AGCCTGTGGGACCAGAGCCTGAAGCCCTGTGTGAAGCTGACCCCCCTGTGTGTGACCCTGAA
CTGCAAGGATGTGAATGCCACCAACACCACCAATGACTCTGAGGGCACTATGGAGAGGGGTG
AGATCAAGAACTGCAGCTTCAACATCACCACCAGCATCAGGGATGAGGTGCAGAAGGAGTAT
GCCCTGTTCTACAAGCTGGATGTGGTGCCCATTGACAACAACAACACCAGCTACAGGCTGAT
CAGGTGTGACACCTCTGTGATCACCCAGGCCTGCCCCAAGATCAGCTTTGAGCCCATCGCCA
TCCACTACTGTGCCCCTGCTGGCTTTGCCATCCTGAAGTGCAATGACAAGACCTTCAATGGC
AAAGGCCCTTGCAAGAATGTGAGCACTGTGCAGTGCACTCATGGCATCAGGCCTGTGGTGAG
CACCCAGCTGCTGCTGAATGGCAGCCTGGCTGAGGAGGAGGTGGTGATCAGGTCTGACAACT
TCACCAACAATGCCAAGACCATCATTGTGCAGC
TGAAGGAGTCTGTGGAGATCAACTGCACCAGGCCCAACAACAACACCAGGAAGAGCATTCAC
ATTGGCCCTGGCAGGGCCTTCTACACCACTGGGGAGATCATTGGGGACATCAGGGAGG
CCCACTGCAACATCAGCAGGGCCAAGTGGAATGACACCCTGAAGGAGATTGTGATCAAGCTG
AGGGAGCAGTTTGAGAACAAGACCATTGTGTTCAATCACAGCTCTGGTGGrGATCCTGAGAT
TGTGATGCACAGCTTCAACTGTGGTGGTGAGTTCTTCTACTGCAACAGCACCCAGCTGTTCA
ACAGCACCTGGAACAACAACACTGAGGGCAGCAACAACACTGAGGGCAACACCATCACCGTG
CCTTGCAGGATCAAGCAGATCATCAACATGTGGCAGGAGGTGGGCAAGGCCATGTATGCTCC
TCCCATC AGGGGCCAGATCAGGTGCAGCAGCAACATCACTGGCCTGCTGCTGACGAGGGATG
GTGGCATCAATGAGAATGGCACTGAGATTTTCAGGCCTGGTGGTGGGGACATGAGGGACAAC
TGGAGGTCTGAGCTGTACAAGTACAAGGTGGTGAAGATTGAGCCCCTTGGTGTGGCTCCCAC
CAAGGCTAAGCGCAGGGTGGTGCAGAGGGAGAAGcgcgctgtgggctgaggatccCGAGGGT
GAGTGCTCCTGCCTGGACGCATCCCGGCTATGCAGCCCCAGTCCAGGGCÃGCAAGGCAGGCC
CCGTCTGCCTCTTCACCCGGAGCCTCTGCCCGCCCCACTCATGCTCAGGGAGAGGGTCTTCT
GGCTTTTTCCCAGGCTCTGGGCAGGCACAGGCTAGGTGCCCCTAACCCAGGCCCTGCACACA
AAGGGGCAGGTGCTGGGCTCAGACCTGCCAAGAGCCATATCCGGGAGGACCCTGCCCCTGAC
CTAAGCCCACCCCAAAGGCCAAACTCTCCACTCCCTCAGCTCGGACACCTTCTCTCCTCCCA
GATTCCAGTAACTCCCAATCTTCTCTCTGCAGAGCCCAAATCTTGTGACAAAACTCACACAT
GCCCACCGTGCCCAGGTAAGCCAGCCCAGGCCTCGCCCTCCAGCTCAAGGCGGGACAGGTGCCCTAGAGTAGCCTGCATCCAGGGACAGGCCCCAGCCGGGTGCTGACACGTCCACCTCCATCTCTTCCTCAGCACCTGftACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTÇCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGGCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGTGGGACCCGTGGGGTGCGAGGGCCACATGGACAGAGGCCGGCTCGGCCCACCCTCTGCCCTGAGAGTGACCGCTGTACCAACCTCTGTCCTACAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGAGTGCGACGGCCGCAGGTAAGCCAGÇCCAGGCCTCGCCCTCCAGCTCAAGGCGGGACAGGTGCCCTAGAGTAGCCTGCATCCAGGGACAGGCCCCAGCCGGGTGCTGACACGTCCACCTCCATCTCTTCCTCAGGTCTGCCCGGGTGGCATCCCTGTGACCCCTCCCCAGTGCCTGTCCTGGCCCTGGAAGTTGCCACTCCAGTGCCCACCAGCCTTGTCCTAATAAAATTAAGTTGCATCATTTTGTCTGACTAGGTGTCCTTCTATAATATTATGGGGTGGAGGGGGGTGGTATGGAGCAAGGGGCCCAAGTTAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTXTGTCCAAACTCATCAATGTATCTTATCATGTCTGgatctggg cgtggttaag
421 ggtgggaaag aatatataag gtgggggtct tatgtagttt tgtatctgtt
ttgcagcagc
481 cgccgccgcc atgagcacca actcgtttga tggaagcatt gtgagctcat
CGGCGSCCGCCCTATTCTATAGTGTCACCTAAATGCTAGaíSCrOSCTGATCAGCCTCGACTG
TGCCTT
CTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCC
ACTCCCAC
TGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGT
GGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCT
CTATGGCTTCTGAGGCGGAAAGAACCTATGGCTTCTGAGGCGGAAAGAACCAACCACCGCGGTGGCGGCCGCCACACAAAAAACCAACACACAGATGTAATGAAAATAAAGATATTTTATTTCTAGAGAAACGATATGGGCTGAATACGGATCCGTATTCAGCCCATATCGTTTCCTGCAGGAATTCGCCCTTTAGATATCATCGATGTCTCGGCGGTGGTGGCGCGTCGCGCCGCTGGGTTTTATAGGGCGCCGCCGCGGCCGCTCGAGCCATAAAAGGCAACTTTCGGAACGGCGCACGCTGATTGGCCCCGCGCCGCTCACTCACCGGCTTCGCCGCACAGTGCAGCATTTTTTTACCCCCTCTCCCCTCCTTTTGCGAAAAAAAAAAAGAGCGAGAGCGAGATTGAGGAAGAGGAGGAGGGAGAGTTTTGGCGTTGGCCGCCTTGGGGTGCTGGGCGTCGACGATATCTAAGGGCGAATTCGATATCAagctagctTgtcgactcg aagatctggg cgtggttaag
421 ggtgggaaag aatatataag gtgggggtct tatgtagttttgtatctgtt ttgcagcagc
481 cgccgccgcc atgagcacca actcgtttga tggaagcattgtgagctcat atttgacaac
541 gcgcatgccc ccatgggccg gggtgcgtca gaatgtgatgggctccagca ttgatggtcg601 ccccgtcctg cccgcaaact ctactacctt gacctacgagaccgtgtctg gaacgccgtt
661 ggagactgca gcctccgccg ccgcttcagc cgctgcagccaccgcccgcg ggattgtgac
721 tgactttgct ttcctgagcc cgcttgcaag cagtgcagcttcccgttcat ccgcccgcga
781 tgacaagttg acggctcttt tggcacaatt ggattctttgacccgggaac ttaatgtcgt
841 ttctcagcag ctgttggatc tgcgccagca ggtttctgccctgaaggctt cctcccctcc
901 caatgcggtt taaaacataa ataaaaaacc agactctgtttggatttgga tcaagcaagt
961 gtcttgctgt ctttatttag gggttttgcg cgcgcggtaggcccgggacc agcggtctcg
1021 gtcgttgagg gtcctgtgta ttttttccag gacgtggtaaaggtgactct ggatgttcag
1081 atacatgggc ataagcccgt ctctggggtg gaggtagcaccactgcagag cttcatgctg
1141 cggggtggtg ttgtagatga tccagtcgta gcaggagcgctgggcgtggt gcctaaaaat
1201 gtctttcagt agcaagctga ttgccagggg caggcccttggtgtaagtgt ttacaaagcg
1261 gttaagctgg gatgggtgca tacgtgggga tatgagatgcatcttggact gtatttttag
1321 gttggctatg ttcccagcca tatccctccg gggattcatgttgtgcagaa ccaccagcac
1381 agtgtatccg gtgcacttgg gaaatttgtc atgtagcttagaaggaaatg cgtggaagaa
1441 cttggagacg cccttgtgac ctccaagatt ttccatgcattcgtccataa tgatggcaat
1501 gggcccacgg gcggcggcct gggcgaagat atttctgggatcactaacgt catagttgtg
1561 ttccaggatg agatcgtcat aggccatttt tacaaagcgcgggcggaggg tgccagactg
1621 cggtataatg gttccatccg gcccaggggc gtagttaccctcacagattt gcatttccca
1681 cgctttgagt tcagatgggg ggatcatgtc tacctgcggggcgàtgaaga aaacggtttc
1741 cggggtaggg gagatcagct gggaagaaag caggttcctgagcagctgcg acttaccgca
1801 gccggtgggc ccgtaaatca cacctattac cgggtgcaactggtagttaa gagagctgca
1861 gctgccgtca tccctgagca ggggggccac ttcgttaagcatgtccctga ctcgcatgtt
1921 ttccctgacc aaatccgcca gaaggcgctc gccgcccagcgatagcagtt cttgcaagga
1981 agcaaagttt ttcaacggtt tgagaccgtc cgccgtaggcatgcttttga gcgtttgacc
2041 aágcagttcc aggcggtccc acagctcggt cacctgctctacggcatctc gatccagcat2101 atctcctcgt ttcgcgggtt ggggcggctt tcgctgtacggcagtagtcg gtgctcgtcc
2161 agacgggcca gggtcatgtc tttccacggg cgcagggtcctcgtcagcgt agtctgggtc
2221 acggtgaagg ggtgcgctcc gggctgcgcg ctggccagggtgcgcttgag gctggtcctg
2281 ctggtgctga agcgctgccg gtcttcgccc tgcgcgtcgg
ccaggtagcá tttgaccatg
2341 gtgtcatagt ccagcccctc cgcggcgtgg cccttggcgc
gcagcttgcc cttggaggag
2401 gcgccgcacg aggggcagtg cagacttttg agggcgtagagcttgggcgc gagaaatacc
2461 gattccgggg agtaggcatc cgcgccgcag gccccgcagacggtctcgca ttccacgagc
2521 caggtgagct ctggccgttc ggggtcaaaa accaggtttcccccatgctt tttgatgcgt
2581 ttcttacctc tggtttccat gagccggtgt ccacgctcggtgacgaaaag gctgtccgtg
2641 tccccgtata cagacttgag agggagttta aacgaattcaatagcttgtt gcatgggcgg
2701 cgatataaaa tgcaaggtgc tgctcaaaaa atcaggcaaagcctcgcgca aaaaagaaag
2761 cacatcgtag tcatgctcat gcagataaag gcaggtaagctccggaacca ccacagaaaa
2821 agacaccatt tttctctcaa acatgtctgc gggtttctgcataaacacaa aataaaataa
2881 caaaaaaaca tttaaacatt agaagcctgt cttacaacaggaaaaacaac ccttataagc
2941 ataagacgga ctacggccat gccggcgtga ccgtaaaaaaactggtcacc gtgattaaaa
3001 agcaccaccg acagctcctç ggtcatgtcc ggagtcataatgtaagactc ggtaaacaca
3061 tcaggttgat tcatcggtca gtgctaaaaa gcgaccgaaatagcccgggg gaatacatac
3121 ccgcaggcgt agagacaaca ttacagcccc cataggaggtataacaaaat taataggaga
3181 gaaaaacaca taaacacctg aaaaaccctc ctgcctaggcaaaatagcac cctcccgctc
3241 cagaacaaca tacagcgctt cacagcggca gcctaacagtcagccttacc agtaaaaaag
3301 aaaacctatt aaaaaaacac cactcgacac ggcaccagctcaatcagtca cagtgtaaaa
3361 aagggccaag tgcagagcga gtatatatag gactaaaaaatgacgtaacg gttaaagtcc
3421 acaaaaaaca cccagaaaac cgcacgcgaa cctacgcccagaaacgaaag ccaaaaaacc
34 81 cacaacttcc tcaaatcgtc acttccgttt: tcccacgttacgtaacttcc cattttaaga
3541 aaactacaat tcccaacaca tacaagttac tccgccctaaaacctacgtc acccgccccg3601 ttcccacgcc ccgcgccacg tcacaaactc caccccctca
ttatcatatt ggcttcaatc
3661 caaaataagg tatattattg atgatgttaa ttaacatgca
tggatccata tgcggtgtga
3721 aataccgcac agatgcgtaa ggagaaaata ccgcatcagg
cgctcttccg cttcctcgct
3781 cactgactcg ctgcgctcgg tcgttcggct gcggcgagcg
gtatcagctc actcaaaggc
3841 ggtaatacgg ttatccacag aatcagggga taacgcagga
aagaacatgt gagcaaaagg
3901 ccagcaaaag gccaggaacc gtaaaaaggc cgcgttgctggcgtttttcc ataggctccg
3961 cccccctgac gagcatcaca aaaatcgacg ctcaagtcagaggtggcgaa acccgacagg
4021 actataaaga taccaggcgt ttccccctgg aagctccctcgtgcgctctc ctgttccgac
4081 cctgccgctt accggatacc tgtccgcctt tctcccttcgggaagcgtgg cgctttçtca
4141 tagctcacgc tgtaggtatc tcagttcggt gtaggtcgttcgctccaagc tgggctgtgt
4201 gcacgaaccc cccgttcagc ccgaccgctg cgccttatcc
ggtaactatc gtcttgagtc
4261 caacccggta agacacgact tatcgccact ggcagcagccactggtaaca ggattagcag
4321 agcgaggtat gtaggcggtg ctacagagtt cttgaagtggtggcctaact acggetacàc
4381 tagaaggaca gtatttggta tctgcgctct gctgaagccagttaccttcg gaaaaagagt
4441 tggtagctct tgatccggca aacaaaccac cgetggtagcggtggttttt ttgtttgcaa
4501 gcagcagatt acgcgcagaa aaaaaggatc tcaagaagatcctttgatct tttctacggg
4561 gtctgácgct cagtggaacg aaaactcacg ttaagggattttggtcatga gattatcaaa
4 621 aaggatcttc acctagatcc ttttaaatta aaaatgaagttttaaatcaa tctaaagtat
4681 atatgagtaa acttggtctg acagttacca atgcttaatcagtgaggcac ctatctcagc
4741 gatctgtcta tttcgttcat ccatagttgc ctgactccccgtcgtgtaga taactacgat
4801 acgggagggc ttaccatctg gccccagtgc tgcaatgataccgcgagaçc cacgctcacc
4861 ggctccagat ttatcagcaa taaaccagcc agccggaagggccgagcgca gaagtggtcc
4921 tgcaacttta tccgcctcca tccagtctat taattgttgccgggaagcta gagtaagtag
4981 ttcgccagtt aatagtttgc gcaacgttgt tgccattgctgcagccatga gattatcaaa
5041 aaggatcttc acctagatcc ttttcacgta gaaagccagtccgcagaaac ggtgctgacc5101 ccggatgaat gtcagctact gggctatctg gacaagggaaaacgcaagcg caaagagaaa
5161 gcaggtagct tgcagtgggc ttacatggcg atagctagactgggcggttt tatggacagc
5221 aagcgaaccg gaattgccag ctggggcgcc ctctggtaaggttgggaagc cctgcaaagt
5281 aaactggatg gctttctcgc cgccaaggat ctgatggcgcaggggatcaa gctctgatca
5341 agagacagga tgaggatcgt ttcgcatgat tgaacaagatggattgcacg caggttctcc ·
5401 ggccgcttgg gtggagaggc tattcggcta tgactgggcacaacagacaa tcggctgctc
54 61 tgatgccgcc gtgttccggc tgtcagcgca ggggcgcccggttctttttg tcaagaccga
5521 cctgtccggt gccctgaatg aactgcaaga cgag^cagcgcggctatcgt ggctggccac
5581 gacgggcgtt ccttgcgcag ctgtgctcga cgttgtcactgaagcgggaa gggáctggct
5641 gctattgggc gaagtgccgg ggcaggatct cctgtcatctcacct-tgctc ctgccgagaa
5701 agtatccatc atggctgatg caatgcggcg gctgcatacgcttgatccgg ctacctgccc
• 5761 attcgaccac caagcgaaac atcgcatcga gcgagcacgtactcggatgg aagccggtct
5821 tgtcgatcag gatgatctgg acgaagagca tcaggggctcgcgccagccg aactgttcgc
5881 caggctcaag gcgagcatgc ccgacggcga ggatctcgtcgtgacccatg gcgatgcctg
5941 cttgccgaat atcatggtgg aaaatggccg cttttctggattcatcgact gtggccggct
6001 gggtgtggcg gaccgctatc aggacatagc gttggctacccgtgatattg ctgaagagct
6061 tggcggcgaa tgggctgacc gcttcctcgt. gctttacggtatcgccgctc ccgattcgca
6121 gcgcatcgcc ttctatcgcc ttcttgacga gttcttctgaattttgttaa aatttttgtt
6181 aaatcagctc attttttaac caataggccg aaatcggcaacatcccttat aaatcaaaag
6241 aatagaccgc gatagggttg agtgttgttc cagtttggaacaagagtcca ctattaaaga
6301 acgtggactc caacgtcaaa gggcgaaaaa ccgtctatcagggcgatggc ccactacgtg
6361 aaccatcacc caaatcaagt tttttgcggt cgaggtgccgtaaagctcta aatcggaacc
6421 ctaaagggag cccccgattt agagcttgac ggggaaagccggcgaacgtg gcgagaaagg
6481 aagggaagaa agcgaaagga gcgggcgcta gggcgctggcaagtgtagcg gtcacgctgc
6541 gcgtaaccac cacacccgcg cgcttaatgc gccgctacagggcgcgtcca ttcgccattc
6601 aggatcgaat taattcttaa tSEQ ID Ne: 3
gaaacgatatgggctgaatacttaagtattcagcccatatcgtttc.
SEQ ID Ns: 4
cgggccccccctcgaggtcgacggtaxcgataagcttgataxcgaattcgcccttagataxc
gtcgacgcccagcaccccaaggcggccaacgccaaaactcxcccxcctcctcttccxcaaxç
tcgcxctcgctctttttttttttcgcaaaaggaggggagagggggtaaaaaaatgctgcact
gtgcggcgaagccggtgagtgagcggcgcggggccaatcagcgigcgccgxtccgaaagttg
ccttttatggctcgagcggccgcggcggcgccctataaaacccagcggcgcgacgcgccacc
accgccgagacatcgatgatatcta
aagggcgaattcctgcagcccgggggatccactagtctagatgcatgctcgagcggccgccagtgtgatggatatctgcagaattcgcccttcagctgcggatccattcgccattcaggctgcgcaactgttgggaagggcgatcggtgcgggcctcttcgctattacgccagctggcgaaagggggatgtgctgcaaggcgattaagttgggtaacgccagggttttcccagtcacgacgttgtaaaacgacggccagtgaattgtaatacgactcactatagggcgaattgggtaccgggccccccctcgaggtcgacggtatcgataagcttgatatcgaattcctgcagcccgggggatcgactagtt
tctagaaataaaatatctttattttcattacatctgtgtgttggttttttgtgtggcisgcggccaccgcggtggagct
Atcgaattcaagcttgtcgactc gaagatcct AG actagtggat cccccgggctgcaggaatt
cgccctttagatatcatcgatgtctcggcggtggtggcgcgtcgcgccgctgggttttatagggcgccgccgcggccgcxcgagccataaaaggcaactttcggaacggcgcacgctgattggccccgcgccgctcactcaccggcttcgccgcacagtgcagcatttxxtxaccccctctcccctccttttgcgaaaaaaaaaaagagcgagagcgagattgaggaagaggaggagggagagttttggcgttggccgccttggggtgctgggcgxcgacgatatcxaagggcgaatt cgatatcaagc ttatcgatac cgtcgacctc gagggggggc ccg
SEQ ID Ns: 5
cgggccccccctcgaggtcgacggtatcgataagcttgatatcgaattcgcccttagatatcgtcgacgcccagcaccccaaggcggcca
acgccaaaacxctccctcctccxcttcctcaatctcgctctcgcxctxtttttttttcgcaa
aaggaggggagagggggtaaaaaaatgctgcactgtgcggcgaagccggtgagtgagcggcg
cggggccaatcagcgtgcgccgttccgaaagttgccttttaxggctcgagcggccgcggcgg
cgccctataaaacccagcggcgcgacgcgccaccaccgccgagacatcgatgatatcta
aagggcgaattcctgcagcccgggggatccactagtctagatgcatgctcgagcggccgcca
gtgtgatggataxcxgcagaaxtcgccctx
cagctgcggatccattcgccatxcaggctgcgcaactgttgggaagggcgatcggtgcgggcctcttcgctattacgccagctggcgaaagggggatgtgcxgcaaggcgattaagttgggtaacgccagggxtttcccagtcacgacg ·ttgtaaaacgacggccagtgaattgtaatacgactcactatagggcgaat
TGGGTACCGGGCCCCCCCTCGAGGTCGACGGTATCGATAAGCTTGATATC
gaattcctgcagcccgggggatccactagtt
tctagaaataaaatatctttattttcattacaictgtgtgttggttttttgtgtggcggccgccaccgcggtggagcta
Tcgaattcaagcttgtcgactc gaagatcgtacaeaggaagtgaeaattttcgcgcggttttaggcggatgttg
tagtaaatttgggcgtaaccgagtaagatttggccattttcgcgggaaaactgaataagaggaagtgaaatctgaàtaattttgtgttactcatagcgcgtaatactggtac
CGGGCCCCCCCTCGAGGTCGACGGTATCGATAAGCTTGATATC
GAATTCGCCCTTAGATATCGTCGACGCCCAGCACCCCAAGGCGGCCA
ACGCCAAAACTCTCCCTCCTCCTCTTCCTCAATCTCGCTCTCGCTCTTTTTTTTTTTCGCAA
AAGGAGGGGAGAGGGGGTAAAAAAATGCTGCACTGTGCGGCGAAGCCGGTGAGTGAGCGGCG
CGGGGCCAATCAGCGTGCGCCGTTCCGAAAGTTGCCTTTTATGGCTCGAGCGGCCGCGGCGG
CGCCCTATAAAACCCAGCGGCGCGACGCGCCACCACCGCCGAGACATCGATGATATCTA
AAGGGCGAATTCCTGCAGCCCGGGGGATCCACTAGTCTAGAACTAGTGGATCCCCCGGGCTG
CAGGAATTC
GATATCAAGCTTATCGATACCGTCGACCTCGAGGGGGGGCCCGGTACCCA
ATTCGCCCTATAGTGAGTCGTATTACAATTCACTGGCCGTCGTTTTACAA
CGTCGTGACTGGGAAAACCCTGGCGTTACCCAACTTAATCGCCTTGCAGC
ACATCCCCCTTTCGCCAGCTGGCGTAATAGCGAAGAGGCCCGCACCGATC
GCCCTTCCCAACAGTTGCGCAGCCTGAATGGCGAATGGATCCGCAGCTG
AAGGGCGAATTCTGCAGATATCCATCACACTGGCGGCCGCTCGAGCATGCA
TCTAGAAATAAAATATCTTTATTTTCATTACATCTGTGTGTTGGTTTTTTGTGTGGCGGCCGCCACCGCGGTGGAGCTA
SEQ ID Ns: 6
taacatcatc aataatatac cttattttgg attgaagcca atatgataatgagggggtgg agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtgacgtagtagt gtggcggaag tgtgatgttg caagtgtggc ggaacacatgtaagcgacgg atgtggcaaa agtgacgttt ttggtgtgcg ccggtgtacacaggaagtga caattttcgc gcggttttag gcggatgttg tagtaaatttgggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataagaggaagtgaaa tctgaataat tttgtgttac tcatagcgcg
taatactGCTAGAgatCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCÇAGTCACGACGTTGTAAAACGACGGCCAGTGAATTGTAATACGACTCACTATAGGGCGAATTGGGT ACTGGCCAcagagctt ggcçcattgcatacgttgtatccatatca ta.atatgtacatttatattggctcatgtccaacattaccgccatgttgacattgattattgactagttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagtcatcgctattaceatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccaccccattgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtctatataagcagagctcgtttagtgaaccgtcagatcgcctggagacgccatccacgctgttttgacctccatagaagacaccgggaccgatccagcctgactctagCctAGCTCtgaagttggtggtgaggccctgggcaggttggtatcaaggttacaagacaggtttaaggagaceaatagaaactgggcatgtggagacagagaagactcttgggtttctgataggcactgactctctctgcctattggtctattttcccacccttaggctgctggtctgagcctagGAGArC3CTCGAGGTCGACGGTAateg
atgcca ccATGGAGAA AATCGTCCTG TTGCTCGCTA TTGTGTCTCT
51 AGTGAAGAGC GATCAAATTT GTATCGGCTA CCATGCCAAT AACTCAACAG101 AGCAGGTCGA TACTATCATG GAGAAAAACG TAACAGTTAC TCATGCCCAA151 GACATCTTGG AAAAGACCCA CAACGGCAAA CTTTGCGACC TGGATGGAGT201 GAAGCCCCTG ATCCTCCGGG ACTGTTCAGT CGCTGGTTGG CTGCTCGGGA251 ACCCTATGTG TGATGAGTTT ATCAACGTGC CTGAATGGTC TTACATTGTG301 GAGAAGGCTA ACCCTACCAA TGACCTCTGC TATCCTGGGT CATTTAACGA351 TTACGAGGAA CTGAAACACC TGTTGTCTAG AATTAACCAC TTTGAAAAGA401 TACAGATTAT ACCCAAGTCT AGTTGGAGTG ATCACGAAGC CTCCTCAGGC451 GTTAGCTCAG CGTGTCCCTA TCTGGGCTCT CCATCCTTCT TTAGAAATGT501 GGTCTGGTTA ATCAAAAAGA ACAGTACCTA CCCAACCATC AAAAAGTCTT551 ATAACAATAC CAATCAGGAG GACCTGCTCG TGTTGTGGGG.TATCCATCAC601 CCGAACGACG CCGCTGAACA GACTAGGCTG TATCAGAACC CCACTACATA651 CATCAGTATT GGCACGAGTA CTCTGAACCA GCGATTAGTG CCAAAGATTG701 CAACACGGAG CAAAGTAAAT GGGCAATCTG GCAGGATGGA GTTTTTCTGG751 ACAATCTTAA AACCCAACGA TGCGATAAAT TTCGAGTCCA ATGGCAATTT801 CATCGCCCCT GAATACGCCT ATAAGATCGT GAAAAAGGGG GACTCTGCAA851 TTATGAAGTC CGAATTAGAG TATGGCAATT GCAACACGAA GTGCCAGACA901 CCAATGGGAG CCATTAATAG CTCAATGCCC TTCCATAATA TTCATCCATT951 GACCATTGGG GAGTGCCCAA AGTACGTGAA GTCCAACCGC CTGGTCCTCG1001 CAACCGGTCT AAGAAATAGC CCGCAGAGAG AATCGCGGAG GAAGAAACGT1051 GGCCTGTTTG GCGCGATTGC CGGATTCATC GAGGGAGGCT GGCAGGGTAT1101 GGTCGATGGT TGGTACGGAT ACCACCATAG CAACGAACAG GGGTCCGGCT1151 ATGCAGCAGA TAAGGAGAGC ACTCAGAAAG CTATTGACGG AGTTACAAAC1201 AAGGTTAATA GTATTATAGA TAAAATGAAC ACGCAATTCG AGGCCGTTGG1251 GAGGGAGTTT AACAATCTGG AACGC.CGGAT CGAAAATCTG AATAAGAAAA1301 TGGAAGACGG CTTCCTTGAC GTGTGGACTT ATAATGCAGA GCTGCTTGTA1351 CTCATGGAGA ACGAGAGGAC CCTGGATTTC CACGATAGCA ACGTGAAGAA1401 CCTTTACGAC AAGGTGAGAC TTCAGCTCCG AGACAACGCC AAGGAGCTGG1451 GGAATGGATG CTTCGAGTTT TACCACAAAT GTGACAATGA GTGCATGGAA1501 AGTATÁCGCA ACGGGACCTA CAATTACCCT CAGTATAGCG AAGAGGCTCG1551 GCTCAAACGC GAAGAGATAA GCGGGGTGAA ATTGGAATCA ATCGGAACAT1601 ATCAAATCCT GTCCATCTAT TCCACCGTCG CCTCTTCGCT GGCCCTCGCT1651 ATCÃTGATGG CTGGTCTGTC CCTATGGATG TGTTCCAATG GAAGCCTTCA1701 GTGCCGTATT TGTATATGAg c
ggccgccctattctatagtgtcacctaaatgctagaccípcgctgatcagcctcgactgtgcc
tt
ctagttgccagccatctgttgtttgcccctcccccgtgccttccttgaccctggaaggtgcc
ACTCCCAC ·
tgtcctttcctaataaaatgaggaaattgcatcgcattgtctgagtaggtgtcattctattc
tggggggt
ggggtggggcaggacagcaagggggaggattgggaagacaatagcaggcatgctggggatgcggtgggct
ctatggcttctgaggcggaaagaaccaa
ccaccgcggtggcggccgccacacaaaaaaccaacacacagatgtaatgaaaataaagatat
TTTATTTCTAGAGAAACGATATGGGCTGAATACGGATCCGTATTCAGCCCATATCGTTTCCTGCAGGAATTCGCCCTTTAGATATCATCGATGTCTCGGCGGTGGTGGCGCGTCGCGCCGCTGGGTTTTATAGGGCGCCGCCGCGGCCGCTCGAGCCATAAAAGGCAACTTTCGGAACGGCGCACGCTGATTGGCCCCGCGCCGCTCACTCACCGGCTTCGCCGCACAGTGCAGCATTTTTTTACCCCCTCTCCCCTCCTTTTGCGAAAAAAAAAAAGAGCGAGAGCGAGATTGAGGAAGAGGAGGAGGGAGAGTTTTGGCGTTGGCCGCCTTGGGGTGCTGGGCGTCGACGATATCTAAGGGCGAATTCGATATCA
AGCTAGCT Tgtcgactcg aagatctggg cgtggttaag
421 ggtgggaaag aatatataag gtgggggtct tatgtagttttgtatctgtt ttgcagcagc481 cgccgccgcc atgagcacca actcgtttga tggaagcattgtgagctcat atttgacaac
541 gcgcatgccc ccatgggccg gggtgcgtca gaatgtgatgggctccagca ttgatggtcg
601 ccccgtcctg cccgcaaact ctactacctt gacctacgagaccgtgtctg gaacgccgtt
661 ggagactgca gcctccgccg ccgcttcagc cgctgcagccaccgcccgcg ggattgtgac
721 tgactttgct ttcctgagcc cgcttgcaag cagtgcagcttcccgttcat ccgcccgcga
781 tgacaagttg acggctcttt tggcacaatt ggattctttgacccgggaac ttaatgtcgt
841 ttctcagcag ctgttggatc tgcgccagca ggtttctgccctgaaggctt cctcccctcc
901 caatgcggtt taaaacataa ataaaaaacc agactctgtttggatttgga tcaagcaagt : ,
961 gtcttgctgt ctttatttag gggttttgcg cgcgcggtaggcccgggacc agcggtctcg
1021 gtcgttgagg gtcctgtgta ttttttccag gacgtggtaaaggtgactct ggatgttcag
1081 atacatgggc ataagcccgt ctctggggtg gaggtagcaccactgcagag cttcatgctg
1141 cggggtggtg ttgtagatga tccagtcgta gcaggagcgctgggcgtggt gcctaaaaat
1201 gtctttcagt agcaagctga ttgccagggg caggcccttggtgtaagtgt ttacaaagcg
1261 gttaagctgg gatgggtgca tacgtgggga tatgagatgcatcttggact gtatttttag
1321 gttggctatg ttcccagcca tatccctccg gggattcatgttgtgcagaa ccaccagcac
1381 agtgtatccg gtgcacttgg gaaatttgtc atgtagcttagaaggaaatg cgtggaagaa
1441 cttggagacg cccttgtgac ctccaagatt ttccatgcattcgtccataa tgatggcaat
1501 gggcccacgg gcggcggcct gggcgaagat atttctgggatcactaacgt catagttgtg
1561 ttccaggatg agatcgtcat aggccatttt tacaaagcgcgggcggaggg tgccagactg
1621 cggtataatg gttccatccg gcccaggggc gtagttaccctcacagattt gcatttccca
1681 cgctttgagt tcagatgggg ggatcatgtc tacctgcggggcgatgaaga aaacggtttc
1741 cggggtaggg gagatcagct gggaagaaag caggttcctgagcagctgcg acttaccgca
1801 gccggtgggc ccgtaaatca cacctattac cgggtgcaactggtagttaa gagagctgca
1861 gctgccgtca tccctgagca ggggggccac ttcgttaagcatgtccctga ctcgcatgtt
1921 ttccctgacc aaatccgcca gaaggcgctc gccgcccagcgatagcagtt cttgcaagga1981 agcaaagttt ttcaacggtt tgagaccgtc cgccgtaggcatgcttttga gcgtttgacc
2041 aagcagttcc aggcggtccc acagctcggt cacctgctctacggcatctc gatccagcat
2101 atctcctegt ttcgcgggtt ggggcggctt tcgctgtacggcagtagtcg gtgctcgtcc
2161 agacgggcca gggtcatgtc tttccacggg cgcagggtcctcgtcagcgt agtctgggtc
2221 acggtgaagg ggtgcgctcc gggctgcgcg ctggccagggtgcgcttgag gctggtcctg
2281 ctggtgctga agcgctgccg gtcttcgccc tgcgcgtcggccaggtagca tttgaccatg
2341 gtgtcatagt ccagcccctc cgcggcgtgg cccttggcgcgcagcttgcc cttggaggag
2401 geg.ccgcacg aggggcagtg cagacttttg agggcgtagagcttgggcgc gagaaatacc
2461 gattccgggg agtaggcatc cgcgccgcag gccccgcagacggtctcgca ttccacgagc
2521 caggtgagct ctggccgttc ggggtcaaaa accaggtttcccccatgctt tttgatgcgt
2581 ttcttacctc tggtttccat gagccggtgt ccacgctcggtgacgaaaag gctgtccgtg.
2641 tccccgtata cagacttgag agggagttta aacgaattcaatagcttgtt gcatgggcgg
2701 cgatataaaa tgcaaggtgc tgctcaaaaa atcaggcaaagcctcgcgca aaaaagaaag
2761 cacatcgtag tcatgctcat gcagataaag gcaggtaagctccggaacca ccacagaaaa
2821 agacaccatt tttctctcaa acatgtctgc gggtttctgcataaacacaa aataaaataa
2881 caaaaaaaca tttaaacatt agaagcctgt cttacaacaggaaaaacaac ccttataagc
2941 ataagacgga ctacggccat gccggcgtga ccgtaaaaaaactggtcacc gtgattaaaa
3001 agcaccaccg acagctcctc ggtcatgtcc ggagtcataatgtaagactc ggtaaacaca
3061 tcaggttgat tcatcggtca gtgctaaaaa gcgaccgaaatagcccgggg gaatacatac
3121 ccgcaggcgt agagacaaca ttacagcccc cataggaggtataacaaaat taataggaga
3181 gaaaaacaca taaacacctg aaaaaccctc ctgcctaggcaaaatagcac cctcccgctc
3241 cagaacaaca tacagcgctt cacagcggca gcctaacagtcagccttacc agtaaaaaag
3301 aaaacctatt aaaaaaacac cactcgacac ggcaccagctcaatcagtca cagtgtaaaa
3361 aagggccaag tgcagagcga gtatatatag gactaaaaaatgacgtaacg gttaaagtcc
3421 acaaaaaaca cccagaaaac cgcacgcgaa cctacgcccagaaacgaaag ccaaaaaacc3481 cacaacttcc tcaaatcgtc acttccgttt tcccacgttacgtaacttcc cattttaaga
3541 aaactacaat tcccaacaca tacaagttac tccgccctaâ
aacctacgtc acccgccccg
3601 ttcccacgcc ccgcgccacg tcacaaactc caccccctca
ttatcatatt ggcttcaatc
3661 caaaataagg tatattattg atgatgttaa ttaacatgca
tggatccata tgcggtgtga
3721 aataccgcac agatgcgtaa ggagaaaata ccgcatcagg
cgctcttccg cttcctcgct
3781 cactgactcg ctgcgctcgg tcgttcggct gcggcgagcggtatcagctc actcaaaggc
3841 ggtaatacgg ttatccacag aatcagggga taacgcaggaaagaacatgt gagcaaaagg
3901 ccagcaaaag gccaggaacc gtaaaaaggc cgcgttgctggcgtttttcc ataggctccg
3961 cc.cccctgac gagcatcaca aaaatcgacg çtcaagtcagaggtggcgaa acccgacagg
4021 actataaaga taccaggcgt ttccccctgg aagctccctcgtgcgctctc ctgttccgac
4081 cctgccgctt accggatacc tgtccgcctt tctcccttcgggaagcgtgg cgctttctca
4141 tagctcacgc tgtaggtatc tcagttcggt gtaggtcgttcgctccaagc tgggctgtgt
4201 gcacgaaccc cccgttcagc ccgaccgctg cgccttatccggtaactatc gtcttgagtc
4261 caacccggta agacacgact tatcgccact ggcagcagccactggtaaca ggattagcag
4321 agcgaggtat gtaggcggtg ctacagagtt cttgaagtggtggcctaact acggctacac
4381 tagaaggaca gtatttggta tctgcgctct gctgaagccagttaccttcg gaaaaagagt
4441 tggtagctct tgatccggca aacaaaccac cgctggtagcggtggttttt ttgtttgcaa
4501 gcagcagatt acgcgcagaa aaaaaggatc tcaagaagatcctttgatct tttctacggg
4561 gtctgacgct cagtggaacg aaaactcacg ttaagggattttggtcatga gattatcaaa
4621 aaggatcttc acctagatcc ttttaaatta aaaatgaagttttaaatcaa tctaaagtat
4681 atatgagtaa acttggtctg acagttacca atgcttaatcagtgaggcac ctatctcagc
4741 gatctgtcta tttcgttcat ccatagttgc ctgactccccgtcgtgtaga taactacgat
4801 acgggagggc ttaccatctg gccccagtgc tgcaatgataccgcgagacc cacgctcacc
4861 ggctccagat ttatcagcaa taaaccagcc agccggaagggccgagcgca gaagtggtcc
4921 tgcaacttta tccgcctcca tccagtctat taattgttgccgggaagcta gagtaagtag4981 ttcgccagtt aatagtttgc gcaacgttgt tgccattgctgcagccatga gattatcaaa
5041 aaggatcttc acctagatcc ttttcacgta gaaagccagt
ccgcagaaac ggtgctgacc
5101 ccggatgaat gtcagctact gggctatctg gacaagggaa
aacgcaagcg caaagagaaa
5161 gcaggtagct tgcagtgggc ttacatggcg atagctagac
tgggcggttt tatggacagc
5221 aagcgaaccg gaattgccag ctggggcgcc ctctggtaaggttgggaagc cctgcaaagt
5281 aaactggatg gctttctcgc cgccaaggat ctgatggcgcaggggatcaa gctctgatca
5341 agagacagga tgaggatcgt ttcgcatgat tgaacaagat
ggattgcacg caggttctcc
5401 ggccgcttgg gtggagaggc tattcggcta tgactgggca
caacagacaa tcggctgctc
54 61 tgatgccgcc gtgttccggc tgtcagcgca ggggcgcccggttctttttg tcaagaccga
5521 cctgtccggt gccctgaatg aactgcaaga cgaggcagcg
cggctatcgt ggctggccac
5.581 gacgggcgtt ccttgcgcag ctgtgctcga cgttgtcact
gaagcgggaa gggactggct
5641 gctattgggc gaagtgccgg ggcaggatct cctgtcatct
caccttgctc ctgccgagaa
5701 agtatccatc atggctgatg caatgcggcg gctgcatacgcttgatccgg ctacctgccc
5761 attcgaccac caagcgaaac atcgcatcga gcgagcacgt
actcggatgg aagccggtct
5821 tgtcgatcag gatgatctgg acgaagagca tcaggggctcgcgccagccg aactgttcgc
5881 caggctcaag gcgagcatgc ccgacggcga ggatctcgtc
gtgacccatg gcgatgcctg
5941 cttgccgaat atcatggtgg aaaatggccg cttttctgga
ttcatcgact gtggccggct
6001 gggtgtggcg gac.cgctatc aggacatagc gttggctacc
cgtgatattg ctgaagagct
6061 tggcggcgaa tgggctgacc gcttcctcgt gctttacggtatcgccgctc ccgattcgca
6121 gcgcatcgcc ttctatcgcc ttcttgacga gttcttct-gaattttgttaa aatttttgtt
6181 aaatcagctc attttttaac caataggccg aaatcggcaacatcccttat aaatcaaaag
6241 aatagaccgc gatagggttg agtgttgttc cagtttggaacaagagtcca ctattaaaga
6301 acgtggactc caacgtcaaa gggcgaaaaa ccgtctatcagggcgatggc ccactacgtg
6361 aaccatcacc caaatcaagt tttttgcggt cgaggtgccgtaaagctcta aatcggaacc
6421 ctaaagggag cccccgattt agagcttgac ggggaaagccggcgaacgtg gcgagaaagg6481 aagggaagaa agcgaaagga gcgggcgcta gggcgctggcaagtgtagcg gtcacgctgc
6541 gcgtaaccac cacacccgcg cgcttaatgc gccgctacagggcgcgtcca ttcgccattc
6601 aggatcgaat taattcttaa t
SEQ ID Ne: 7
taacatcatc aataatatac cttattttgg attgaagcca atatgataatgagggggtgg agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtgacgtagtagt gtggcggaag tgtgatgttg caagtgtggc ggaacacatgtaagcgacgg atgtggcaaa agtgacgttt ttggtgtgcg ccggtgtacacaggaagtga caattttcgc gcggttttag gcggatgttg tagtaaatttgggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataagaggaagtgaaa tctgaataat tttgtgttac tcatagcgcg
taatactGCTAGAgatCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTftACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTGTAATACGACTCACTÁTAGGGCGAATTGGGTACTGGCCAca gagcttggcccattgcatacgttgtatccatatcataatatgtacatttatattggctcatgtccaacattaccgccatgttgacattgattattgactagttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgccfcattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaag-tacgccccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagtcatcgcta-ttaccatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccaccccattgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggagg-tctatataagcagagctcgtttagtgaaccgtcagatcgcctggagacgccatccacgctgttttgacctccatagaagacaccgggaccgatccagcctgactctagCctÁGCTCtgaagttggtggtgaggccctggigcaggttggtatcaaggt-tacaagacaggtttaaggagaccaatagaaactgggcatgtggagacagagaagactGttgggtttctgataggcactgactctctctgcctattggtctattttcccacccttaggctgctggtctgagcctagGÃ<SA3TC2X:TCGAGGTCGACGGTA2tegatgcca ccATGGAGAA AATCGTCGTG TTGCTCGCTA TTGTGTCTCT
51 AGTGAAGAGC GATCAAATTT GTATCGGCTA CCATGCCAAT AACTCAACAG101 AGCAGGTCGA TACTATCATG GAGAAAAACG TAACAGTTAC TCATGCCCAA151 GACATCTTGG AAAAGACCCA CAACGGCAAA CTTTGCGACC TGGATGGAGT201 GAAGCCCCTG ATCCTCCGGG ACTGTTCAGT CGCTGGTTGG CTGCTCGGGA251 ACCCTATGTG TGATGAGTTT ATCAACGTGC CTGAATGGTC TTACATTGTG301 GAGAAGGCTA ACCCTACCAA TGACCTCTGC TATCCTGGGT CATTTAACGÃ351 TTACGAGGAA CTGAAACACC TGTTGTCTAG AATTAACCAC TTTGAAAAGA401 TACAGATTAT ACCCAAGTCT AGTTGGAGTG ATCACGAAGC CTCCTCAGGC451 GTTAGCTCAG CGTGTCCCTA TCTGGGCTCT CCATCCTTCT TTAGAAATGT501 GGTCTGGTTA ATCAAAAAGA ACAGTACCTA CCCAACCATC AAAAAGTCTT551 ATAACAATAC CAATCAGGAG GACCTGCTCG TGTTGTGGGG TATCCATCAC601 CCGAACGACG CCGCTGAACA GACTAGGCTG TATCAGAACC CCACTACATA651 CATCAGTATT GGCACGAGTA CTCTGAACCA GCGATTAGTG CCAAAGATTG701 CAACACGGAG CAAAGTAAAT GGGCAATCTG GCAGGATGGA GTTTTTCTGG751 ACAATCTTAA AACCCAACGA TGCGATAAAT TTCGAGTCCA ATGGCAATTT801 CATCGCCCCT GAATACGCCT ATAAGATCGT GAAAAAGGGG GACTCTGCAA851 TTATGAAGTC CGAATTAGAG TATGGCAATT GCAACACGAA GTGCCAGACA901 CCAATGGGAG CCATTAATAG CTCAATGCCC TTCCATAATA TTCATCCATT951 GACCATTGGG GAGTGCCCAA AGTACGTGAA GTCCAACCGC CTGGTCCTCG1001 CAACCGGTCT AAGAAATAGC ÇCGCAGAGAG AATCGCGGAG GAAGAAACGT1051 GGCCTGTTTG GCGCGATTGC CGGATTCATC GAGGGAGGCT GGCAGGGTAT1101 GGTCGATGGT TGGTACGGAT ACCACCATAG CAACGAACAG GGGTCCGGCT1151 ATGCAGCAGA TAAGGAGAGC ACTCAGAAAG CTATTGACGG AGTTACAAAÇ1201 AAGGTTAATA GTATTATAGA TAAAATGAAC ACGiCAATTCG AGGCCGTTGG1251 GAGGGAGTTT AACAATCTGG AACGCCGGAT CGAAAATCTG AATAAGAAAA1301 TGGAAGACGG CTTCCTTGAC GTGTGGACTT ATAATGCAGA GCTGCTTGTA1351 CTCATGGAGA ACGAGAGGAC CCTGGATTTC CACGATAGCA ACGTGAAGAA1401 CCTTTACGAC AAGGTGAGAC TTCAGCTCCG AGACAACGCC AAGGAGCTGG1451 GGAATGGATG CTTCGAGTTT TACCACAAAT GTGACAATGA GTGCATGGAA1501 AGTATACGCA ACGGGACCTA CAATTACCCT CAGTATAGCG AAGAGGCTCG1551 GCTCAAACGC GAAGAGATAA GCGGGGTGAA ATTGGAATCA ATCGGAAÇAT1601 ATCAAATCCT GTCCATCTAT TCCACCGTCG CCTCTTCGCT GGCCCTCGCT1651 ATCATGATGG CTGGTCTGTC CCTATGGATG TGTTCCAATG GAAGCCTTCA1701 GTGCCGTATT TGTATATGAg c
GGCCGCCCTATTCTATAGTGTCACCTAAATGCTAGaCCTCGCTGATCAGCCTCGACTGTGCCTT.
CTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCAC
TGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGT
GGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCT
CTATGGCTTCTGAGGCGGAAAGAACCAA
TGATATCGAATTCGCCCTTAGATATCGTCGACGCCCAGCACCCCAAGGCGGCCAACGCCAAAACTCTCCCTCCTCCTCTTCCTCAATCTCGCTCTCGCTCTTTTTTTTTTTÇGCAAAAGGAGGGGAGAGGGGGTAAAAAAATGCTGCACTGTGCGGCGAAGCCGGTGAGTGAGCGGCGCGGGGCCaft-ATCAGCGTGCGCCGTTCCGAAAGTTGCCTTTTATGGCTCGAGCGGCCGCGGCGGCGCCCTATAAAACCCAGCGGCGCGACGCGCCACCACCGCCGAGACATCGATGATATCTAAAGGGCGAATTCCTGCAGgaaacgatatgggctgaatacggatccgtattcagcccata-tcgtttcTCTAGAA
ataaaatatctttattttcattacatctgtgtgttggttttttgtgtggcggccgccaccgc
GGTGG
agctTgtegactcg aagatctggg cgtggttaag
421 ggtgggaaag aatatataag gtgggggtct tatgtagttttgtatctgtt ttgcagcagc
481 cgccgccgcc atgagcacca actcgtttga tggaagcattgtgagctcat atttgacaac
541 gcgcatgccc ccatgggccg gggtgcgtca gaatgtgatgggctccagca ttgatggtcg
601 ccccgtcctg cccgcaaact ctactacctt gacctacgagaccgtgtctg gaacgccgtt
661 ggagactgca gcctccgccg ccgcttcagc cgctgcagccaccgcccgcg ggattgtgac
721 tgactttgct ttcctgagcc cgcttgcaag cagtgcagcttcccgttcat ccgcccgcga
781 tgacaagttg acggctcttt tggcacaatt ggattctttgacccgggaac ttaatgtcgt841 ttctcagcag ctgttggatc tgcgccagca ggtttctgccctgaaggctt cctcccctcc
901 caatgcggtt taaaacataa ataaaaaacc agactctgtttggatttgga tcaagcaagt
961 gtcttgctgt ctttatttag gggttttgcg cgcgcggtaggcccgggacc agcggtctcg
1021 gtcgttgagg gtcctgtgta ttttttccag gacgtggtaaaggtgactct ggatgttcag
1081 atacatgggc ataagcccgt ctctggggtg gaggtagcaccactgcagag cttcatgctg
1141 cggggtggtg ttgtagatga tccagtcgta gcaggagcgctgggcgtggt gcctaaaaat
1201 gtctttcagt agcaagctga ttgccagggg caggcccttggtgtaagtgt ttacaaagcg
1261 gttaagctgg gatgggtgca tacgtgggga tatgagatgcatcttggact gtatttttag
1321 gttggctatg ttcccagcca tatccctccg gggattcatgttgtgcagaa ccaccagcac
1381 agtgtatccg gtgcacttgg gaaatttgtc atgtagcttagaaggaaatg cgtggaagaa
1441 cttggagacg cccttgtgac ctccaagatt ttccatgcattcgtccataa tgatggcaat
1501 gggcccacgg gcggcggcct gggcgaagat atttctgggatcactaacgt catagttgtg
1561 ttccaggatg agatcgtcat aggccatttt tacaaagcgcgggcggaggg tgccagactg
1621 cggtataatg gttccatccg gcccaggggc gtagttaccctcacagattt gcatttccca
1681 cgctttgagt tcagatgggg ggatcatgtc tacctgcggggcgatgaaga aaacggtttc
1741 cggggtaggg gagatcagct gggaagaaag caggttcctgagcagctgcg acttaccgca
1801 gccggtgggc ccgtaaatca cacctattac cgggtgcaactggtagttaa gagagctgca .
1861 gctgccgtca tccctgagca ggggggccac ttcgttaagcatgtccctga ctcgcatgtt
1921 ttccctgacc aaatccgcca gaaggcgctc gccgcccagcgatagcagtt cttgcaagga
1981 agcaaagttt ttcaacggtt tgagaccgtc cgccgtaggcatgcttttga gcgtttgacc
2041 aagcagttcc aggcggtccc acagctcggt cacctgctctacggcatctc gatccageat
2101 atctcctcgt ttcgcgggtt ggggcggctt tcgctgtacggcagtagtcg gtgctcgtcc
2161 agacgggcca gggtcatgtc tttccacggg cgcagggtcctcgtcagcgt agtctgggtc
2221 acggtgaagg ggtgcgctcc gggctgcgcg ctggccagggtgcgcttgag gctggtcctg
2281 ctggtgctga agcgctgccg gtcttcgccc tgcgcgtcggccaggtagca tttgaccatg2341 gtgtcatagt ccagcccctc cgcggcgtgg cccttggcgcgcagcttgcc cttggaggag
2401 gcgccgcacg aggggcagtg cagacttttg agggcgtagagcttgggcgc gagaaatacc
2461 gattccgggg agtaggcatc cgcgccgcag gccccgcaga
cggtctcgca ttccacgagc
2521 caggtgagct ctggccgttc ggggtcaaaa accaggtttc
ccccatgctt tttgatgcgt
2581 ttcttacctc tggtttccat gagccggtgt ccacgctcgg
tgacgaaaag gctgfcccgtg
2641 tccccgtata cagacttgag agggagttta aacgaattca
atagcttgtt gcatgggcgg
2701 cgatataaaa tgcaaggtgc tgctcaaaaa atcaggcaaa
gcctcgcgca aaaaagaaag
2761 cacatcgtag tcatgctcat gcagataaag gcaggtaagctccggaacca ccacagaaaa
2821 agacaccatt tttctctcaa acatgtctgc gggtttctgcataaacacaa aataaaataa
2881 caaaaaaaca tttaaacatt agaagcctgt cttacaacag
gaaaaacaac ccttataagc
2941 ataagacgga ctacggccat gccggcgtga ccgtaaaaaa
actggtcacc gtgattaaaa
3001 agcaccaccg acagctcctc ggtcatgtcc ggagtcataa
tgtaagactc ggtaaacaca
3061 tcaggttgat tcatcggtca gtgctaaaaa gcgaccgaaatagcccgggg gaatacatac
3121 ccgcaggcgt agagacaaca ttacagcccc cataggaggt
ataacaaaat taataggaga
3181 gaaaaacaca taaacacctg aaaaaccctc ctgcctaggcaaaatagcac cctcccgctc
3241 cagaacaaca tacagcgctt cacagcggca gcctaacagt
cagccttacc agtaaaaaag
3301 aaaacctatt aaaaaaacac cactcgacac ggcaccagct
caatcagtca cagtgtaaaa
3361 aagggccaag tgcagagcga gtatatatag gactaaaaaa
tgacgtaacg gttaaagtcc
3421 acaaaaaaca cccagaaaac cgcacgcgaa cctacgccca
gaaacgaaag ccaaaaaacc
3481 cacaacttcc tcaaatcgtc acttccgttt tcccacgttacgtaacttcc cattttaaga
3541 aaactacaat tcccaacaca tacaagttac tccgccctaa
aacctacgtc acccgccccg ·
3601 ttcccacgcc ccgcgccacg tcacaaactc caccccctca
ttatcatatt ggcttcaatc
3661 caaaataagg tatattattg atgatgttaa ttaacatgca
tggatccata tgcggtgtga
3721 aataccgcac agatgcgtaa ggagaaaata ccgcatcagg
cgctcttccg cttcctcgct
3781 cactgactcg ctgcgctcgg tcgttcggct gcggcgagcggtatcagctc actcaaaggc3841 ggtaatacgg ttatccacag aatcagggga taacgcaggaaagaacatgt gagcaaaagg
3901 ccagcaaaag gccaggaacc gtaaaaaggc cgcgttgctggcgtttttcc ataggctccg
3961 cccccctgac gagcatcaca aaaatcgacg ctcaagtcagaggtggcgaa acccgacagg
4021 actataaaga taccaggcgt ttccccctgg aagctccctcgtgcgctctc ctgttccgac
4081 cctgccgctt accggatacc tgtccgcctt tctcccttcgggaagcgtgg cgctttctca
4141 tagctcacgc tgtaggtatc tcagttcggt gtaggtcgttcgctccaagc tgggctgtgt
4201 gcacgaaccc cccgttcagc ccgaccgctg cgccttatccggtaactatc gtcttgagtc
4261 caacccggta agacacgact tatcgccact ggcagcagccactggtaaca ggattagcag
4321 agcgaggtat gtaggcggtg ctacagagtt cttgaagtggtggcctaact acggctacac
4381 tagaaggacá gtatttggta tctgcgctct gctgaagccagttaccttcg gaaaaagagt
4441 tggtagctct tgatccggca aacaaaccac cgctggtagcggtggttttt ttgtttgcaa
4501 gcagcagatt acgcgcagaa aaaaaggatc tcaagaagatcctttgatct tttctacggg
4561 gtctgacgct cagtggaacg aaaactcacg ttaagggattttggtcatga gattatcaaa
4621 aaggatcttc acctagatcc ttttaaatta aaaatgaagttttaaatcaa tctaaagtat
4681 atatgagtaa acttggtctg acagttacca atgcttaatcagtgaggcac ctatctcagc
4741 gatctgtcta tttcgttcat ccatagttgc ctgactccccgtcgtgtaga taactacgat
4801 acgggagggc ttaccatctg gccccagtgc tgcaatgataccgcgagacc cacgctcacc
4861 ggctccagat ttatcagcaa taaaccagcc agccggaagggccgagcgca gaagtggtcc
4921 tgcaacttta tccgcctcca tccagtctat taattgttgccgggaagcta gagtaagtag
4981 ttcgccagtt aatagtttgc gcaacgttgt tgccattgctgcagccatga gattatcaaa
5041 aaggatcttc acctagatcc ttttcacgta gaaagccagtccgcagaaac ggtgctgacc
5101 ccggatgaat gtcagctact gggctatctg gacaagggaaaacgcaagcg caaagagaaa
5161 gcaggtagct tgcagtgggc ttacatggcg atagctagactgggcggttt tatggacagc
5221 aagcgaaccg gaattgccag ctggggcgcc ctctggtaaggttgggaagc cctgcaaagt
5281 aaactggatg gctttctcgc cgccaaggat ctgatggcgcaggggatcaa gctctgatca5341 agagacagga tgaggatcgt ttcgcatgat tgaacaagatggattgcacg caggttctcc
5401 ggccgcttgg gtggagaggc tattcggcta tgactgggcacaacagacaa tcggctgctc
5461 tgatgccgcc gtgttccggc tgtcagcgca ggggcgcccggttctttttg tcaagaccga
5521 cctgtccggt gccctgaatg aactgcaaga cgaggcagcgcggctatcgt ggctggccac
5581 gacgggcgtt ccttgcgcag ctgtgctcga cgttgtcactgaagcgggaa gggactggct
5641 gctattgggc gaagtgccgg ggcaggatct cctgtcatctcaccttgctc ctgccgagaa
5701 agtatccatc atggctgatg caatgcggcg gctgcatacgcttgatccgg ctacctgccc
57 61 attcgaccac caagcgaaac atcgcatcga gcgagcacgtactcggatgg aagccggtct
5821 tgtcgatcag gatgatctgg acgaagagca tcaggggctcgcgccagccg aactgttcgc
5881 caggctcaag gcgagcatgc ccgacggcga ggatctcgtcgtgacccatg gcgatgcctg
5941 cttgccgaat atcatggtgg aaaatggccg cttttctggattcatcgact gtggccggct
6001 gggtgtggcg gaccgctatc aggacatagc gttggctacccgtgatattg ctgaagagct
6061 tggcggcgaa tgggctgacc gcttcctcgt gctttacggtatcgccgctc ccgattcgca
6121 gcgcatcgcc ttctatcgcc ttcttgacga gttcttctgaattttgttaa aatttttgtt
6181 aaatcagctc attttttaac caataggccg aaatcggcaacatcccttat aaatcaaaag
6241 aatagaccgc gatagggttg agtgttgttc cagtttggaacaagagtcca ctattaaaga
6301 acgtggactc caacgtcaaa gggcgaaaaa ccgtctatcagggcgatggc ccactacgtg
6361 aaccatcacc caaatcaagt tttttgcggt cgaggtgccgtaaagctcta aatcggaacc
6421 *ctaaagggag cccccgattt agagcttgac ggggaaagccggcgaacgtg gcgagaaagg
6481 aagggaagaa agcgaaagga gcgggcgcta gggcgctggcaagtgtagcg gtcacgctgc
6541 gcgtaaccac cacacccgcg cgcttaatgc gccgctacagggcgcgtcca ttcgccattc
6601 aggatcgaat taattcttaa t
SEQ ID: 8 GATGGTGCTTCAAGCTAGTACttaaGTACTAGCTTGAAGCACCATCSBQ ID: 9 GATGGTGCTTCAAGCTAGTACggatCCGTACTAGCTTGAAGCACCATCSEQ ID: 10 GAAACGATATGGGCTGAATACggatCcGTATTCAGCCCATATCGTTTCSEQ ID: 11 CCTAATAATTAT CAAAATGTggatccACATTTTGATAATTATTAGGSEQ ID: 12 CCTAATAATTAT CAAAATGTaattACATTTTGATAATTATTAGGSBQ ID: 13 (DSlc)
ltaacatcatc aataatatac cttattttgg attgaagcca atatgataatgagggggtgg
61 agtttgtgac gtggcgeggg gcgtgggaac ggggcgggtgacgtagtagt gtggeggaag
121 tgtgatgttg eaagtgtggc ggaacacatg taagcgacggatgtggeaaa agtgaegttt
181 ttggtgtgcg ceggtgtaca eaggaagtga caattttcgcgeggttttag geggatgttg
241 tagtaaattt gggcgtaacc gagtaagatt tggccattttegcgggaaaa ctgaataaga
301 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcgtaataetgta atagtaatca
361 attaeggggt eattagttea tagcccatat atggagttccgcgttacata acttaeggta
421 aatggcccge ctggctgacc geecaacgac cccegcccattgacgteaat aatgaegtat
481 gttcccatag taacgccaat agggactttc cattgacgtcaatgggtgga gtatttacgg
541 taaactgccc acttggeagt acatcaagtg tatcatatgecaagtacgcc ccctattgac
601 gtcaatgacg gtaaatggcc egcctggcat tatgeccagtaeatgacctt atgggaettt
661 cctacttggc agtaeatcta cgtat^tagto ategote^teccatggtgat gcggttttgg
721 eagtacatca atgggcgtgg atagcggttt gactcacggggatttccaag tctccacccc
781 attgacgtca atgggagttt gttttggcac caaaatcaacgggactttec aaaatgtegt
84i:aacaactccg ccccattgac gcaaatgggc ggtaggegtgtaeggtggga ggtctatata
901 agcagagctg gtttagtgaa ccgtcagatc cgctagagatetGGTACCGAGCTCGGATCCGCCACCATGGAGGCAAACCTACTGGTCCTGTTATGTGCACTTGCAGCTGCAGATGCAGACACAATATGTATAGGCTACCATGCGAACAATTCAACCGACACTGGTGACACAGTActcgagaaga atgtgaoagt gacacactct gttaaoctgo181 tegaagaeag ecacaaegga aaactatgta gattaaaaggaatagcecca etaeaattgg
241 ggaaatgtaa catcgccgga tggctcttgg gaaacccagaatgegaccca ctgcttccag
301 tgagatcatg gtectaca.tt gtagaaacac caaactctgagaatggaata tgttatccag
361 gagatttcat cgactatgag gagctgaggg agcaattgagetcagtgtca tcattegaaa
421 gattcgaaat atttcceaaa gaaagctcat ggcccaaecacaacacaacc aaaggagtaa
481 cggcagcatg ctcccatgcg gggaaaagca gtttttacagaaatttgcta tggctgacgg541 agaaggaggg ctcataccca aagctgaaaa attcttatgtgaacaagaaa gggaaagaag
601 tccttgtact gtggggtatt catcacccgt ctaacagtaaggatcaacag aatatctatc
661 agaatgaaaa tgcttatgtc tctgtagtga cttcaàattataacaggaga tttaccccgg
721 aaatagcaga aagacccaaa gtaagagatc aagctgggaggatgaactat tactggacct
781 tgctaaaacc cggagacaca ataatatttg aggcaaatggaaatctaata gcaccaaggt
841 atgctttcgc actgagtaga ggctttgggt ccggcatcatcacctcaaac gcatcaatgc
901 atgagtgtaa cacgaagtgt caaacacccc tgggagctataaacagcagt ctccctttcc
961 agaatataca cccagtcaca ataggagagt gcccaaaatacgtcaggagt gccaaattga .
1021 ggatggttac aggactaagg aacattccgt ccattcaatccagaggtcta tttggagcca
1081 ttgccggttt tattgaaggg ggatggactg gaatgatagatggatggtac ggttatcatc
1141 atcagaatga acagggatca ggctatgcag cggatcaaaaaagcacacaa aatgccatta
1201 acgggattac àaacaaggtg aactctgtta tcgagaaaatgaacattcaa ttcacagctg
1261 tgggtaaaga attcaacaaa ttagaaaaaa ggatggaaaatttaaataaa aaagttgatg
1321 atggatttct ggacatttgg acatataatg cagaattgttagttctac-tg gaaaatgaaa
1381 ggactctgga tttccatgac tcaaatgtga agaatctgtatgagaaagta aaaagccaat
1441 taaagaataa tgccaaagaa atcggaaatg gatgttttgagttctaccac aagtgtgaca
1501 atgaatgcat ggaaagtgta agaaatggga cttatgattatcccaaatat tcagaagagt
1561 caaagttgaa cagggaaaag gtagatggag tgaaattggaatcaatgggg atctatcaga
1621 ttctggcgat ctactcaact gtcgccagtt cactggtgctttt.ggtctcc ctgggggcaa
1681 tcagtttctg gatgtgttct aatggatctt tgcagtgcagaatatgcatc tgagattaga
1741 atttcagaga tatgaggaaa aacacccttg tttctactCCCAAGCTTTAATGCGGTAGTTTATCACAGTTAAATTGCTAA
CGCAGTCAGGCACCGTGTATGAAATCTAACAATGCGCTCATCGTCATCCTCGGCACCGTCACCCTGGATGCTGTAGGCATAGGCTTGGTXATGCCGGTACTGCCGGGCCTCTTGCGGGATGGGCGGCCGCtcgagcet aagcttctag ataagatatc cgatccaccg gatctagataactgatcata
1021 atcagccata ccacatttgt agaggtttta cttgctttaaaaaacctccc acacctcccc
1081 ctgaacctga aacataaaat gaatgcaatt gttgttgttaacttgtttat tgcagcttat1141 aatggttaca aataaagcaa tagcatcaca aatttcacaaataaagcatt tttttcactg
1201 cattctagtt gtggtttgtc caaactcatc aatgtatcttaacgcggatc tgggcgtggt
1261 taagggtggg aaagaatata taaggtgggg gtcttatgtagttttgtatc tgttttgcag
1321 cagccgccgc cgccatgagc accaactcgt ttgatggaagcattgtgagc tcatatttga
1381 caacgcgcat gcccccatgg gccggggtgc gtcagaatgtgatgggctcc agcattgatg
1441 gtcgccccgt cctgcccgca aactctacta ccttgacctacgagaccgtg tctggaacgc
1501 cgttggagac tgcagcctcc gccgccgctt cagccgctgcagccaccgcc cgcgggattg
1561 tgactgactt tgctttcctg agcccgcttg caagcagtgcagcttcccgt tcatccgccc
1621 gcgatgacaa gttgacggct cttttggcac aattggattctttgacccgg gaacttaatg
1681 tcgtttctca gcagctgttg gatctgcgcc agcaggtttctgccctgaag gcttcctccc
1741 ctcccaatgc ggtttaaaac ataaataaaa aaccagactctgtttggatt tggatcaagc
1801 aagtgtcttg ctgtctttat ttaggggttt tgcgcgcgcggtaggcccgg gaccagcggt
1861 ctcggtcgtt gagggtcctg tgtatttttt ccaggacgtggtaaaggtga ctctggatgt
1921 tcagatacat gggcataagc ccgtetctgg ggtggaggtagcaccactgc agagcttcat
1981 gctgcggggt ggtgttgtag atgatccagt cgtagcaggagcgctgggcg tggtgcctaa
2041 aaatgtcttt cagtagcaag ctgattgcca ggggcaggcccttggtgtaa gtgtttacaa
2101 agcggttaag ctgggatggg tgcatacgtg gggatatgagatgcatcttg gactgtattt
2161 ttaggttggc tatgttccca gccatatccc tccggggattcatgttgtgc agaaccacca
2221 gcacagtgta tccggtgcac ttgggaaatt tgtcatgtagcttagaagga aatgcgtgga
2281 agaacttgga gacgcccttg tgacctccaa gattttccatgcattcgtcc ataatgatgg
2341 caatgggccc acgggcggcg gcctgggcga agatatttctgggatcacta acgtcatagt
2401 tgtgttccag gatgagatcg tcataggcca tttttacaaagcgcgggcgg agggtgccag
24 61 actgcggtat aatggttcca tccggcccag gggcgtagttaccctcacag atttgcattt
2521 cccacgcttt gagttcagat ggggggatca tgtctacctgcggggcgatg aagaaaacgg
2581 tttccggggt aggggagatc agctgggaag aaagcaggttcctgagcagc tgcgacttac2641 cgcagccggt gggcccgtaa atcacaccta ttaccgggtg
caactggtag ttaagagagc
2701 tgcagctgcc gtcatccctg agcagggggg ccacttcgtt
aagcatgtcc ctgactcgca
2761 tgttttccct gaccaaatcc gccagaaggc gctcgccgcc
cagcgatagc agttcttgca
2821 aggaagcaaa gtttttcaac ggtttgagac cgtccgccgtaggcatgctt ttgagcgttt
2881 gaccaagcag ttccaggcgg tcccacagct cggtcacctg
ctctacggca tctcgatcca
2941 gcatatctcc tcgtttcgcg ggttggggcg gctttcgctgtacggcagta gtcggtgctc
3001 gtccagacgg gccagggtca tgtctttcca cgggcgcagggtcctcgtca gcgtagtctg
3061 ggtcacggtg aaggggtgcg ctccgggctg cgcgctggccagggtgcgct tgaggctggt
3121 cctgctggtg ctgaagcgct gccggtcttc gccctgcgcgtcggccaggt agcatttgac
3181 catggtgtca tagtccagcc cctccgcggc gtggcccttggcgcgcagct tgcccttgga
3241 ggaggcgccg cacgaggggc agtgcagact tttgagggcgtagagcttgg gcgcgagaaa
3301 taccgattcc ggggagtagg catccgcgcc gcaggccccgcagacggtct cgcattccac
3361 gagccaggtg agctctggcc gttcggggtc aaaaaccaggtttcccccat gctttttgat
3421 gcgtttctta cctctggttt ccatgagccg gtgtccacgctcggtgacga aaaggctgtc
3481 cgtgtccccg tatacagact tgagagggag tttaaacgaa
ttcaatagct tgttgcatgg
3541 gcggcgatat aaaatgcaag gtgctgctca aaaaatcaggcaaagcctcg cgcaaaaaag
3601 aaagcacatc gtagtcatgc tcatgcagat aaaggcaggtaagctccgga accaccacag
3661 aaaaagacac catttttctc tcaaacatgt ctgcgggttt
ctgcataaac acaaaataaa
3721 ataacaaaaa aacatttaaa cattagaagc ctgtcttacaacaggaaaaa caacccttat
3781 aagcataaga cggactacgg ccatgccggc gtgaccgtaaaaaaactggt caccgtgatt
3841 aaaaagcacc accgacagct cctcggtcat gtccggagtcataatgtaag actcggtaaa
3901 cacatcaggt tgattcatcg gtcagtgcta aaaagcgaccgaaatagccc gggggaatac
3961 atacccgcag gcgtagagac aacattacag cccccataggaggtataaca aaattaatag
4021 gagagaaaaa cacataaaca cctgaaaaac cctcctgcct
aggcaaaata gcaccctccc
4081 gctccagaac aacatacagc gcttcacagc ggcagcctaacagtcagcct taccagtaaa4141 aaagaaaacc tattaaaaaa acaccactcg acacggcaccagctcaatca gtcacagtgt
4201 aaaaaagggc caagtgcaga gcgagtatat ataggactaaaaaatgacgt aacggttaaa
4261 gtccacaaaa aacacccaga aaaccgcacg cgaacctacgcccagaaacg aaagccaaaa
4321 aacccacaac ttcctcaaat cgtcacttcc gttttcccacgttacgtaac ttcccatttt
4381 aagaaaacta caattcccaa cacatacaag ttactccgccctaaaaccta cgtcacccgc
4441 cccgttccca cgccccgcgc cacgtcacaa actccaccccctcattatca tattggcttc
4501 aatccaaaat aaggtatatt attgatgatg ttaattaacatgcatggatc catatgcggt
4561 gtgaaatacc gcacagatgc gtaaggagaa aataccgcatcaggcgctct tccgcttcct
4621 cgctcactga ctcgctgcgc tcggtcgttc ggctgcggcgagcggtatca gctcactcaa
4681 aggcggtaat acggttatcc acagaatcag gggataacgcaggaaagaac atgtgagcaa
4741 aaggccagca aaaggccagg aaccgtaaaa aggccgcgttgctggcgttt ttccataggc
4801 tccgcccccc tgacgagcat cacaaaaatc gacgctcaagtcagaggtgg cgaaacccga
4861 caggactata aagataccag gcgtttcccc ctggaagctccctcgtgcgc tctcctgttc
4921 cgaccctgcc gcttaccgga tacctgtccg cctttctcccttcgggaagc gtggcgcttt
4981 ctcatagctc acgctgtagg tatctcagtt cggtgtaggtcgttcgctcc aagctgggct
5041 gtgtgcacga accccccgtt cagcccgacc gctgcgccttatccggtaac tatcgtcttg
5101 agtccaaccc ggtaagacac gacttatcgc cactggcagcagccactggt aacaggatta
5161 gcagagcgag gtatgtaggc ggtgctacag agttcttgaagtggtggcct aactacggct
5221 acactagaag gacagtattt ggtatctgcg ctctgctgaagccagttacc ttcggaaaaa
5281 gagttggtag ctcttgatcc ggcaaacaaa ccaccgctggtagcggtggt ttttttgttt
5341 gcaagcagca gattacgcgc agaaaaaaag gátctcaagaagatcctttg atcttttcta
5401 cggggtctga cgctcagtgg aacgaaaact cacgttaagggattttggtc atgagattat
5461 caaaaaggat cttcacctag atccttttaa attaaaaatgaagttttaaa tcaatctaaa
5521 gtatatatga gtaaacttgg tctgacagtt accaatgcttaatcagtgag gcacctatct
5581 cagcgatctg tctatttcgt tcatccatag ttgcctgactccccgtcgtg tagataacta5641 cgatacggga gggcttacca tctggcccca gtgctgcaat
gataccgcga gacccacgct
5701 caccggctcc agatttatca gcaataaacc agccagccgg
aagggccgag cgcagaagtg
5761 gtcctgcaac tttatccgcc tccatccagt ctattaattg
ttgccgggaa gctagagtaa
5821 gtagttcgcc agttaatagt ttgcgcaacg ttgttgccat
tgctgcagcc atgagattat
5881 caaaaaggat cttcacctag atccttttca cgtagaaagccagtccgcag aaacggtgct
5941 gaccccggàt gaatgtcagc tactgggcta tctggacaagggaaaacgca agcgcaaaga
6001 gaaagcaggt agcttgcagt gggcttacat ggcgatagct
agactgggcg gttttatgga
6061 cagcaagcga accggaattg ccagctgggg cgccctctggtaaggttggg aagccctgca
6121 aagtaaactg gatggctttc tcgccgccaa ggatctgatg
gcgcagggga tcaagctctg
6181 atcaagagac aggatgagga tcgtttcgca tgattgaaca
agatggattg cacgcaggtt
6241 ctccggccgc ttgggtggag aggctattcg gctatgactgggcacaacag acaatcggct
6301 gctctgatgc cgccgtgttc cggctgtcag cgcaggggcgcccggttctt tttgtcaaga
6361 ccgacctgtc cggtgccctg aatgaactgc aagacgaggc
agcgcggcta tcgtggctgg
6421 ccacgacggg cgttccttgc gcagctgtgc tcgacgttgt
cactgaagcg ggaagggact
6481 ggctgctatt gggcgaagtg ccggggcagg atctcctgtc
atctcacctt gctcctgccg
6541 agaaagtatc catcatggct gatgcaatgc ggcggctgca
tacgcttgat ccggctacct
6601 gcccattcga ccaccaagcg aaacatcgca tcgagcgagc
acgtactcgg atggaagccg
6661 gtcttgtcga tcaggatgat ctggacgaag agcatcaggggctcgcgcca gccgaactgt
6721 tcgccaggct çaaggcgagc atgcccgacg gcgaggatct
cgtcgtgacc catggcgatg
6781 cctgcttgcc gaatatcatg gtggaaaatg gccgcttttc
tggattcatc gactgtggcc
6841 ggctgggtgt ggcggaccgc tatcaggaca tagcgttggc
tacccgtgat attgctgaag
6901 agcttggcgg cgaatgggct gaccgcttcc tcgtgcttta
cggtatcgcc gctcccgatt
6961 cgcagcgcat cgccttctat cgccttcttg acgagttcttctgaattttg ttaaaatttt
7021 tgttaaatca gctcattttt taaccaatag gccgaaatcggcaacatccc ttataaatca
7081 aaagaataga ccgcgatagg gttgagtgtt gttccagtttggaacaagag tccactatta7141 aagaacgtgg actccaacgt caaagggcga aaaaccgtctatcagggcga tggcccacta
7201 cgtgaaccat cacccaaatc aagttttttg cggtcgaggtgccgtaaagc tctaaatcgg
7261 aaccctaaag ggagcccccg atttagagct tgacggggaaagccggcgaa cgtggcgaga
7321 aaggaaggga agaaagcgaa aggagcgggc gctagggcgctggcaagtgt agcggtcacg
7381 ctgcgcgtaa ccaccacacc cgcgcgctta atgcgccgctacagggcgcg tccattcgcc
7441 attcaggatc gaattaattc ttaatSEQ ID:14 DS2beta-luc
taacatcatc aataatatac cttattttgg attgaagcca atatgataatgagggggtgg agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtgacgtagtagt gtggcggaag tgtgatgttg caagtgtggc ggaacacatgtaagcgacgg atgtggcaaa agtgacgttt ttggtgtgcg ccggtgtacacaggaagtga caattttcgc gcggttttag gcggatgttg tagtaaatttgggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataagaggaagtgaaa tctgaataat tttgtgttac tcatagcgcg
taatactGCTAGAgatCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGC
CAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTGTAATACGACTCACTA
TAGGGCGAATTGGGXACTGGCCAcagagcttggcccattgcatacgttgtatccatatcata
atatgtacatttatattggctcatgtccaacattaccgccatgttgacattgattattgact
agttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgt
tacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgt
caataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtg
gagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgcc
ccctatt gacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgacctt^tf^
gggactttcctacttggcagtacatctacgta-ttagfccategcfcafcfcaccatggtgatgcgg
ttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctcca
ccccattgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtc
gtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggt ctatata
agcagagctcgtttagtgaaccgtcagatcgcctggagacgccatccacgctgttttgacct
ccatagaagacaccgggaccgatccagcctgactctagCctAGCTCtgaagttggtggtgag
gccctgggcaggttggtatcaaggttacaagacaggtttaaggagaccaatagaaactgggo
afcgfcggagacagagaagactcttgggtttctgataggcactgactctctctgcctattggtc
tattttcccacccttaggctgctggtctgagcctagGAGATCTCTCGAGGTCGACGGTATCGATGGGrACCG<^GGCCCCCCTATTCTATAGTGTCACCTAAATGCTAGA<5CrCGCTGATCAGCCTCGACTGTGCCTT
CTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCAC
TGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGT
GGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCT
CTATGGCTTCTGAGGCGGAAAGAACCTATGGCTTCXGAGGCGGAAAGAACCAACCACCGCGGTGGCGGCCGCCACACAAAAAACCAACACACAGATGTAATGAAAATAAAGATATTTTATTTCTAGAGAAACGATATGGGCTGAATACGGATCCGTATTCAGCCCATATCGTTTCCTGCAGGAATTCGCCCTTTAGATATCATCGATGTCTCGGCGGTGGTGGCGCGTCGCGCCGCTGGGTTTTATAGGGCGCCGCCGCGGCCGCTCGAGCCATAAAAGGCAACTTTCGGAACGGCGCACGCTGATTGCCCGCGCCGCTCACTCACCGGCTTCGCCGCACAGTGCAGCATTTTTTTACCCCCTCTCCCCCTTTTGCGAAAAAAAAAAAGAGCGAGAGCGAGATTGAGGAAGAGGAGGAGGGAGAGTT1GCGTTGGCCGCCTTGGGGTGCTGGGCGTCGACGATATCTAAGGGCGAATTCGATATCAaçagctTgtcgaotcg aagatctggg cgtggttaag
421 ggtgggaaag aatatataag gtgggggtct tatgtagttttgtatctgtt ttgcagcagc
481 cgccgccgcc atgagcacca actcgtttga tggaagcattgtgagctcat atttgacaac
541 gcgcatgccc ccatgggccg gggtgcgtca gaatgtgatgggctccagca ttgatggtcg
601 ccccgtcctg cccgcaaact ctactacctt gacctacgagaccgtgtctg gaacgccgtt
661 ggagactgca gcctccgccg ccgcttcagc cgctgcagccaccgcccgcg ggattgtgac
721 tgactttgct ttcctgagcc cgcttgcaag cagtgcagcttcccgttcat ccgcccgcga
781 tgacaagttg acggctcttt tggcacaatt ggattctttgacccgggaac ttaatgtcgt
841 ttctcagcag ctgttggatc tgcgccagca ggtttctgccctgaaggctt cctcccctcc
901 caatgcggtt taaaacataa ataaaaaacc agactctgtttggatttgga tcaagcaagt
961 gtcttgctgt ctttatttag gggttttgcg cgcgcggtaggcccgggácc agcggtctcg
1021 gtcgttgagg gtcctgtgta ttttttccag gacgtggtaa
aggtgactct ggatgttcag
1081 atacatgggc ataagcccgt ctctggggtg gaggtagcaccactgcagag cttcatgctg
1141 cggggtggtg ttgtagatga tccagtcgta gcaggagcgctgggcgtggt gcctaaaaat
1201 gtctttcagt agcaagctga ttgccagggg caggcccttggtgtaagtgt ttacaaagcg
12 61 gttaagctgg gatgggtgca tacgtgggga tatgagatgcatcttggact gtatttttag
1321 gttggctatg ttcccagcca tatccctccg gggattcatgttgtgcagaa ccaccagcac
1381 agtgtatccg gtgcacttgg gaaatttgtc atgtagcttagaaggaaatg cgtggaagaa
14 41 cttggagacg cccttgtgac ctccaagatt ttccatgcattcgtccataa tgatggcaat
1501 gggcccacgg gcggcggcct gggcgaagat atttctgggatcactaacgt catagttgtg
1561 ttccaggatg agatcgtcat aggccatttt tacaaagcgcgggcggaggg tgccagactg
1621 cggtataatg gttccatccg gcccaggggc gtagttaccctcacagattt gcatttccca
1681 cgctttgagt tcagatgggg ggatcatgtc tacctgcggggcgatgaaga aaacggtttc
1741 cggggtaggg gagatcagct gggaagaaag caggttcctgagcagctgcg acttaccgca1801 gccggtgggc ccgtaaatca cacctattac cgggtgcaactggtagttaa gagagctgca
1861 gctgccgtca tccctgagca ggggggccac ttcgttaagcatgtccctga ctcgcatgtt
1921 ttccctgacc aaatccgcca gaaggcgctc gccgcccagcgatagcagtt cttgcaagga
1981 agcaaagttt ttcaacggtt tgagaccgtc cgccgtaggcatgcttttga gcgtttgacc
2041 aagcagttcc aggcggtccc acagctcgg€ cacctgctctacggcatctc gatccagcat
2101 atctcctcgt ttcgcgggtt ggggcggctt tcgctgtacggcagtagtcg gtgctcgtcc
2161 agacgggcca gggtcatgtc tttccacggg cgcagggtcctcgtcagcgt agtctgggtc
2221 acggtgaagg ggtgcgctcc gggctgcgcg ctggccagggtgcgcttgag gctggtcctg
2281 ctggtgctga agcgctgccg gtcttcgccc tgcgcgtcggccaggtagca tttgaccatg
2341 gtgtcatagt ccagcccctc cgcggcgtgg cccttggcgcgcagcttgcc cttggaggag
2401 gcgccgcacg aggggcagtg cagacttttg agggcgtagagcttgggcgc gagaaatacc
2461 gattccgggg agtaggcatc cgcgccgcag gccccgcagacggtctcgca ttccacgagc
2521 caggtgagct ctggccgttc ggggtcaaaa accaggtttcccccatgctt tttgatgcgt
2581 ttcttacctc tggtttccat gagccggtgt ccacgctcggtgacgaaaag gctgtccgtg
2641 tccccgtata cagacttgag agggagttta aacgaattcaatagcttgtt gcatgggcgg
2701 cgatataaaa tgcaaggtgc tgctcaaaaa atcaggcaaagcctcgcgca aaaaagaaag
2761 cacatcgtag tcatgctcat gcagataaag gcaggtaagctccggaacca ccacagaaaa
2821 agacaccatt tttctctcaa acatgtctgc gggtttctgcataaacacaa aataaaataa
2881 caaaaaaaca tttaaacatt agáagcctgt cttacaacaggaaaaacaac ccttataagc
2941 ataagacgga ctacggccat gccggcgtga ccgtaaaaaaactggtcacc gtgattaaaa
3001 agcaccaccg acagctcctc ggtcatgtcc ggagtcataatgtaagactc ggtaaacaca
3061 tcaggttgat tcatcggtca gtgctaaaaa gcgaccgaaatagcccgggg gaatacatac
3121 ccgcaggcgt agagacaaca ttacagcccc cataggaggtataacaaaat taataggaga
3181 gaaaaacaca taaacacctg aaaaaccctc ctgcctaggcaaaatagcac cctcccgctc
3241 cagaacaaca tacagcgctt cacagcggca gccrtaacagtcagccttacc agtaaaaaag3301 aaaacctatt aaaaaaacac cactcgacac ggcaccagctcaatcagtca cagtgtaaaa
3361 aagggccaag tgcagagcga gtatatatag gactaaaaaatgacgtaacg gttaaagtcc
3421 acaaaaaaca cccagaaaac cgcacgcgaa cctacgcccagaaacgaaag ccaaaaaacc
3481 cacaacttcc tcaaatcgtc acttccgttt tcccacgttacgtaacttcc cattttaaga
3541 aaactacaat tcccaacaca tacaagttac tccgccctaaaacctacgtc acccgccccg
3601 ttcccacgcc ccgcgccacg tcacaaactc caccccctcattatcatatt ggcttcaatc
3 661 caaaataagg tatattattg atgatgttaa ttaacatgcatggatccata tgcggtgtga
3721 aataccgcac agatgcgtaa ggagaaaata ccgcatcaggcgctcttccg cttcctcgct
3781 cactgactcg ctgcgctcgg tcgttcggct gcggcgagcggtatcagctc actcaaaggc
3841 ggtaatacgg ttatccacag aatcagggga taacgcaggaaagaacatgt gagcaaaagg
3901 ccagcaaaag gccaggaacc gtaaaaaggc cgcgttgctggcgtttttcc ataggctccg
3961 cccccctgac gagcatcaca aaaatcgacg ctcaagtcagaggtggcgaa acccgacagg
4021 actataaaga taccaggcgt ttccccctgg aagctccctcgtgcgctctc ctgttccgac
4081 cctgccgctt accggatacc tgtccgcctt tctcccttcgggaagcgtgg cgctttctca
4141 tagctcacgc tgtaggtatc tcagttcggt gtaggtcgttcgctccaagc tgggctgtgt
4201 gcacgaaccc cccgttcagc ccgaccgctg cgccttatccggtaactatc gtcttgagtc
4261 caacccggta agacacgact tatcgccact ggcagcagccactggtaaca ggattagcag
4321 agcgaggtat gtaggcggtg ctacagagtt cttgaagtggtggcetaact acggctacac
4381 tagaaggaca gtatttggta tctgcgctct gctgaagccagttaccttcg gaaaaagagt
4441 tggtagctct tgatccggca aacaaaccac cgctggtagcggtggttttt ttgtttgcaa
4501 gcagcagatt acgcgcagaa aaaaaggatc tcaagaagatcctttgatct tttctacggg
4561 gtctgacgct cagtggaacg aaaactcacg ttaagggattttggtcatga gattatcaaa
4621 aaggatcttc acctagatcc ttttaaatta aaaatgaagttttaaatcaa tctaaagtat
4681 atatgagtaa acttggtctg acagttacca atgcttaatcagtgaggcac ctatctcagc
4741 gatctgtcta tttcgttcat ccatagttgc ctgactccccgtcgtgtaga taactacgat4801 acgggagggc ttaccatctg gccccagtgc tgcaatgataccgcgagacc cacgctcacc
4861 ggctccagat ttatcagcaa taaaccagcc agccggaagggccgagcgca gaagtggtcc
4921 tgcaacttta tccgcctcca tccagtctat taattgttgccgggaagcta gagtaagtag
4981 ttcgccagtt aatagtttgc gcaacgttgt tgccattgctgcagccatga gattatcaaa
5041 aaggatcttc acctagatcc ttttcacgta gaaagccagtccgcagaaac ggtgctgacc
5101 ccggatgaat gtcagctact gggctatctg gacaagggaaaacgcaagcg caaagagaaa
5161 gcaggtagct tgcagtgggc ttacatggcg atagctagactgggcggttt tatggacagc
5221 aagcgaaccg gaattgccag ctggggcgcc ctctggtaaggttgggaagc cctgcaaagt
5281 aaactggatg gctttctcgc cgccaaggat ctgatggcgcaggggatcaa gctctgatca
5341 agagacagga tgaggatcgt ttcgcatgat tgaacaagatggattgcacg caggttctcc
5401 ggccgcttgg gtggagaggc tattcggcta tgactgggcacaacagacaa tcggctgctc
5461 tgatgccgcc gtgttccggc tgtcagcgca ggggcgcccggttctttttg tcaagaccga
5521 cctgtccggt gccctgaatg aactgcaaga cgaggcagcgcggctatcgt ggctggccac
5581 gacgggcgtt ccttgcgcag ctgtgctcga cgttgtcactgaagcgggaa gggactggct
5641 gctattgggc gaagtgccgg ggcaggatct cctgtcatctcaccttgctc ctgccgagaa
5701 agtatccatc atggctgatg caatgcggcg gctgcatacgcttgatccgg ctacctgccc
57 61 attcgaccac caagcgaaac atcgcatcga gcgagcacgtactcggatgg aagccggtct
5821 tgtcgatcag gatgatctgg acgaagagca tcaggggctcgcgccagccg aactgttcgc
5881 caggctcaag gcgagcatgc ccgacggcga ggatctcgtcgtgacccatg gcgatgcctg
5941 cttgccgaat atcatggtgg aaaatggccg cttttctggattcatcgact gtggccggct .
6001 gggtgtggcg gaccgctatc aggacatagc gttggctacccgtgatattg ctgaagagct
6061 tggcggcgaa tgggctgacc gcttcctcgt gctttacggtatcgccgctc ccgattcgca
6121 gcgcatcgcc ttctatcgcc ttcttgacga gttcttctgaattttgttaa aatttttgtt
6181 aaatcagctc attttttaac caataggccg aaatcggcaacatcccttat aaatcaaaag
6241 aatagaccgc gatagggttg agtgttgttc cagtttggaacaagagtcca ctattaaaga6301 acgtggactc caacgtcaaa gggcgaaaaa ccgtctatcagggcgatggc ccactacgtg
6361 aaccatcacc caaatcaagt tttttgcggt cgaggtgccgtaaagctcta aatcggaacc
6421 ctaaagggag cccccgattt agagcttgac ggggaaagccggcgaacgtg gcgagaaagg
6481 aagggaagaa agcgaaagga gcgggcgcta gggcgctggcaagtgtagcg gtcacgctgc
6541 gcgtaaccac cacacccgcg cgcttaatgc gccgctacagggcgcgtcca ttcgccattc
6601 aggatcgaat taattcttaa t
SEQ XD: 15 taacatcatc aataatatac cttattttgg attgaagcca
atatgataat gagggggtgg agtttgtgac gtggcgcggg gcgtgggaac
ggggcgggtg acgtagtagt gtggcggaag tgtgatgttg caagtgtggc
ggaacacatg taagcgacgg atgtggcaaa agtgacgttt ttggtgtgcg
ccggtgtaca caggaagtga caattttcgc gcggttttag gcggatgttg
tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaa
ctgaataaga ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg
taatactGCTAGAgatCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGC
CAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTGTAATACGACTCACTA
TAGGGCGAATTGGGTACT.GGCCAcagagcttggcccattgcatacgttgtatccatatcata
atatgtacatttatattggctcatgtccaacattaccgccatgttgacattgattattgact
agttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgt
tacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgt.
caataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtg
gagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgcc
ccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttat
gggactttcctacttggcagtacatctaegfcattagfcca-tcgetafcfcaceatggtgatgcgg
ttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctcca
ccccattgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtc
gtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtctatata
agcagagctcgtttagtgaaccgtcagatcgcctggagacgccatccacgctgttttgacct
ccatagaagacaccgggaccgatccagcctgactctagCctAGCTCtgaagttggtggtgag
gccctgggcaggttggtatcaaggttacaagacaggtttaaggagaccaatagaaactgggc
atgtggagacagagaagaatcttgggtttctgataggcactgactctctctgcctattggtc
tattttCCCacccttaggctgctggtctgagcetaçrCAGATCITCTCGAGGTCGACGGTJürCGí
ATG GGTACCG GCGGCCGCCCTATTCTATAGTGTCACCTAAATGCTAGaGCTCGCTGATCAGC
CTCGACTGTGCCTT
CTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCAC
TGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGT
GGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCT
CTATGGCTTCTGAGGCGGAAAGAACCAAAGCTTAGGCTCGAGCGGCC
GCCACACAAAAAACCAACACACAGATGTAATGAAAATAAAGATATTTTATTTCTAGAGAAACGATATGGGCTGAATACGGATCCGTATTCAGCCCATATCGTTTCCCAGATCTCTAGCGGATCTGACGGTTCACTAAACCAGCTCTGCTtatatagacctcccaccgtacacgcctaccgcccatttgcgtcaatggggcggagttgttacgacattttggaaagtcccgttgattttggtgccaaaacaaactcccattgacgtcaatggggtggagacttggaaatccccgtgagtcaaaccgctatccacgcccattgatgtactgccaaaaccgcatcaccatggtaatagcgatgactaatacgtagatgtactgccaagtaggaaagtcccataaggtcatgtactgggcataatgccaggcgggccatttaccgtcattgacgtcaatagggggcgtacttggcatatgatacacttgatgtactgccaagtgggcagtttaccgtaaatactccacccattgacgtcaatggaaagtccctattggcgttactatgggaac
ataCgtcattattgacgtcaatgggcgggggtcgttgggcggtcagccaggcgggccatt
taccgtaagttatgtaacgcggaactccatatatgggctatgaactaatgaccccgtaat
tgattactattacagtattacgcgctatgagtaacacaaaattattcagatttcacttcc
tcttattcagttttcccgcgaaaatggccaaatcttactcggttacgcccaaatttacta
caacatccgcctaaaaccgcgcgaaaattgtcacttcctgtgtacaccggcgcacaccaa
aaacgtcacttttgccacatccgtcgcttacatgtgttccgccacacttgcaacatcaca
cttccgc cacactactacgtcacccgccccgttcccacgccccgcgccacgtcacaaact
ccaccccctcattatcatattggcttcaatccaaaataaggtatattattgatgatgttaag
ctt
gtcgactcg aagatctggg cgtggttaag
421 ggtgggaaag aatatataag gtgggggtct tatgtagttttgtatctgtt ttgcagcagc
481 cgccgccgcc atgagcacca actcgtttga tggaagcattgtgagctcat atttgacaac
541 gcgcatgccc ccatgggccg gggtgcgtca gaatgtgatgggctccagca ttgatggtcg
601 ccccgtcctg cccgcaaact ctactacctt gacctacgagaccgtgtctg gaacgccgtt
661 ggagactgca gcctccgccg ccgcttcagc cgctgcagccaccgcccgcg ggattgtgac
721 tgactttgct ttcctgagcc cgcttgcaag cagtgcagcttcccgttcat ccgcccgcga
781 tgacaagttg acggctcttt tggcacaatt ggattctttgacccgggaac ttaatgtcgt
841 ttctcagcag ctgttggatc tgcgccagca ggtttctgccctgaaggctt cctcccctcc
901 caatgcggtt taaaacataa ataaaaaacc agactctgtttggatttgga tcaagcaagt
961 gtcttgctgt ctttatttag gggttttgcg cgcgcggtaggcccgggacc agcggtctcg
1021 gtcgttgagg gtcctgtgta ttttttccag gacgtggtaaaggtgactct ggatgttcag
1081 atacatgggc ataagcccgt ctctggggtg gaggtagcaccactgcagag cttcatgctg
1141 cggggtggtg ttgtagatga tccagtcgta gcaggagcgctgggcgtggt gcctaaaaat
1201 gtctttcagt agcaagctga ttgccagggg caggcccttggtgtaagtgt ttacaaagcg
1261 gttaagctgg gatgggtgca tacgtgggga tatgagatgcatcttggact gtatttttag
1321 gttggctatg ttcccagcca tatccctccg gggattcatgttgtgcagaa ccaccagcac
1381 agtgtatccg gtgcacttgg gaaatttgtc atgtagcttagaaggaaatg cgtggaagaa1441 cttggagacg cccttgtgac ctccaagatt ttccatgcattcgtccataa tgatggcaat
1501 gggcccacgg gcggcggcct gggcgaagat atttctgggatcactaacgt catagttgtg
1561 ttccaggatg agatcgtcat aggccatttt tacaaagcgcgggcggaggg tgccagactg
1621 cggtataatg gttccatccg gcccagggge gtagttaccctcacagattt gcatttccca
1681 cgctttgagt tcagatgggg ggatcatgtc tacctgcggggcgatgaaga aaacggtttc
1741 cggggtaggg gagatcagct gggaagaaag caggttcctgagcagctgcg acttaccgca
1801 gccggtgggc ccgtaaatca cacctattac cgggtgcaàctggtagttaa gagagctgca
1861 gctgccgtca tccctgagca ggggggccac ttcgttaagcatgtccctga ctcgcatgtt
1921 ttccctgacc aaatccgcca gaaggcgctc gccgcccagcga-tagcagtt cttgcaagga
1981 agcaaagttt ttcaacggtt tgagaccgtc cgccgtaggcatgcttttga gcgtttgacc
2041 aagcagttcc aggcggtccc acagctcggt cacctgctct.acggcatctc gatccagcat
2101 atctcctcgt ttcgcgggtt ggggcggctt tcgctgtacggcagtagtcg gtgctcgtcc
2161 agacgggcca gggtcatgtc tttccacggg cgcagggtcctcgtcagcgt agtctgggtc
2221 acggtgaagg ggtgcgctcc gggctgcgcg ctggccagggtgcgcttgag gctggtcctg
2281 ctggtgctga agcgctgccg gtcttcgccc tgcgcgtcggccaggtagca tttgaccatg
2341 gtgtcatagt ccagcccctc cgcggcgtgg cccttggcgcgcagcttgcc cttggaggag
2401 gcgccgcacg aggggcagtg cagacttttg agggcgtagagcttgggcgc gagaaatacc
2461 gattccgggg agtaggcatc cgcgccgcag gccccgcagacggtctcgca ttccacgagc
2521 caggtgagct ctggccgttc ggggtcaaaa accaggtttcccccatgctt tttgatgcgt
2581 ttcttacctc tggtttccat gagccggtgt ccacgctcggtgacgaaaag gctgtccgtg
2641 tccccgtata cagacttgag agggagttta aacgaattcaatagcttgtt gcatgggcgg
2701 cgatataaaa tgcaaggtgc tgctcaaaaa atcaggcaaagcctcgcgca aaaaagaaag
2761 cacatcgtag tcatgctcat gcagataaag gcaggtaagctccggaacca ccacagaaaa
2821 agacaccatt tttctctcaa acatgtctgc gggtttctgcataaacacaa aataaaataa
2881 caaaaaaaca tttaaacatt agaagcctgt cttacaacaggaaaaacaac ccttataagc2941 ataagacgga ctacggccat gccggcgtga ccgtaaaaaaactggtcacc gtgattaaaa
3001 agcaccaccg acagctcctc ggtcatgtcc ggagtcataatgtaagactc ggtaaacaca
3061 tcaggttgat tcatcggtca gtgctaaaaa gcgaccgaaatagcccgggg gaatacatac
3121 ccgcaggcgt agagacaaca ttacagcccc cataggaggtataacaaaat taataggaga
3181 gaaaaacaca taaacacctg aaaaaccctc ctgcctaggcaaaatagcac cctcccgctc
3241 cagaacaaca tacagcgctt cacagcggca gcctaacagtcagccttacc agtaaaaaag
3301 aaaacctatt aaaaaaacac cactcgacac ggcaccagctcaatcagtca cagtgtaaaa
3361 aagggccaag tgcagagcga gtatatatag gactaaaaaatgacgtaacg gttaaagtcc
3421 acaaaaaaca cccagaaaac cgcacgcgaa cctacgcccagaaacgaaag ccaaaaaacc
3481 cacaacttcc tcaaatcgtc acttccgttt tcccacgtt.acgtaacttcc cattttaaga
3541 aaactacaat tcccaacaca tacaagttac tccgccctaaaacctacgtc acccgccccg
3601 ttcccacgcc ccgcgccacg tcacaaactc caccccctcattatcatatt ggcttcaatc
3661 caaaataagg tatattattg atgatgttaa ttaacatgcatggatccata tgcggtgtga
3721 aataccgcac agatgcgtaa ggagaaaata ccgcatcaggcgctcttccg cttcctcgct
3781 cactgactcg ctgcgctcgg tcgttcggct gcggcgagcggtatcagctc actcaaaggc
3841 ggtaatacgg ttatccacag aatcagggga taacgcaggaaagaacatgt gagcaaaagg
3901 ccagcaaaag gccaggaacc gtaaaaaggc cgcgttgetggcgtttttcc ataggctccg
3961 cccccctgac gagcatcaca aaaatcgacg ctcaagtcagaggtggcgaa acccgacagg
4021 actataaaga taceaggcgt ttccccctgg aagctccctcgtgcgctctc ctgttccgac
4 081 cctgccgctt accggatacc tgtccgcctt tctcccttcgggaagcgtgg cgctttctca
4141 tagctcacgc tgtaggtatc tcagttcggt gtaggtcgttcgctccaagc tgggctgtgt
4201 gcacgaaccc cccgttcagc ccgaccgctg cgccttatccggtaactatc gtcttgagtc
4261 caacccggta agacacgact tatcgccact ggcagcagccactggtaaca ggattagcag
4321 agcgaggtat gtaggcggtg ctacagagtt cttgaagtggtggcctaact acggctacac
4381 tagaaggaca gtatttggta tctgcgctct gctgaagccagttaccttcg gaaaaagagt4441 tggtagctct tgatccggca aacaaaccac cgctggtagcggtggttttt ttgtttgcaa
501 gcagcagatt acgcgcagaa aaaaaggatc tcaagaagatcctttgatct tttctacggg
4 561 gtctgacgct cagtggaacg aaaactcacg ttaagggattttggtcatga gattatcaaa
4 621 aaggatcttc acctagatcc ttttaaatta aaaatgaagttttaaatcaa tctaaagtat
4 681 atatgagtaa acttggtctg acagttacca atgcttaatcagtgaggcac ctatctcagc
47 41 gatctgtcta tttcgttcat ccatagttgc ctgactccccgtcgtgtaga taactacgat
4801 acgggagggc ttaccatctg gccccagtgc tgcaatgataccgcgagacc cacgctcacc
4861 ggctccagat ttatcagcaa taaaccagcc agccggaagggccgagcgca gaagtggtcc
4 921 tgcaacttta tccgcctcca tccagtctat taattgttgccgggaagcta gagtaagtag
4981 ttcgccagtt aatagtttgc gcaacgttgt tgccattgctgcagccatga gattatcaaa
5041 aaggatcttc acctagatcc ttttcacgta gaaagccagtccgcagaaac ggtgctgacc
5101 ccggatgaat gtcagctact gggctatctg gacaagggaaaacgcaagcg caaagagaaa
5161 gcaggtagct tgcagtgggc ttacatggcg atagctagactgggcggttt tatggacagc
5221 aagcgaaccg gaattgccag ctggggcgcc ctctggtaaggttgggaagc cctgcaaagt
5281 aaactggatg gctttctcgc cgccaaggat ctgatggcgcaggggatcaa gctctgatca
5341 agagacagga tgaggatcgt ttcgcatgat tgaacaagatggattgcacg caggttctcc
5401 ggccgcttgg gtggagaggc tattcggcta tgactgggcacaacagacaa tcggctgctc
5461 tgatgccgcc gtgttccggc tgtcagcgca ggggcgcccggttctttttg tcaagaccga
5521 cctgtccggt gccctgaatg aactgcaaga cgaggcagcgcggctatcgt ggdtggccac
5581 gacgggcgtt ccttgcgcag ctgtgctcga cgttgtcactgaagcgggaa gggactggct
5641 gctattgggc gaagtgccgg ggcaggatct cctgtcatctcaccttgctc ctgccgagaa
5701 agtatccatc atggctgatg caatgcggcg gctgcatacgcttgatccgg ctacctgccc
57 61 attcgaccac caagcgaaac atcgcatcga gcgagcacgtactcggatgg aagccggtct
5821 tgtcgatcag gatgatctgg acgaagagca tcaggggctcgcgccagccg aactgttcgc
5881 caggctcaag gcgagcatgc ccgacggcga ggatctcgtcgtgacccatg gcgatgcctg5941 cttgccgaat atcatggtgg aaaatggccg cttttctggattcatcgact gtggccggct
6001 gggtgtggcg gaccgctatc aggacatagc gttggctacccgtgatattg ctgaagagct
6061 tggcggcgaa tgggctgacc gcttcctcgt gctttacggtatcgccgctc ccgattcgca
6121 gcgcatcgcc ttctatcgcc ttcttgacga gttcttctgaattttgttaa aatttttgtt
6181 aaatcagctc attttttaac caataggccg aaatcggcaacatcccttat aaatcaaaag
6241 aatagaccgc gatagggttg agtgttgttc cagtttggaacaagagtcca ctattaaaga
6301 acgtggactc caacgtcaaa gggcgaaaaa ccgtctatcagggcgatggc ccactacgtg
6361 aaccatcacc caaatcaagt tttttgcggt cgaggtgccgtaaagctcta aatcggaacc
6421 ctaaagggag cccccgattt agagcttgac ggggaaagccggcgaacgtg gcgagaaagg
6481 aagggaagaa agcgaaagga gcgggcgcta gggcgctggcaagtgtagcg gtcacgctgc
6541 gcgtaaccac cacacccgcg cgcttaatgc gccgctacagggcgcgtcca ttcgccattc
6601 aggatcgaat taattcttaa t
SEQ ID: 16 vetor HA shuttle, CMV-Iuc
taacatcatc aataatatac cttattttgg attgaagcca atatgataatgagggggtgg agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtgacgtagtagt gtggcggaag tgtgatgttg caagtgtggc ggaacacatgtaagcgacgg atgtggcaaa agtgacgttt ttggtgtgcg ccggtgtacacaggaagtga caattttcgc gcggttttag gcggatgttg tagtaaatttgggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataagaggaagtgaaa tctgaataat tttgtgttac tcatagcgcg
taatactGCTASAgat-CTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTGTAATACGACTCACTATAGGGCGAATTGGGTACTGGCCAcagagct tggcccattgcatacgttgtatccatat cataatatgtacatttatattggctcatgtccaacattaccgccatgttgacattgattattgactagttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtaeatctacgrtattagtca.tcgcta-ttaceatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccaccccattgacgtcaatgggagtttgttttggcaccáaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggt ctat ataagcagagctcgtttagtgaaccgtcagatcgcctggagacgccatccacgctgttttgacctccatagaagacaccgggaccgatccagcctgactctagCctAGCTCtgaagttggtggtgaggccctgggcaggttggtatcaaggttacaagacaggtttaaggagaccaatagaaactgggcatgtggagacagagaagactcttgggtttctgataggcactgactctctctgcctattggtct a ttttcccacccttaggctgctggtctgagccfcagGAGA TCTCTCGAGGTCGACGGTATcgatgcca ccATGGAGAA AATCGTCCTG TTGCTCGCTA TTGTGTCTCT
51 AGTGAAGAGC GATCAAATTT GTATCGGCTA CCATGCCAAT AACTCAACAG101 AGCAGGTCGA TACTATCATG GAGAAAAACG TAACAGTTAC TCATGCCCAA151 GACATCTTGG AAAAGACCCA CAACGGCAAA CTTTGCGACC TGGATGGAGT201 GAAGCCCCTG ATCCTCCGGG ACTGTTCAGT CGCTGGTTGG CTGCTCGGGA251 ACCCTATGTG TGATGAGTTT ATCAACGTGC CTGAATGGTC TTACATTGTG301 GAGAAGGCTA ACCCTACCAA TGACCTCTGC TATCCTGGGT CATTTAACGA351 TTACGAGGAA CTGAAACACC TGTTGTCTAG AATTAACCAC TTTGAAAAGA401 TACAGATTAT ACCCAAGTCT AGTTGGAGTG ATCACGAAGC CTCCTCAGGC4 51 GTTAGCTCAG CGTGTCCCTA TCTGGGCTCT CCATCCTTCT TTAGAAATGT501 GGTCTGGTTA ATCAAAAAGA ACAGTACCTA CCCAACCATC AAAAAGTCTT551 ATAACAATAC CAATCAGGAG GACCTGCTCG TGTTGTGGGG TATCCATCAC601 CCGAACGACG CCGCTGAACA GACTAGGCTG TATCAGAACC CCACTACATA651 CATCAGTATT GGCACGAGTA CTCTGAACCA GCGATTAGTG CCAAAGATTG701 CAACACGGAG CAAAGTAAAT GGGCAATCTG G CAGGATGGA GTTTTTCTGG751 ACAATCTTAA AACCCAACGA TGCGATAAAT TTCGAGTCCA ATGGCAATTT801 CATCGCCCCT GAATACGCCT ATAAGATCGT GAAAAAGGGG GACTCTGCAA851 TTATGAAGTC CGAATTAGAG TATGGCAATT GCAACACGAA GTGCCAGACA901 CCAATGGGAG CCATTAATAG CTCAATGCCC TTCCATAATA TTCATCCATT951 GACCATTGGG GAGTGCCCAA AGTACGTGAA GTCCAACCGC CTGGTCCTCG1001 CAACCGGTCT AAGAAATAGC CCGCAGAGAG AATCGCGGAG GAAGAAACGT1051 GGCCTGTTTG GCGCGATTGC CGGATTCATC GAGGGAGGCT GGCAGGGTAT1101 GGTCGATGGT TGGTACGGAT ACCACCATAG CAACGAACAG GGGTCCGGCT1151 ATGCAGCAGA TAAGGAGAGC ACTCAGAAAG CTATTGACGG AGTTACAAAC1201 AAGGTTAATA GTATTATAGA TAAAATGAAC ACGCAATTCG AGGCCGTTGG1251 GAGGGAGTTT AACAATCTGG AACGCCGGAT CGAAAATCTG AATAAGAAAA1301 TGGAAGACGG CTTCCTTGAC GTGTGGACTT ATAATGCAGA GCTGCTTGTA1351 CTCATGGAGA ACGAGAGGAC CCTGGATTTC CACGATAGCA ACGTGAAGAA1401 CCTTTACGAC AAGGTGAGAC TTCAGCTCCG AGACAACGCC AAGGAGCTGG1451 GGAATGGATG CTTCGAGTTT TACCACAAAT GTGACAATGA GTGCATGGAA1501 AGTATACGCA ACGGGACCTA CAATTACCCT CAGTATAGCG AAGAGGCTCG1551 GCTCAAACGC GAAGAGATAA GCGGGGTGAA ATTGGAATCA ATCGGAACAT1601 ATCAAATCCT GTCCATCTAT TCCACCGTCG CCTCTTCGCT GGCCCTCGCT1651 ATCATGATGG CTGGTCTGTC CCTATGGATG TGTTCCAATG GAAGCCTTCA1701 GTGCCGTATT TGTATATGAg C
GGCCGCCCTATTCTATAGTGTCACCTAAATGCTAGAGCrCGCTGATCAGCCTCGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGCTTCTGAGGCGGAAAGAACCAAAGCTtaacatcatc aataatataccttattttgg attgaagcca atatgataat gagggggtgg
61 agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtgacgtagtagt gtggcggaag
121 tgtgatgttg caagtgtggc ggaacacatg taagcgacggatgtggcaaa agtgacgttt181 ttggtgtgcg ccggtgtaea caggaagtga caattttcgcgcggttttag gcggatgttg
241 tagtaaattt gggcgtaacc gagtaagatt tggccattttcgcgggaaaa ctgaataaga
301 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcgtaatactgta atagtaatca
361 attacggggt cattagttca tagcccatat atggagttccgcgttacata acttacggta
421 aatggcccgc ctggctgacc gcccaacgac ccccgcccattgacgtcaat aatgacgtat
481 gttcccatag taacgccaat agggactttc cattgacgtcaatgggtgga gtatttacgg
541 taaactgccc acttggcagt acatcaagtg tatcatatgccaagtacgcc ccctattgac
601 gtcaatgacg gtaaatggcc cgcctggcat tatgcccagtacatgacctt atgggacttt
661 cctacttggc agtacatcta cgtattagtc atcgctattaccatggtgat gcggttttgg
721 cagtacatca atgggcgtgg atagcggttt gactcacggggatttccaag tcteeacccc
781 attgacgtca atgggagttt gttttggcac eaaaateaacgggactttcc aaaatgtcgt
841 aacaactccg ccccattgac gcaaatgggc ggtaggcgtgtacggtggga ggtctatata
901 agcagagctg gtttagtgaa ccgtcagatccgctagAGATCTOGgaaacgatatgggctgaatacggatecgtattcagcccatategtttcT CT AGA AAT AAA ATA TCT TTA TTT TCA TTA CAT CTG TGT GTT GGTTTT TTG TGT GGC
GG CCGCtcgragcct AAGCTTctag ataagatatc cgatccaccg gatctagataactgatcata
1021 atcagccata ccacatttgt agaggtttta cttgctttaaaaaacctccc acacctcccc
1081 etgaaeetga aacataaaat gaatgcaatt gttgttgttaacttgtttat tgcagcttat
1141 aatggttaca aataaagcaa tagcatcaca aatttcacaaataaagcatt tttttcactg
1201 cattctagtt gtggtttgtc caaactcatc aatgtatcttaacgcggatc tgggcgtggt
1261 taagggtggg aaagaatata taaggtgggg gtcttatgtagttttgtatc tgttttgcag
1321 cagccgccgc cgccatgagc accaactegt ttgatggaag cattgtgAGCTTgtcgactcg aagatctggg cgtggttaag
421 ggtgggaaag aatatataag gtgggggtct tatgtagttttgtatctgtt ttgeageagc
4 81 cgccgccgcc atgagcacca actcgtttga tggaagcattgtgagctcat atttgacaac
541 gcgcatgccc ecatgggccg gggtgcgtca gaatgtgatgggctccagca ttgatggtcg
601 ccccgtcctg cccgcaaact ctactacctt gacctacgagaccgtgtctg gaacgccgtt661 ggagactgca gcctccgccg ccgcttcagc cgctgcagccaccgcccgcg ggattgtgac
721 tgactttgct ttcctgagcc cgcttgcaag cagtgcagcttcccgttcat ccgcccgcga
781 tgacaagttg acggctcttt tggçacaatt ggattctttgacccgggaac ttaatgtcgt
841 ttctcagcag ctgttggatc tgcgccagca ggtttctgccctgaaggctt cctcccctcc
901 caatgcggtt taaaacataa ataaaaaacc agactctgtttggatttgga tcaagcaagt
961 gtcttgctgt ctttatttag gggttttgcg cgcgcggtaggcccgggacç agcggtctcg
1021 gtcgttgagg gtcctgtgta ttttttccag gacgtggtaaaggtgactct ggatgttcag
1081 atacatgggc ataagcccgt ctctggggtg gaggtagcaccactgcagag cttcatgctg
1141 cggggtggtg ttgtagatga tccagtcgta gcaggagcgctgggcgtggt gcctaaaaat
1201 gtctttcagt agcaagctga ttgccagggg caggcccttggtgtaagtgt ttacaaagcg
1261 gttaagctgg gatgggtgca tacgtgggga tatgagatgcatcttggact gtatttttag
1321 gttggctatg ttcccagcca tatccctccg gggattcatgttgtgcagaa ccaccagcac
1381 agtgtatccg gtgcacttgg gaaatttgtc atgtagcttagaaggaaatg cgtggaagaa
14 41 cttggagacg cccttgtgac ctccaagatt ttccatgcattcgtccataa tgatggcaat
1501 gggcccacgg gcggcggcct gggcgaagat atttctgggatcactaacgt catagttgtg
1561 ttccaggatg agatcgtcat aggccatttt tacaaagcgcgggcggaggg tgccagactg
1621 cggtataatg gttccatccg gcccaggggc gtagttaccctcacagattt gcatttccca
1681 cgctttgagt tcagatgggg ggatcatgtc tacctgcggggcgatgaaga aaacggtttc
1741 cggggtaggg gagatcagct. gggaagaaag caggttcctgagcagctgcg acttaccgca
1801 gccggtgggc ccgtaaatca cacctattac cgggtgcaactggtagttaa gagagctgca
1861 gctgccgtca tccctgagca ggggggccac ttcgttaagcatgtccctga ctcgcatgtt
1921 ttccctgacc aaatccgcca gaaggcgctc gccgcccagcgatagcagtt cttgcaagga
1981 agcaaagttt ttcaacggtt tgagaccgtc cgccgtaggcatgcttttga gcgtttgacc
2041 aagcagttcc aggcggtccc acagctcggt cacctgctctacggcatctc gatccagcat
2101 atctcctcgt ttcgcgggtt ggggcggctt tcgctgtacggcagtagtcg gtgctcgtcc2161 agacgggcca gggtcatgtc tttccacggg cgcagggtcctcgtcagcgt agtctgggtc
2221 acggtgaagg ggtgcgctcc gggctgcgcg ctggccagggtgcgcttgag gctggtcctg
2281 ctggtgctga agcgctgccg gtcttcgccc tgcgcgtcggccaggtagca tttgaccatg
2341 gtgtcatagt ccagcccctc cgcggcgtgg cccttggcgcgcagcttgcc cttggaggag
2401 gcgccgcacg aggggcagtg cagacttttg agggcgtagagcttgggcgc gagaaatacc
2461 gattccgggg agtaggcatc cgcgccgcag gccccgcagacggtctcgca ttccacgagc
2521 caggtgagct ctggccgttc ggggtcaaaa accaggtttcccccatgctt tttgatgcgt
2581 ttcttacctc tggtttccat gagccggtgt ccacgctcggtgacgaaaag gctgtccgtg
2641 tccccgtata cagacttgag agggagttta aacgaattcaatagcttgtt gcatgggcgg
2701 cgatataaaa tgcaaggtgc tgctcaaaaa atcaggcaaagcctcgcgca aaaaagaaag
2761 cacatcgtag tcatgctcat gcagataaag gcaggtaagctccggaacca ccacagaaaa
2821 agacaccatt tttctctcaa acatgtctgc gggtttctgcataaacacaa aataaaataa
2881 caaaaaaaca tttaaacatt agaagcctgt cttacaacaggaaaaacaac ccttataagc
2941 ataagacgga ctacggccat gccggcgtga ccgtaaaaaaactggtcacc gtgattaaaa
3001 agcaccaccg acagctcctc ggtcatgtcc ggagtcataatgtaagactc ggtaaacaca
3061 tcaggttgat tcatcggtca gtgctaaaaa gcgaccgaaatagcccgggg gaatacatac
3121 ccgcaggcgt agagacaaca ttacagcccc cataggaggtataacaaaat taataggaga
3181 gaaaaacaca taaacacctg aaaaaccctc ctgcctaggcaaaatagcac cctcccgctc
3241 cagaacaaca tacagcgctt cacagcggca gcctaacagtcagccttacc agtaaaaaag
3301 aaaacctatt aaaaaaacac cactcgacac ggcaccagctcaatcagtca cag-tgtaaaa
3361 aagggccaag tgcagagcga gtatatatag gactaaaaaatgacgtaacg gttaaagtcc
3421 acaaaaaaca cccagaaaac cgcacgcgaa cctacgcccagaaacgaaag ccaaaaaacc
3481 cacaacttcc tcaaatcgtc acttccgttt tcccacgttacgtaacttcc cattttaaga
3541 aaactacaat tcccaacaca tacaagttac tccgccctaaaacctacgtc acccgccccg
3601 ttcccacgcc ccgcgccacg tcacaaactc caccccctcattatcatatt ggcttcaatc3661 caaaataagg tatattattg atgatgttaa ttaacatgcatggatccata tgcggtgtga
3721 aataccgcac agatgcgtaa ggagaaaata ccgcatcaggcgctcttccg cttcctcgct
3781 cactgactcg ctgcgctcgg tcgttcggct gcggcgagcggtatcagctc actcaaaggc
3841 ggtaatacgg ttatccacag aatcagggga taacgcaggaaagaacatgt gagcaaaagg
3901 ccagcaaaag gccaggaacc gtaaaaaggc cgcgttgctggcgtttttcc ataggctccg
3961 cccccctgac gagcatcaca aaaatcgacg ctcaagtcagaggtggcgaa acccgacagg
4 021 actataaaga taccaggcgt ttccccctgg aagctccctcgtgcgctctc ctgttccgac
4081 cctgccgctt accggatacc tgtccgcctt tctcccttcgggaagcgtgg cgctttctca
4141 tagctcacgc tgtaggtatc tcagttcggt gtaggtcgttcgctccaagc tgggctgtgt
4201 gcacgaaccc cccgttcagc ccgaccgctg cgccttatccggtaactatc gtcttgagtc
4261 caacccggta agacacgact tatcgccact ggcagcagccactggtaaca ggattagcag
4321 agcgaggtat gtaggcggtg ctacagagtt cttgaagtggtggcctaact acggctacac
4381 tagaaggaca gtatttggta tctgcgctct gctgaagccagttaccttcg gaaaaagagt
4 441 tggtagctct tgatccggca aacaaaccac çgctggtagcggtggttttt ttgtttgcaa
4501 gcagcagatt acgcgcagaa aaaaaggatc tcaagaagatcctttgatct tttctacggg
4561 gtctgacgct cagtggaacg aaaactcacg ttaagggattttggtcatga gattatcaaa
4 621 aaggatcttc acctagatcc ttttaaatta aaaatgaagttttaaatcaa tctaaagtat
4681 atatgagtaa acttggtctg acagttacca atgcttaatcagtgaggcac ctatctcagc
4741 gatctgtcta tttcgttcat ccatagttgc ctgactccccgtcgtgtaga taactacgat
4801 acgggagggc ttaccatctg gccccagtgc tgcaatgataccgcgagacc cacgctcacc
4861 ggctccagat ttatcagcaa taaaccagcc agccggaagggccgagcgca gaagtggtcc
4 921 tgcaacttta tccgcctcca tccagtctat taattgttgccgggaagcta gagtaagtag
4981 ttcgccagtt aatagtttgc gcaacgttgt tgccattgctgcagccatga gattatcaaa
5041 aaggatcttc acctagatcc ttttcacgta gaaagccagtccgcagaaac ggtgctgacc
5101 ccggatgaat gtcagctact gggctatctg gacaagggaaaacgcaagcg caaagagaaa5161 gcaggtagct tgcagtgggc ttacatggcg atagctagactgggcggttt tatggacagc
5221 aagcgaaccg gaattgccag ctggggcgcc ctctggtaaggttgggaagc cctgcaaagt
5281 aaactggatg gctttctcgc cgccaaggat ctgatggcgcaggggatcaa gctctgatca
5341 agagacagga tgaggatcgt ttcgcatgat tgaacaagatggattgcacg caggttctcc
5401 ggccgcttgg gtggagaggc tattcggcta tgactgggcacaacagacaa tcggctgctc
5461 tgatgccgcc gtgttccggc tgtcagcgca ggggcgcccggttctttttg tcaagaccga
5521 cctgtccggt gccctgaatg aactgcaaga cgaggcagcgcggctatcgt ggctggccac
5581 gacgggcgtt ccttgcgcag ctgtgctcga cgttgtcactgaagcgggaa gggactggct
5641 gctattgggc gaagtgccgg ggcaggatct cctgtcatctcaccttgctc ctgccgagaa
5701 agtatccatc atggctgatg caatgcggcg gctgcatacgcttgatccgg ctacctgccc
5761 attcgaccac caagcgaaac atcgcatcga gcgagcacgt.actcggatgg aagccggtct
5821 tgtcgatcag gatgatetgg acgaagagca tcaggggctcgcgccagccg aactgttcgc
5881 caggctcaag gcgagcatgc ccgacggcga ggatctcgtcgtgacccatg gcgatgcctg
5941 cttgccgaat atcatggtgg aaaatggccg cttttctggattcatcgact gtggccggct
6001 gggtgtggcg gaccgctatc aggacatagc gttggctacccgtgatattg ctgaagagct
6061 tggcggcgaa tgggctgacc gcttcctcgt gctttacggtatcgccgctc ccgattcgca
6121 gcgcatcgcc ttctatcgcc ttcttgacga gttcttctgaattttgttaa aatttttgtt
6181 aaatcagctc attttttaac caataggccg aaatcggcaacatcccttat aaatcaaaag
6241 aatagaccgc gatagggttg agtgttgttc cagtttggaacaagagtcca ctattaaaga
6301 acgtggactc caacgtcaaa gggcgaaaaa ccgtctatcagggcgatggc ccactacgtg
6361 aaccatcacc caaatcaagt tttttgcggt cgaggtgccgtaaagctcta aatcggaacc
6421 ctaaagggag cccccgattt agagcttgac ggggaaagccggcgaacgtg gcgagaaagg
6481 aagggaagaa agcgaaagga gcgggcgcta gggcgctggcaagtgtagcg gtcacgctgc
6541 gcgtaaccac cacacccgcg cgcttaatgc gccgctacagggcgcgtcca ttcgccattc
6601 aggatcgaat taattcttaa t1 taaggatccn nncctgtcct cgaccgatgc ccttgagagc cttcaacccgtcagctcct
61 tccggtgggc gcggggcatg actatcgtcg ccgcacttatgactgtcttc tttatcatgc
121 aactcgtagg acaggtgccg gcagcgctct gggtcattttcggcgaggac cgctttcgct
181 ggagcgcgac gatgatcggc ctgtcgcttg cggtattcggaatcttgcac gccctcgctc
241 aagccttcgt cactggtccc gccaccaaac gtttcggcgagaagcaggcc attatcgccg
301 gcatggcggc cgacgcgctg ggctacgtct tgctggcgttcgcgacgcga ggctggatgg
361 ccttccccat tatgattctt ctcgcttccg gcggcatcgggatgcccgcg ttgcaggcca
421 tgctgtccag gcaggtagat gacgaccatc agggacagcttcaaggatcg ctcgcggctc
481 ttaccagcct aacttcgatc actggaccgc tgatcgtcacggcgatttat gccgcctcgg
541 cgagcacatg gaacgggttg gcatggattg taggcgccgccctatacctt gtctgcctcc
601 ccgcgttgcg tcgcggtgca tggagccggg ccacctcgacctgaatggaa gccggcggca
661 cctcgctaac ggattcacca ctccaagaat tggagccaatcaattcttgc ggagaactgt
721 gaatgcgcaa accaaccctt ggcagaacat atccatcgcg
tccgccatct ccagcagccg -------------
781 cacgcggcgc atctcgggca gcgttgggtc ctggccacgggtgcgcatga tcgtgctcct
841 gtcgttgagg acccggctag gctggcgggg ttgccttactggttagcaga atgaatcacc
901 gatacgcgag cgaacgtgaa gcgactgctg ctgcaaaacgtctgcgacct gagcaacaac
961 atgaatggtc ttcggtttcc gtgtttcgta aagtctggaaacgcggaagt cagcgccctg
1021 caccattatg ttccggatct gcatcgcagg atgctgctggctaccctgtg gaacacctac
1081 atctgtatta acgaagcgct ggcattgacc ctgagtgatttttctctggt cccgccgcat
1141 ccataccgcc agttgtttac cctcacaacg ttccagtaaccgggcatgtt catcatcagt
1201 aacccgtatc gtgagcatcc tctctcgttt catcggtatcattaccccca tgaacagaaa
1261 ttccccctta cacggaggca tcaagtgacc aaacaggaaaaaaccgccct taacatggcc
1321 cgctttatca gaagccagac attaacgctt ctggagaaactcaacgagct ggacgcggat
1381 gaacaggcag acatctgtga atcgcttcac gaccacgctgatgagcttta ccgcagctgc
14 41 ctcgcgcgtt tcggtgatga cggtgaaaac ctctgacacatgcagctccc ggagacggtc1501 acagcttgtc tgtaagcgga tgccgggagc agacaagccc gtcagggcgc gtcagcgggt
1561 gttggcgggt gtcggggcgc agccatgacc cagtcacgtagcgatagcgg agtgtatact
1621 ggcttaacta tgcggçatca gagcagattg tactgagagtgcaccatatg cggtgtgaaa
1681 taccgcacag atgcgtaagg agaaaatacc gcatcaggcgctcttccgct tcctcgctca
1741 ctgactcgçt gcgctcggtc gttcggctgc ggcgagcggtatcagctcac tcaaaggcgg
1801 taatacggtt atccacagaa tcaggggata acgcaggaaagaacatgtga gcaaaaggcc
1861 agcaaaaggc caggaaccgt aaaaaggccg cgttgctggcgtttttccat aggctccgcc
1921 cccctgacga gcatcacaaa aatcgacgct caagtcagaggtggcgaaac ccgacaggac
1981 tataaagata ccaggcgttt ccccctggaa gctccctcgtgcgctctcct gttccgaccc
2041 tgccgcttac cggatacctg tccgcctttc tcccttcgggaagcgtggcg ctttctcaat
2101 gctcacgctg taggtatctc agttcggtgt aggtcgttcgctccaagctg ggctgtgtgc
2161 acgaaccccc cgttcagccc gaccgctgcg ccttatccggtaactatcgt cttgagtcca
2221 acccggtaag acacgactta tcgccactgg cagcagccactggtaacagg attagcagag
2281 cgaggtatgt aggcggtgct acagagttct tgaagtggtggcctaactac ggctacacta
2341 gaaggacagt atttggtatc tgcgctctgc tgaagccagttaccttcgga aaaagagttg
2401 gtagctcttg atccggcaaa caaaccaccg ctggtagcggtggttttttt gtttgcaagc
2461 agcagattac gcgcagaaaa aaaggatctc aagaagatcctttgatcttt tctacggggt
2521 ctgacgctca gtggaacgaa aactcacgtt aagggattttggtcatgaga ttatcaaaaa
2581 ggatcttcac ctagatcctt ttaaattaaa aatgaagttttaaatcaatc taaagtatat
2641 atgagtaaac ttggtctgac agttaccaat gcttaatcagtgaggcacct atctcagcga
2701 tctgtctatt tcgttcatcc atagttgcct gactccccgtcgtgtagata actacgatac
2761 gggagggctt accatctggc cccagtgctg caatgataccgcgagaccca cgctcaccgg
2821 ctccagattt atcagcaata aaccagccag ccggaagggccgagcgcaga agtggtcctg
2881 caactttatc cgcctccatc cagtctatta attgttgccgggaagctaga gtaagtagtt
2941 cgccagttaa tagtttgcgc aacgttgttg ccâttgctgc agccatgagattatcaaaaaggatcttc acctagatcc ttttcacgta gaaagccagt ccgcagaaacggtgctgacc
ccggatgaat gtcagctact gggctatctg gacaagggaa aacgcaagcgcaaagagaaa
gcaggtagct tgcagtgggc ttacatggcg atagctagac tgggcggttttatggacagc
aagcgaaccg gaattgccag ctggggcgcc ctctggtaag gttgggaagccctgcaaagt
aaactggatg gctttctcgc cgccaaggat ctgatggcgc aggggatcaagctctgatca
agagacagga tgaggatcgt ttcgcatgat tgaacaagat ggattgcacgcaggttctcc
ggccgcttgg gtggagaggc tattcggcta tgactgggca caacagacaatcggctgctc
tgatgccgcc gtgttccggc tgtcagcgca ggggcgcccg gttctttttgtcaagaccga
cctgtccggt gccctgaatg aactgcaaga cgaggcagcg cggctatcgtggctggccac
gacgggcgtt ccttgcgcag ctgtgctcga cgttgtcact gaagcgggaagggactggct
gctattgggc gaagtgccgg ggcaggatct cctgtcatct caccttgctcctgccgagaa
agtatccatc atggctgatg caat.gcggcg gctgcatacg cttgatccggctacctgccc
attcgaccac caagcgaaac atcgcatcga gcgagcacgt actcggatggaagccggtct
tgtcgatcag gatgatctgg acgaagagca tcaggggctc gcgccagccgaactgttcgc
caggctcaag gcgagcatgc ccgacggcga ggatctcgtc gtgacccatggcgatgcctg
cttgccgaat atcatggtgg aaaatggccg cttttctgga ttcatcgactgtggccggct
gggtgtggcg gaccgctatc aggacatagc gttggctacc cgtgatattgctgaagagct
tggcggcgaa tgggctgacc gcttcctcgt gctttacggt atcgccgctcccgattcgca
gcgcatcgcc ttctatcgcc ttcttgacga gttcttctga attttgttaaaatttttgtt
aaatcagctc attttttaac caataggccg aaatcggcaa catcccttataaatcaaaag
aatagaccgc gatagggttg agtgttgttc cagtttggaa caagagtccactattaaaga
acgtggactc caacgtcaaa gggcgaaaaa ccgtctatca gggcgatggcccactacgtg
aaccatcacc caaatcaagt tttttgcggt cgaggtgccg taaagctctaaatcggaacc
ctaaagggag cccccgattt agagcttgac ggggaaagcc ggcgaacgtggcgagaaagg
aagggaagaa agcgaaagga gcgggcgcta gggcgctggc aagtgtagcggtcacgctgcgcgtaaccac cacacccgcg cgcttaatgc gccgctacag ggcgcgtccattcgccattc
aggatcgaat taattcttaa ttaacatcatc aataatatac cttattttggattgaagcca atatgataat gagggggtgg agtttgtgac gtggcgcggggcgtgggaac ggggcgggtg acgtagtagt gtggcggaag tgtgatgttgcaagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgtttttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttaggcggatgttg tagtaaattt gggcgtaacc gagtaagatt tggccattttcgcgggaaaa ctgaataaga ggaagtgaaa -tctgaataat tttgtgttactcatagcgcg
taatactGCTAGAgatCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTGTAATACGACTCACTATAGGGCGAATTGGGTACTGGCCAcagagcttggcccattgcatacgttgtatccatatcataatatgtacatttatattggctcatgtccaacattaccgccatgttgacattgattattgactagttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattag-tcatcgc-tattaccatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccaccccattgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggt ctatataagcagagctcgtttagtgaaccgtcagatcgcctggagacgccatccacgctgttttgacctccatagaagacaccgggaccgatccagcctgactctagCctAGCTCtgaagttggtggtgaggccctgggcaggttggtatcaaggttacaagacaggtttaaggagaccaatagaaactgggcatgtggagacagagaagaetcttgggtttctgataggcactgactctctctgcctattggtctattttcccacccttaggctgctggtctgagcctagGAGATCrCTCGAGGTCGACGGTArcgatgcca ccATGGAGAA AATCGTCCTG TTGCTCGCTA TTGTGTCTCTAGTGAAGAGCGATCAAATTT GTATCGGCTA CCATGCCAAT AACTCAACAGAGCAGGTCGATACTATCATG GAGAAAAACG TAACAGTTAC TCATGCCCAAGACATCiTGG AAAAGACCCA CAACGGCAAA CTTTGCGACC TGGATGGAGTGAAGCCCCTG ATCCTCCGGG ACTGTTCAGT CGCTGGTTGG CTGCTCGGGAACCCTATGTG TGATGAGTTT ATCAACGTGC CTGAATGGTC TTACATTGTGGAGAAGGCTA ACCCTACCAA TGACCTCTGC TATCCTGGGT CATTTAACGATTACGAGGAA CTGAAACACC TGTTGTCTAG AATTAACCAC TTTGAAAAGATACAGATTAT ACCCAAGTCT AGTTGGAGTG ATCACGAAGC CTCCTCAGGCGTTAGCTCAG CGTGTCCCTA TCTGGGCTCT CCATCCTTCT TTAGAAATGTGGTCTGGTTA ATCAAAAAGA ACAGTACCTA CCCAACCATC AAAAAGTCTTATAACAATAC CAATCAGGAG GACCTGCTCG TGTTGTGGGG TATCCATCACCCGAACGACG CCGCTGAACA GACTAGGCTG TATCAGAACC CCACTACATACATCAGTATT GGCACGAGTA CTCTGAACCA GCGATTAGTG CCAAAGATTGCAACACGGAG CAAAGTAAAT GGGCAATCTG GCAGGATGGA GTTTTTCTGGACAATCTTAA AACCCAACGA TGCGATAAAT TTCGAGTCCA ATGGCAATTTCATCGCCCCT GAATACGCCT ATAAGATCGT GAAAAAGGGG GACTCTGCAATTATGAAGTC CGAATTAGAG TATGGCAATT GCAACACGAA GTGCCAGACACCAATGGGAG CCATTAATAG CTCAATGCCC TTCCATAATA TTCATCCATTGACCATTGGG GAGTGCCCAA AGTACGTGAA GTCCAACCGC CTGGTCCTCGCAACCGGTCT AAGAAATAGC CCGCAGAGAG AATCGCGGAG GAAGAAACGTGGCCTGTTTG GCGCGATTGC CGGATTCATC GAGGGAGGCT GGCAGGGTATGGTCGATGGT TGGTACGGAT ACCACCATAG CAACGAACAG GGGTCCGGCTATGCAGCAGA TAAGGAGAGC ACTCAGAAAG CTATTGACGG AGTTACAAACAAGGTTAATA GTATTATAGA TAAAATGAAC ACGCAATTCG AGGCCGTTGGGAGGGAGTTT AACAATCTGG AACGCCGGAT CGAAAATCTG AATAAGAAAATGGAAGACGG CTTCCTTGAC GTGTGGACTT ATAATGCAGA GCTGCTTGTACTCATGGAGA ACGAGAGGAC CCTGGATTTC CACGATAGCA ACGTGAAGAA1401 CCTTTACGAC AAGGTGAGAC TTCAGCTCCG AGACAACGCCAAGGAGCTGGGGAATGGATG CTTCGAGTTT TACCACAAAT GTGACAATGAGTGCATGGAAAGTATACGCA ACGGGACCTA CAATTACCCT CAGTATAGCGAAGAGGCTCGGCTCAAACGC GAAGAGATAA GCGGGGTGAA ATTGGAATCAATCGGAACATATCAAATCCT GTCCATCTAT TCCACCGTCG CCTCTTCGCTGGCCCTCGCTATCATGATGG CTGGTCTGTC CCTATGGATG TGTTCCAATGGAAGCCTTCAGT GCCGTATT TGTATATGAg C(SGCCGOCCTATTCTATAGTGTCACCTAAATGCTACaGCrOSCTGATCAGCCTCGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGCTTCTGAGGCGGAAAGAACCAAAGCTt aacatcatc aataatataccttattttgg attgaagcca atatgataat gagggggtggagtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagtgtggcggaagtgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaaagtgacgtttttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttaggcggatgttgtagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaactgaataagaggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgtaatagtaatcaattacggggt cattagttca tagcccatat atggagttcc gcgttacataacttacggtaaatggcccgc ctggctgacc gcccaacgac ccccgcccat tgacgtcaataatgacgtatgttcccatag taacgccaat agggactttc cattgacgtc aatgggtggagtatttacggtaaactgccc acttggcagt acatcaagtg tatcatatgc caagtacgccccctattgacgtcaatgacg gtaaatggcc cgcctggcat tatgcccagt acatgaccttatgggactttcctacttggc agtacatcta cgtattagtc atcgctatta ccatggtgatgcggttttggcagtacatca atgggcgtgg atagcggttt gactcacggg gatttccaagtctccaccccattgacgtca atgggagttt gttttggcac caaaatcaac gggactttccaaaatgtcgtaacaactccg ccccattgac gcaaatgggc ggtaggcgtg tacggtgggaggtctatataagcagagctg gtttagtgaa cegtcagatccgctagAGATCraGgaaacgatatgggctgaataeggafccegtattcagcccatatcgtttcXCT AGA AAT AAA ATA TCT TTA TTT TCA TTA CAT CTG TGT GTT GGTTTT TTG TGT GGC
GG CCGCtcgagcct AAGCTTctag ataagatatc cgatccaccg gatctagataactgatcata
atcagccata ccacatttgt agaggtttta cttgctttaa aaaacctcccacacctcccc
ctgaacctga aacataaaat gaatgcaatt gttgttgtta acttgtttattgcagcttat
aatggttaca aataaagcaa tagcatcaca aatttcacaa ataaagcatttttttcactg
cattctagtt gtggtttgte caaactcatc aatgtatctt aacgcggatctgggcgtggt
taagggtggg aaagaatata taaggtgggg gtcttatgta gttttg-tafcctgttttgcag
cagcegecgc egceatgagc aecaaetcgt ttgatggaag cattgtgAGCTTgtcgactcg aagatetggg egtggttaag
ggtgggaaag aatatataag gtgggggtct tatgtagttt tgtatctgttttgeagcage
cgccgccgec atgagcacea actcgtttga tggaagcatt gtgagctcatatttgacaac
gcgcatgcccttgatggtcg
ccccgtcctggaacgccgtt
ggagactgcaggattgtgac
tgactttgctccgcccgcga
tgacaagttgttaatgtcgt
ttctcagcagcctcccctcc
caatgcggtt taaaacataa atàaaaaace agaetetgtt tggatttggatcaagcaagt
gtcttgctgt ctttatttag gggttttgcg cgcgcggtag gcccgggaccagcggtetcg
gtcgttgagg gtcctgtgta ttttttccag gacgtggtaa aggtgactctggatgttcag
atacatgggc ataagcccgt ctctggggtg gaggtagcac cactgcagagcttcatgctg
eggggtggtg ttgtagatga tccagtcgta geaggagcge tgggcgtggtgeetaaaaat
gtctttcagt agcaagctga ttgccagggg caggcccttg gtgtaagtgtttacaaagcg
gttaàgctgg gatgggtgca tacgtgggga tatgagatgc atcttggactgtatttttag
gttggctatg ttcccagcca tatccctccg gggattcatg ttgtgcagaaccaccagcac
ccatgggccg gggtgcgtcacccgcaaaet ctactaccttgcctccgccg ccgcttcagcttcctgagcc cgcttgcaagacggctcttt tggcacaattctgttggatc tgcgccagca
gaatgtgatg ggctccagcagacctacgag accgtgtctgcgctgcagcc accgcccgcgcagtgcagct tcccgttcatggattctttg acccgggaacggtttctgcc ctgaaggcttagtgtatccg gtgcacttgg gaaattt.gtc atgtagctta gaaggaaatgcgtggaagaa
cttggagacg cccttgtgac ctccaagatt ttccatgcat tcgtccataatgatggcaat
gggcccacgg gcggcggcct gggcgaagat atttctggga tcactaacgtcatagttgtg
ttccaggatg agatcgtcat aggccatttt tacaaagcgc gggcggagggtgccagactg
cggtataatg gttccatccg gcccaggggc gtagttaccc tcacagatttgcatttccca
cgctttgagt tcagatgggg ggatcatgtc tacctgcggg gcgatgaagaaaacggtttc
c^gggtaggg gagatcagct gggaagaaag caggttcctg agcagctgcgacttaccgca
gccggtgggc ccgtaaatca cacctattac cgggtgcaac tggtagttaagagagct
g cagctgccgt catccctgag caggggggcc
acttcgttaa gcatgtccct gactcgcatg ttttccctga ccaaatccgccagaaggcgc
tcgccgccca gcgatagcag ttcttgcaag gaagcaaagt ttttcaacggtttgagaccg
tccgccgtag gcatgctttt gagcgtttga ccaagcagtt ccaggcggtcccacagctcg
gtcacctgct ctacggcatc tcgatccagc atatctcctc gtttcgcgggttggggcggc
tttcgctgta cggcagtagt cggtgctcgt ccagacgggc cagggtcatgtctttccacg
ggcgcagggt cctcgtcagc gtagtctggg tcacggtgaa ggggtgcgctccgggctgcg
cgctggccag ggtgcgcttg aggctggtcc tgctggtgct gaagcgctgccggtcttcgc
cctgcgcgtc ggccaggtag catttgacca tggtgtcata gtccagcccctccgcggcgt
ggcccttggc gcgcagcttg cccttggagg aggcgccgca cgaggggcagtgcagacttt
tgagggcgta gagcttgggc gcgagaaata ccgattccgg ggagtaggcatccgcgccgc
aggccccgca gacggtctcg cattccacga gccaggtgag ctctggccgttcggggtcaa
aaaccaggtt tcccccatgc tttttgatgc gtttcttacc tctggtttccatgagccggt
gtccacgctc ggtgacgaaa aggctgtccg tgtccccgta tacagacttgagaggcctgt
cctcgagcgg tgttccgcgg tcctcctcgt atagaaactc ggaccactctgagacaaagg
ctcgcgtcca ggccagcacg aaggaggcta agtgggaggg gtagcggtcgttgtccacta
gggggtccac tcgctccagg gtgtgaagac acatgtcgcc ctcttcggcatcaaggaagg
tgattggttt gtaggtgtag gccacgtgac cgggtgttcc tgaaggggggctataaaagggggtgggggc gcgttcgtcc tcactctctt ccgcatcgct gtctgcgagggccagctgtt
ggggtgagta ctccctctga aaagcgggca tgacttctgc gctaagattgtcagtttcca
6301 aaaacgagga ggatttgata ttcacctggc ccgcggtgatgcctttgagg gtggccgcat
6361 ccatctggtc agaaaagaca atctttttgt tgtcaagcttggtggcaaac gacccgtaga
6421 gggcgttgga cagcaacttg gcgatggagc gcagggtttggtttttgtcg cgatcggcgc
6481 gctccttggc cgcgatgttt agctgcacgt attcgcgcgcaacgcaccgc cattcgggaa
6541 agacggtggt gcgctcgtcg ggcaccaggt gcacgcgccaaccgcggttg tgcagggtga
6601 caaggtcaac gctggtggct acctctccgc gtaggcgctcgttggtccag cagaggcggc
6661 cgcccttgcg cgagcagaat ggcggtaggg ggtctagctgcgtctcgtcc ggggggtctg
6721 cgtccacggt aaagaccccg ggcagcaggc gcgcgtcgaagtagtctatc ttgcatcctt
6781 gcaagtctag cgcctgctgc catgcgcggg cggcaagcgcgcgctcgtat gggttgagtg
6841 ggggacccca tggcatgggg tgggtgagcg cggaggcgtacatgccgcaa atgtcgtaaa
6901 cgtagagggg ctctctgagt attccaagat atgtagggtagcatcttcca ccgcggatgc
6961 tggcgcgcac gtaatcgtat agttcgtgcg agggagcgaggaggtcggga ccgaggttgc
7021 tacgggcggg ctgctctgct cggaagacta tctgcctgaagatggcatgt gagttggatg
7081 atatggttgg acgctggaag acgttgaagc tggcgtctgtgagacctacc gcgtcacgca
7141 cgaaggaggc gtaggagtcg cgcagcttgt tgaccagctcggcggtgacc tgcacgtcta
7201 gggcgcagta gtccagggtt tccttgatga tgtcatacttatcctgtccc ttttttttcc
7261 acagctcgcg gttgaggaca aactcttcgc ggtctttccagtactcttgg atcggaaacc
7321 cgtcggcctc cgaacggtaa gagcctagca tgtagaactggttgacggcc tggtaggcgc
7381 agcatccctt ttctacgggt agcgcgtatg cctgcgcggccttccggagc gaggtgtggg
7441 tgagcgcaaa ggtgtccctg accatgactt tgaggtactggtatttgaag tcagtgtcgt
7501 cgcatccgcc ctgctcccag agcaaaaagt ccgtgcgctttttggaacgc ggatttggca
7561 gggcgaaggt gacatcgttg aagagtatct ttcccgcgcgaggcataaag ttgcgtgtga
7 621 tgcggaaggg tcccggcacc tcggaacggt tgttaattacctgggcggcg agcacgatct7681 cgtcaaagcc gttgatgttg tggcccacaa tgtaaagttccaagaagcgc gggatgccct
7741 tgatggaagg caatttttta agttcctcgt aggtgagctcttcaggggag ctgagcccgt
7801 gctctgaaag ggcccagtct gcaagatgag ggttggaagcgacgaatgag ctccacaggt
7861 cacgggccat tagcatttgc aggtggtcgc gaaaggtcctaaactggcga cctatggcca
7921 ttttttctgg ggtgatgcag tagaaggtaa gcgggtcttgttcccagcgg tcccatccaa
7981 ggttcgcggc taggtctcgc gcggcagtca ctagaggctcatctccgccg aacttcatga
8041 ccagcatgaa gggcacgagc tgcttcccaa aggcccccatccaagtatag gtctctacat
8101 cgtaggtgac aaagagacgc tcggtgcgag gatgcgagccgatcgggaag aactggatct
8161 cccgccacca attggaggag tggctattga tgtggtgaaagtagaagtcc ctgcgacggg
8221 ccgaacactc gtgctggctt ttgtaaaaac gtgcgcagtactggcagcgg tgcacgggct
8281 gtacatcctg cacgaggttg acctgacgac cgcgcacaaggaagcagagt gggaatttga
8341 gcccctcgcc tggcgggttt ggctggtggt cttctacttcggctgcttgt ccttgaccgt
8401 ctggctgctc gaggggagtt acggtggatc ggaccaccacgccgcgcgag cccaaagtcc
84 61 agatgtccgc gcgcggcggt cggagcttga tgacaacatcgcgcagatgg gagctgtcca
8521 tggtctggag ctcccgcggc gtcaggtcag gcgggagctcctgcaggttt acctcgcata
8581 gacgggtcag ggcgcgggct agatccaggt gatacctaatttccaggggc tggttggtgg
8 641 cggcgtcgat ggcttgcaag aggccgcatc cccgcggcgcgactacggta cçgcgcggcg
8701 ggcggtgggc cgcgggggtg tccttggatg atgcatctaaaagcggtgac gcgggcgagc
8761 ccccggaggt agggggggct ccggacccgc cgggagagggggcaggggca cgtcggcgcc
8821 gcgcgcgggc aggagctggt gctgcgcgcg taggttgctggcgaacgcga cgacgcggcg
8881 gttgatctcc tgaatctggc gcctctgcgt gaagacgacgggcccggtga gcttgagcct
8941 gaaagagagt tcgacagaat caatttcggt gtcgttgacggcggcctggc gcaaaatctc
9001 ctgcacgtct cctgagttgt cttgataggc gatctcggccatgaactgct cgatctcttc
9061 ctcctggaga tctccgcgtc cggctcgctc cacggtggcggcgaggtcgt tggaaatgcg
9121 ggccatgagc tgcgagaagg cgttgaggcc tccctcgttccagacgcggc tgtagaccac9181 gcccccttcg gcatcgcggg cgcgcatgac cacctgcgcgagattgagct ccacgtgccg
9241 ggcgaagacg gcgtagtttc gcaggcgctg aaagaggtagttgagggtgg tggcggtgtg
9301 ttctgccacg aagaagtaca taacccagcg tcgcaacgtggattcgttga tatcccccaa
9361 ggcctcaagg cgctccatgg cctcgtagaa gtccacggcgaagttgaaaa actgggagtt
9421 gcgcgccgac acggttaact cctcctccag aagacggatgagctcggcga cagtgtcgcg
94 81 cacctcgcgc tcaaaggcta caggggcctc ttcttcttcttcaatctcct cttccataag
9541 ggcctcccct tcttcttctt ctggcggcgg tgggggaggggggacacggc ggcgacgacg
9601 gcgcaccggg aggcggtcga caaagcgctc gatcatctccccgcggcgac ggcgcatggt
9661 ctcggtgacg gcgcggccgt tctcgcgggg gcgcagttggaagacgccgc ccgtcatgtc
9721 ccggttatgg gttggcgggg ggctgccatg cggcagggatacggcgctaa cgatgcatct
9781 caacaattgt tgtgtaggta ctccgccgcc gagggacctgagcgagtccg catcgaccgg
9841 atcggaaaac ctctcgagaa aggcgtctaa ccagtcacagtcgcaaggta ggctgagcac
9901 cgtggcgggc ggcagcgggc ggcggtcggg gttgtttctggcggaggtgc tgctgatgat
9961 gtaattaaag taggcggtct tgagacggcg gatggtcgacagaagcacca tgtccttggg
10021 tccggcctgc tgaatgcgca ggcggtcggc catgccccaggcttcgtttt gacatcggcg
10081 caggtctttg tagtagtctt gcatgagcct ttctaccggcacttcttctt ctccttcctc
10141 ttgtcctgca tctcttgcat ctatcgctgc ggcggcggcggagtttggcc gtaggtggcg
10201 ccctcttcct cccatgcgtg tgaccccgaa gcccctcatcggctgaagca gggctaggtc
10261 ggcgacaacg cgctcggcta atatggcctg ctgcacctgcgtgagggtag actggaagtc
10321 atccatgtcc acaaagcggt ggtatgcgcc cgtgttgatggtgtaagtgc agttggccat
10381 aacggaccag ttaacggtct ggtgacccgg ctgcgagagctcggtgtacc tgagacgcga
104 41 gtaagccctc gagtcaaata cgtagtcgtt gcaagtccgcaccaggtact ggtatcccac
10501 caaaaagtgc ggcggcggct ggcggtagag gggccagcgtagggtggccg gggctccggg
10561 ggcgagatct tccaacataa ggcgatgata tccgtagatgtacctggaca tccaggtgat
10621 gccggcggcg gtggtggagg cgcgcggaaa gtcgcggacgcggttccaga tgttgcgcag10681 cggcaaaaag tgctccatgg tcgggacgct ctggccggtcaggcgcgcgc aatcgttgac
10741 gctctaccgt gcaaaaggag agcctgtaag cgggcactcttccgtggtct ggtggataaa
10801 ttcgcaaggg tatcatggcg gacgaccggg gttcgagccccgtatccggc cgtccgccgt
10861 gatccatgcg gttaccgccc gcgtgtcgaa cccaggtgtgcgacgtcaga caacggggga
10921 gtgctccttt tggcttcctt ccaggcgcgg cggctgctgcgctagctttt ttggccactg
10981 gccgcgcgca gcgtaagcgg ttaggctgga aagcgaaagcattaagtggc tcgcrtccctg
11041 tagccggagg gttattttcc aagggttgag tcgcgggacccccggttcga gtctcggacc
11101 ggccggactg cggcgaacgg gggtttgcct ccccgtcatgcaagaccccg cttgcaaatt
11161 cctccggaaa cagggacgag cccctttttt gcttttcccagatgcatccg gtgctgcggc
11221 agatgcgccc ccctcctcag cagcggcaag agcaagagcagcggcagaca tgcagggcac
11281 cctcccctcc tcctaccgcg tcaggagggg cgacatccgcggttgacgcg gcagcagatg
11341 gtgattacga acccccgcgg cgccgggccc ggcactacctggacttggag gagggcgagg
11401 gcctggcgcg gctaggagcg ccctctcctg agcggtacccaagggtgcag ctgaagcgtg
114 61 atacgcgtga ggcgtacgtg ccgcggcaga acctgtttcgcgaccgcgag ggagaggagc
11521 ccgaggagat gcgggatcga aagttccacg cagggcgcgagctgcggcat ggcctgaatc
11581 gcgagcggtt gctgcgcgag gaggactttg agcccgacgcgcgaaccggg attagtcccg
11641 cgcgcgcaca cgtggcggcc gccgacctgg taaccgcatacgagcagacg gtgaaccagg
11701 agattaactt tcaaaaaagc tttaacaacc' acgtgcgtacgcttgtggcg cgcgaggagg
11761 tggctatagg actgatgcat ctgtgggact ttgtaagcgcgctggagcaa aacccaaata
11821 gcaagccgct catggcgcag ctgttcctta tagtgcagcacagcagggac aacgaggcat
11881 tcagggatgc gctgctaaac atagtagagc ccgagggccgctggctgctc gatttgataa
11941 acatcctgca gagcatagtg gtgcaggagc gcagcttgagcctggctgac aaggtggccg
12001 ccatcaacta ttccatgctt agcctgggca agttttacgcccgcaagata taccataccc
12061 cttacgttcc catagacaag gaggtaaaga tcgaggggttctacatgcgc atggcgctga
12121 aggtgcttac cttgagcgac gacctgggcg tttatcgcaacgagcgcatc cacaaggccg12181 tgagcgtgag ccggcggcgc gagctcagcg accgcgagctgatgcacagc ctgcaaaggg
12241 ccctggctgg cacgggcagc ggcgatagag aggccgagtcctactttgac gcgggcgctg
12301 acctgcgctg ggccccaagc cgacgcgccc tggaggcagctggggccgga cctgggctgg
12361 cggtggcacc cgcgcgcgct ggcaacgtcg gcggcgtggaggaatatgac gaggacgatg
12421 agtacgagcc agaggacggc gagtactaag cggtgatgtttctgatcaga tgatgcaaga
124 81 cgcaacggac ccggcggtgc gggcggcgct gcagagccagccgtccggcc ttaactccac
12541 ggacgactgg cgccaggtca tggaccgcat catgtcgctgactgcgcgca atcctgacgc
12601 gttccggcag cagccgcagg ccaaccggct ctccgcaattctggaagcgg tggtcccggc
12661 gcgcgcaaac cccacgcacg agaaggtgct ggcgatcgtaaacgcgctgg ccgaaaacag
12721 ggccatccgg cccgacgagg ccggcctggt ctacgacgcgctgcttcagc gcgtggctcg
12781 ttacaacagc ggcaacgtgc agaccaacct ggaccggctggtgggggatg tgcgcgaggc
12841 cgtggcgcag cgtgagcgcg cgcagcagca gggcaacctgggctccatgg ttgcactaaa
12901 cgccttcctg agtacacagc ccgccaacgt gccgcggggacaggaggact acaccaactt
12961 tgtgagcgca ctgcggctaa tggtgactga gacaccgcaaagtgaggtgt açcagtctgg
13021 gccagactat tttttccaga ccagtagaca aggcctgcagaccgtaaacc tgagccaggc
13081 tttcaaaaac ttgcaggggc tgtggggggt gcgggctcccacaggcgacc gcgcgaccgt
13141 gtctagcttg ctgacgccca actcgcgcct gttgctgctgctaatagcgc ccttcacgga
13201 cagtggcagc gtgtcccggg acacatacct aggtcacttgctgacactgt accgcgaggc
13261 cataggtcag gcgcatgtgg acgagcatac tttccaggagattacaagtg tcagccgcgc
13321 gctggggcag gaggacacgg gcagcctgga ggcaaccctaaactacctgc tgaccaaccg
13381 gcggcagaag atcccctcgt tgcacagttt aaacagcgaggaggagcgca ttttgcgcta
13441 cgtgcagcag agcgtgagcc ttaacctgat gcgcgacggggtaacgccca gcgtggcgct
13501 ggacatgacc gcgcgcaaca tggaaccggg catgtatgcctcaaaccggc cgtttatcaa
13561 ccgcctaatg gactacttgc atcgcgcggc cgccgtgaaccccgagtatt tcaccaatgc
13621 catcttgaac ccgcactggc taccgccccc tggtttctacaccgggggat tcgaggtgcc13681 cgagggtaac gatggattcc tctgggacga catagacgacagcgtgtttt ccccgcaacc
13741 gcagaccctg ctagagttgc aacagcgcga gcaggcagaggcggcgctgc gaaaggaaag
13801 cttccgcagg ccaagcagct tgtccgatct aggcgctgcggccccgcggt. cagatgctag
13861 tagcccattt ccaagcttga tagggtctct taccagcactcgcaccaccc gcccgcgcct
13921 gctgggcgag gaggagtacc taaacaactc gctgctgcagccgcagcgcg aaaaaaacct
13981 gcctccggca tttcccaaca acgggataga gagcctagtggacaagatga gtagatggaa
14041 gacgtacgcg caggagcaca gggacgtgcc aggcccgcgcccgcccaccc gtcgtcaaag
14101 gcacgaccgt cagcggggtc tggtgtggga ggacgatgactcggcagacg acagcagcgt
14161 cctggatttg ggagggagtg gcaacccgtt tgcgcaccttcgccccaggc tggggagaat
14221 gttttaaaaa aaaaaaagca tgatgcaaaa taaaaaactcaccaaggcca tggcaccgag
14281 cgttggtttt cttgtattcc ccttagtatg cggcgcgcggcgatgtatga ggaaggtcct
14341 cctccctcct acgagagtgt ggtgagcgcg gcgccagtggcggcggcgct gggttctccc
14401 ttcgatgctc ccctggaccc gccgtttgtg cctccgcggtacctgcggcc taccgggggg
14461 agaaacagca tccgttactc tgagttggca cccctattcgacaccacccg tgtgtacctg
14521 gtggacaaca agtcaacgga tgtggcatcc ctgaactaccagaacgacca cagcaacttt
14581 ctgaccacgg tcattcaaaa caatgactac agcccgggggaggcaagcac acagaccatc
14641 aatcttgacg accggtcgca ctggggcggc gacctgaaaaccatcctgca taccaacatg
14701 ccaaatgtga acgagttcat gtttaccaat aagtttaaggcgcgggtgat ggtgtcgcgc
14761 ttgcctacta aggacaatca ggtggagctg aaatacgagtgggtggagtt cacgctgccc
14821 gagggcaact actccgagac catgaccata gaccttatgaacaacgcgat cgtggagcac
14881 tacttgaaag tgggcagaca gaacggggtt ctggaaagcgacatcggggt aaagtttgac
14941 acccgcaact tcagactggg gtttgacccc gtcactggtcttgtcatgcc tggggtatat
15001 acaaacgaag ccttccatcc agacatcatt ttgctgccaggatgcggggt ggacttcacc
15061 cacagccgcc tgagcaactt gttgggcatc cgcaagcggcaacccttcca ggagggcttt
15121 aggatcacct acgatgatct ggagggtggt aacattccçgcactgttgga tgtggacgcc15181 taccaggcga gcttgaaaga tgacaccgaa cagggcgggggtggcgcagg cggcagcaac
15241 agcagtggca gcggcgcgga agagaactcc aacgcggcagccgcggcaat gcagccggtg
15301 gaggacatga acgatcatgc cattcgcggc gacacctttgccacacgggc tgaggagaag
15361 cgcgctgagg ccgaagcagc ggccgaagct gccgcccccgctgcgcaacc cgaggtcgag
15421 aagcctcaga agaaaccggt gatcaaaccc ctgacagaggacagcaagaa acgcagttac
15481 aacctaataa gcaatgacag caccttcacc cagtaccgcagctggtacct tgcatacaac
15541 tacggcgacc ctcagaccgg aatccgctca tggaccctgctttgcactcc tgacgtaacc
15601 tgcggctcgg agcaggtcta ctggtcgttg ccagacatgatgcaagaccc cgtgaccttc
15661 cgctccacgc gccagatcag caactttccg gtggtgggcgccgagctgtt gcccgtgcac
15721 tccaagagct tctacaacga ccaggccgtc tactcccaactcatccgcca gtttacctct
15781 ctgacccacg tgttcaatcg ctttcccgag aaccagattttggcgcgccc gccagccccc
15841 accatcacca ccgtcagtga aaacgttcct gctctcacagatcacgggac gctaccgctg
15901 cgcaacagca tcggaggagt ccagcgagtg accattactgacgccagacg ccgcacctgc
15961 ccctacgttt acaaggccct gggcatagtc tcgccgcgcgtcctatcgag ccgcactttt
16021 tgagcaagca tgtccãtcct tatatcgccc agcaataacacaggctgggg cctgcgcttc
16081 ccaagcaaga tgtttggcgg ggccaagaag cgctccgaccaacacccagt gcgcgtgcgc
16141 gggcactacc gcgcgccctg gggcgcgcac aaacgcggccgcactgggcg caccaccgtc
16201 gatgacgcca tcgacgcggt ggtggaggag gcgcgcaactacacgcccac gccgccacca
16261 gtgtccacag tggacgcggc cattcagacc gtggtgcgcggagcccggcg ctatgctaaa
16321 atgaagagac ggcggaggcg cgtagcacgt cgccaccgccgccgacccgg cactgccgcc
16381 caacgcgcgg cggcggccct gcttaaccgc gcacgtcgcaccggccgacg ggcggccatg
164 41 cgggccgctc gaaggctggc cgcgggtatt gtcactgtgccccccaggtc caggcgacga
16501 gcggccgccg cagcagccgc ggccattagt gctatgactcagggtcgcag gggcaacgtg
16561 tattgggtgc gcgactcggt tagcggcctg-cgcgtgcccgtgcgcacccg ccccccgcgc
16621 aactagattg caagaaaaaa ctacttagac tcgtactgttgtatgtatcc agcggcggcg16681 gcgcgcaacg aagctatgtc caagcgcaaa atcaaagaagagatgctcca ggtcatcgcg
16741 ccggagatct atggcccccc gaagaaggaa gagcaggattacaagccccg aaagctaaag
16801 cgggtcaaaa agaaaaagaa agatgatgat gatgaacttgacgacgaggt ggaactgctg
16861 cacgctaccg cgcccaggcg acgggtacag tggaaaggtcgacgcgtaaa acgtgttttg
16921 cgacccggca ccaccgtagt ctttacgccc ggtgagcgctccacccgcac ctacaagcgc
16981 gtgtatgatg aggtgtacgg cgacgaggac ctgcttgagcaggccaacga gcgcctcggg
17041 gagtttgcct acggaaagcg gcataaggac atgctggcgttgccgctgga cgagggcaac
17101 ccaacaccta gcctaaagcc cgtaacactg cagcaggtgctgcccgcgct tgcaccgtcc
17161 gaagaaaagc gcggcctaaa gcgcgagtct ggtgacttggcacccaccgt gcagctgatg
17221 gtacccaagc gccagcgact ggaagatgtc ttggaaaaaatgaccgtgga acctgggctg
17281 gagcccgagg tccgcgtgcg gccaatcaag caggtggcgccgggactggg cgtgcagacc
17341 gtggacgttc agatacccac taccagtagc accagtattgccaccgccac agagggcatg
17401 gagacacaaa cgtccccggt tgcctcagcg gtggcggatgcçgcggtgca ggcggtcgct
17461 gcggccgcgt ccaagacctc tacggaggtg caaacggacccgtggatgtt tcgcgtttca
17521 gccccccggc gcccgcgcgg ttcgaggaag tacggcgccgccagcgcgct actgcccgaa
17581 tatgccctac atccttccat tgcgcctacc cccggctatcgtggctacac ctaccgcccc
17641 agaagacgag caactacccg acgccgaacc accactggaacccgccgccg ccgtcgccgt
17701 cgccagcccg tgctggcccc gatttccgtg cgcagggtggctcgcgaagg aggcaggacc
177 61 ctggtgctgc caacagcgcg ctaccacccc agcatcgtttaaaagccggt ctttgtggtt
17821 cttgcagata tggccctcac ctgccgcctc cgtttcccggtgccgggatt ccgaggaaga
17881 atgcaccgta ggaggggcat ggccggccac ggcctgacgggcggcatgcg tcgtgcgcac
17 941 caccggcggc ggcgcgcgtc gcaccgtcgc atgcgcggcggtatcctgcc cctccttatt
18001 ccactgatcg ccgcggcgat tggcgccgtg cccggaattgcatccgtggc cttgcaggcg
18061 cagagacact gattaaaaac aagttgcatg tggaaaaatcaaaataaaaa gtctggactc
18121 tcacgctcgc ttggtcctgt aactattttg tagaatggaagacatcaact ttgcgtctct18181 ggccccgcga cacggctcgc gcccgttcat gggaaactggcaagatatcg gcaccagcaa
18241 tatgagcggt ggcgccttca gctggggctc gctgtggagcggcattaaaa atttcggttc
18301 caccgttaag aactatggca gcaaggcctg gaacagcagcacaggccaga tgctgaggga
18361 taagttgaaa gagcaaaatt tccaacaaaa ggtggtagatggcctggcct ctggcattag
18421 cggggtggtg gacctggcca accaggcagt gcaaaataagattaacagta agcttgatcc
18481 ccgccctccc gtagaggagc ctccaccggc cgtggagacagtgtctccag aggggcgtgg
18541 cgaaaagcgt ccgcgccccg acagggaaga aactctggtgacgcaaatag acgagcctcc
18601 ctcgtacgag gaggcactaa agcaaggcct gcccaccacccgtcccatcg cgcccatggc
18661 taccggagtg ctgggccagc acacacccgt aacgctggácctgcctcccc ccgccgacac
18*7 21 ccagcagaaa cctgtgctgc caggcccgac cgccgttgttgtaacccgtc ctagccgcgc
18781 gtccctgcgc cgcgccgcca gcggtccgcg atcgttgcggcccgtagcca gtggcaactg
18841 gcaaagcaca ctgaacagca tcgtgggtct gggggtgcaatccctgaagc gccgacgatg
18901 cttctgaata gctaacgtgt cgtatgtgtg tcatgtatgcgtccatgtcg ccgccagagg
18961 agctgctgag ccgccgcgcg cccgctttcc aagatggctaccccttcgat gatgccgcag
19021 tggtcttaca tgcacatctc gggccaggac gcctcggagtacctgagccc cgggctggtg
19081 cagtttgccc gcgccaccga gacgtacttc agcctgaataacaagtttag aaaccccacg
19141 gtggcgccta cgcacgacgt gaccacagac cggtcccagcgtttgacgct gcggttcatc
19201 cctgtggacc gtgaggatac tgcgtactcg tacaaggcgcggttcaccct agctgtgggt
19261 gataaccgtg tgctggacat ggcttccacg tactttgacatccgcggcgt gctggacagg
19321 ggccctactt ttaagcccta ctctggcact gcctacaacgccctggctcc caagggtgcc
19381 ccaaatcctt gcgaatggga tgaagctgct actgctcttgaaataaacct agaagaagag
19441 gacgatgaca acgaagacga agtagacgag caagctgagcagcaaaaaac tcacgtattt
19501 gggcaggcgc cttattctgg tataaatatt acaaaggagggtattcaaat aggtgtcgaa
19561 ggtcaaacac ctaaatatgc cgataaaaca tttcaacctgaacctcaaat aggagaatct
•19621 cagtggtacg aaactgaaat taatcatgca gctgggagagtccttaaaaa gactacccca19681 atgaaaccat gttacggttc atatgcaaaa cccacaaatgaaaatggagg gcaaggcatt
19741 cttgtaaagc aacaaaatgg aaagctagaa agtcaagtggaaatgcaatt tttctcaact
19801 actgaggcga ccgcaggcaa tggtgataac ttgactcctaaagtggtatt gtacagtgaa
19861 gatgtagata tagaaacccc agacactcat atttcttacatgcccactat taaggaaggt
19921 aactcacgag aactaatggg ccaacaatct atgcccaacaggcctaatta cattgctttt
19981 agggacaatt ttattggtct aatgtattac aacagcacgggtaatatggg tgttctggcg
20041 ggccaagcat cgcagttgaa tgctgttgta gatttgcaagacagaaacac agagctttca
20101 taccagcttt tgcttgattc cattggtgat agaaccaggtacttttctat gtggaatcag
20161 gctgttgaca gctatgatcc agatgttaga attattgaaaatcatggaac tgaagatgaa
20221 cttccaaatt actgctttcc actgggaggt gtgattaatacagagactct taccaaggta
20281 aaacctaaaa caggtcagga aaatggatgg gaaaaagatgctacagaatt ttcagataaa
20341 aatgaaataa gagttggaaa taattttgcc atggaaatcaatctaaatgc caacctcftgg
20401 agaaatttcc "tgtactccaa catagcgctg tatttgcccgacaagctaaa gtacagtcct
204 61 tccaacgtaa aaatttctga taacccaagc acctacgactacatgaacaa gcgagtggtg
20521 gctcccgggt tagtggactg ctacattaac cttggagcacgctggtccct tgactatatg
20581 gacaacgtca acccatttaa ccaccaccgc aatgctggcctgcgctaccg ctcaatgttg
20641 ctgggcaatg gtcgctatgt gcccttccac atccaggtgcctcagaagtt ctttgccatt
20701 aaaaacctcc ttctcctgcc gggctrcatac acctacgagtggaacttcag gaaggatgtt
207 61 aacatggttc tgcagagctc cctaggaaat gacctaagggttgacggagc cagcattaag
20821 tttgatagca tttgccttta cgccaccttc ttccccatggcccacaacac cgcctccacg
20881 cttgaggcca tgcttagaaa cgacaccaac gaccagtcctttaacgacta tctctccgcc
20941 gccaacatgc tctaccctat acccgccaac gctaccaacgtgcccatatc catcccctcc
21001 cgcaactggg cggctttccg cggctgggcc ttcacgcgccttaagactaa ggaaacccca
21061 tcactgggct cgggctacga cccttattac acctactctggctctatacc ctacctagat
21121 ggaacctttt acctcaacca cacctttaag aaggtggccattacctttga ctcttctgtc21181 agctggcctg gcaatgaccg cctgcttacc cccaacgagtttgaaattaa gcgctcagtt
21241 gacggggagg gttacaacgt tgcccagtgt aacatgaccaaagactggtt cctggtacaa
21301 atgctagcta actacaacat tggctaccag ggcrttctatatcccagagag ctacaaggac
21361 cgcatgtact ccttctttag aaacttccag cccatgagccgtcaggtggt. ggatgatact
21421 aaatacaagg actaccaaca ggtgggcatc ctacaccaacacaacaactc tggatttgtt
21481 ggctaccttg cccccaccat gcgcgaagga caggcctaccctgctaactt cccctatccg
21541 cttataggca agaccgcagt tgacagcatt acccagaaaaagtttctttg cgatcgcacc
21601 ctttggcgca tcccattctc cagtaacttt atgtccatgggcgcactcac agacctgggc
21661 caaaaccttc tctacgccaa ctccgcccac gcgctagacatgacttttga ggtggatccc
21721 atggacgagc ccacccttct ttatgttttg tttgaagtctttgacgtggt ccgtgtgcac
21781 cggccgcacc gcggcgtcat cgaaaccgtg tacctgcgcacgcccttctc ggccggcaac
21841 gccacaacat aaagaagcaa gcaacatcaa caacagctgccgccatgggc tccagtgagc
21901 aggaactgaa agccattgtc aaagatcttg gttgtgggccatattttttg ggcacctatg
21961 acaagcgctt tccaggcttt gtttctccac acaagctcgcctgcgccata gtcaatacgg
22021 ccggtcgcga gactgggggc gtacactgga tggcctttgcctggaacccg cactcaaaaa
22081 catgctacct ctttgagccc tttggctttt ctgaccagcgactcaagcag gtttaccagt
22141 ttgagtacga gtcactcctg cgccgtagcg ccattgcttcttcccccgac cgctgtataa
22201 cgctggaaaa gtccacccaa agcgtacagg ggcccaactcggccgcctgt ggactattct
22261 gctgcatgtt tctccacgcc tttgccaact ggccccaaactcccatggat cacaacccca
22321 ccatgaacct tattaccggg gtacccaact ccatgctcaacagtccccag gtacagccca
22381 ccctgcgtcg caaccaggaa cagctctaca gcttcctggagcgccactcg" ccctacttcc
22441 gcagccacag tgcgcagatt aggagcgcca cttctttttgtcacttgaaa aacatgtaaa
22501 aataatgtac tagagacact ttcaataaag gcaaatgcttttatttgtac actctcgggt
22561 gattatttac ccccaccctt gccgtctgcg ccgtttaaaaatcaaagggg ttctgccgcg
22621 catcgctatg cgccactggc agggacacgt tgcgatactggtgtttagtg ctccacttaa22681 actcaggcac aaccatccgc ggcagctcgg tgaagttttcactccacagg ctgcgcacca
22741 tcaccaacgc gtttagcagg tcgggcgccg atatcttgaagtcgcagttg gggcctccgc
22801 cctgcgcgcg cgagttgcga tacacagggt tgcagcactggaacactatc agcgccgggt
22861 ggtgcacgct ggccagcacg ctcttgtcgg agatcagatccgcgtccagg tcctccgcgt
22921 tgctcagggc gaacggagtc aactttggta gctgccttcccaaaaagggc gcgtgcccag
22981 gctttgagtt gcactcgcac cgtagtggca tcaaaaggtgaccgtgcccg gtctgggcgt
23041 taggatacag cgcctgcata aaagccttga tctgcttaaaagccacctga gcctttgcgc
23101 cttcagagaa gaacatgccg caagacttgc cggaaaactgattggccgga caggccgcgt
23161 cgtgcacgca gcaccttgcg tcggtgttgg agatctgcaccacatttcgg ccccaccggt
23221 tcttcacgat cttggccttg ctagactgct ccttcagcgcgcgctgcccg ttttcgctcg
23281 tcacatccat ttcaatcacg tgctccttat ttatcataatgcttccgtgt agacacttaa
23341 gctcgccttc gatctcagcg cagcggtgca gccacaacgcgcagcccgtg ggctcgtgat
23401 gcttgtaggt cacctctgca aacgactgca ggtacgcctgcaggaatcgc cccatcatcg
23461 tcacaaaggt cttgttgctg gtgaaggtca gctgcaacccgcggtgctcc tcgttcagcc
23521 aggtcttgca tacggccgcc agagcttcca cttggtcaggcagtagtttg aagttcgcct
23581 ttagatcgtt atccacgtgg tacttgtcca tcagcgcgcgcgcagcctcc atgcccttct
23641 cccacgcaga cacgatcggc acactcagcg ggttcatcaccgtaatttca ctttccgctt
23701 cgctgggctc ttcctcttcc tcttgcgtcc gcataccacgcgccactggg tcgtcttcat
23761 tcagccgccg cactgtgcgc ttacctcctt tgccatgcttgattagcacc ggtgggttgc
23821 tgaaacccac catttgtagc gccacatctt ctctttcttcctcgctgtcc acgattacct
23881 ctggtgatgg cgggcgctcg ggcttgggag aagggcgcttctttttcttc ttgggcgcaa
23941 tggccaaatc cgccgccgag gtcgatggcc gcgggctgggtgtgcgcggc accagcgcgt
24001 cttgtgatga gtcttcctcg tcctcggact cgatacgccgcctcatccgc ttttttgggg
24061 gcgcccgggg aggcggcggc gacggggacg gggacgacacgtcctccatg gttgggggac
24121 gtcgcgccgc accgcgtccg cgctcggggg tggtttcgcgctgctcctct tcccgactgg24181 ccatttcctt ctcctatagg cagaaaaaga tcatggagtcagtcgagaag aaggacagcc
24241 taaccgcccc ctctgagttc gccaccaccg cctccaccgatgccgccaac gcgcctacca
24301 ccttccccgt cgaggcaccc ccgcttgagg aggaggaagtgattatcgag caggacccag
24361 gttttgtaag cgaagacgac gaggaccgct cagtaccaacagaggataaa aagcaagacc
24421 aggacaacgc agaggcaaac gaggaacaag tcgggcggggggacgaaagg catggcgact
24481 acctagatgt gggagacgac gtgctgttga agcatctgcagcgccagtgc gccattatct
24541 gcgacgcgtt gcaagagcgc agcgatgtgc ccctcgccatagcggatgtc agccttgcct
24601 acgaacgcca cctattctca ccgcgcgtac cccccaaacgccaagaaaac ggcacatgcg
24 661 agcccaaccc gcgcctcaac ttctaccccg tatttgccgtgccagaggtg cttgccacct
24721 atcacatctt tttccaaaac tgcaagatac ccctatcctgccgtgccaac cgcagccgag
24781 cggacaagca gctggccttg cggcagggcg ctgtcatacctgatatcgcc tcgctcaacg
24841 aagtgccaaa aatctttgag ggtcttggac gcgacgagaagcgcgcggca aacgctctgc
24901 aacaggaaaa cagcgaaaat gaaagtcact ctggagtgttggtggaactc gagggtgaca
24 961 acgcgcgcct agccgtacta aaacgcagca tcgaggtcacccactttgcc tacccggcac
25021 ttaacctacc ccccaaggtc atgagcacag tcatgagtgagctgatcgtg cgccgtgcgc
25081 agcccctgga gagggatgca aatttgcaag aacaaacagaggagggccta cccgcagttg
25141 gcgacgagca gctagcgcgc tggcttcaaa cgcgcgagcctgccgacttg gaggagcgac
25201 gcaaactaat. gatggccgca gtgctcgtta ccgtggagcttgagtgcatg cagcggttct
25261 ttgctgaccc ggagatgcag cgcaagctag aggaaacattgcactacacc tttcgacagg
25321 gctacgtacg ccaggcctgc aagatctcca acgtggagctctgcaacctg gtctcctacc
25381 ttggaatttt gcacgaaaac cgccttgggc aaaacgtgcttcattccacg ctcaagggcg
254 41 aggcgcgccg cgactacgtc cgcgactgcg tttacttatttctatgctac acctggcaga '
25501 cggccatggg cgtttggcag cagtgcttgg aggagtgcaacctcaaggag ctgcagaaac
25561 tgctaaagca aaacttgaag gacctatgga cggccttcaacgagcgctcc gtggccgcgc
25621 acctggcgga catcattttc cccgaacgcc tgettaaaaccctgcaacag ggtctgccag25681 acttcaccag tcaaagcatg ttgcagaact ttaggaactttatcctagag cgctcaggaa
257 41 tcttgcccgc cacctgctgt gcacttccta gcgactttgtgcccattaag taccgcgaat
25801 gccctccgcc gctttggggc cactgctacc ttctgcagctagccaactac cttgcctacc
25861 actctgacat aatggaagac gtgagcggtg acggtctactggagtgtcac tgtcgctgca
25921 acctatgcac cccgcaccgc tccctggttt gcaattcgcagctgcttaac gaaagtcaaa
25981 ttatcggtac ctttgagctg cagggtccct cgcctgacgaaaagtccgcg gctccggggt
26041 tgaaactcac tccggggctg'tggacgtcgg cttaccttcgcaaatttgta cctgaggact
26101 accacgccca cgagattagg ttctacgaag accaatcccgcccgccaaat gcggagctta
26161 ccgcctgcgt cattacccag ggccacattc ttggccaattgcaagccatc aacaaagccc
26221 gccaagagtt tctgctacga aagggacggg gggtttacttggacccccag tccggcgagg
26281 agctcaaccc aatccccccg ccgccgcagc cctatcagcagcagccgcgg gcccttgctt
26341 cccaggatgg cacccaaaaa gaagctgcag ctgccgccgccacccacgga cgaggaggaa
264 01 tactgggaca gtcaggcaga ggaggttttg gácgaggaggaggaggacat gatggaagac
264 61 tgggagagcc tagacgagga agcttccgag gtcgaagaggtgtcagacga aacaccgtca
26521 ccctcggtcg cattcccctc gccggcgccc cagaaatcggcaaccggttc cagcatggct
26581 acaacctccg ctcctcaggc gccgccggca ctgcccgttcgccgacccaa ccgtagatgg
26641 gacaccactg gaaccagggc cggtaagtcc aagcagccgccgccgttagc·ccaagagcaa
26701 caacagcgcc aaggctaccg ctcatggcgc gggcacaagaacgccatagt tgcttgcttg
267 61 caagactgtg ggggcaacat ctccttcgcc cgccgctttcttctctacca tcacggcgtg
26821 gccttccccc gtaacatcct gcattactac cgtcatctctacagcccata ctgcaccggc
268 81 ggcagcggca gcggcagcaa cagcagcggc cacacagaagcaaaggcgac cggatagcaa
26941 gactctgaca aagcccaaga aatccacagc ggcggcagcagcaggaggag gagcgctgcg
27001 tctggcgccc aacgaacccg tatcgacccg cgagcttagaaacaggattt ttcccactct
27061 gtatgctata tttcaaeaga gcaggggcca agaacaagagctgaaaataa aaaacaggtc
27121 tctgcgatcc ctcacccgca gctgcctgta tcacaaaagcgaagatcagc ttcggcgcac27181 gctggaagac gcggaggctc tcttcagtaa atactgcgcgctgactctta aggactagtt
27241 tcgcgccctt tctcaaattt aagcgcgaaa actacgtcatctccagcggc cacacccggc
27301 gccagcacct gtcgtcagcg ccattatgag caaggaaattcccacgccct acatgtggag
27361 ttaccagcca caaatgggac ttgcggctgg agctgcccaagactactcaa cccgaataaa
27421 ctacatgagc gcgggacccc acatgatatc ccgggtcaacggaatccgcg cccaccgaaa
27481 ccgaattctc ttggaacagg cggctattac caccacacctcgtaataacc ttaatccccg
27541 tagttggccc gctgccctgg tgtaccagga aagtcccgctcccaccactg tggtacttcc
27 601 cagagacgcc caggccgaag ttcagatgac taactcaggggcgcagcttg cgggcggctt
27661 tcgtcacagg gtgcggtcgc ccgggcaggg tataactcacctgacaatca gagggcgagg
27721 tattcagctc aacgacgagt cggtgagctc ctcgcttggtctccgtccgg acgggacatt
27781 tcagatcggc ggcgccggcc gtccttcatt cacgcctcgtcaggcaatcc taactctgca
27841 gacctcgtcc tctgagccgc gctctggagg cattggaactctgcaattta ttgaggagtt
27901 tgtgccatcg gtctacttta accccttctc gggacctcccggccactatc cggatcaatt
27 961 tattcctaac tttgacgcgg taaaggactc ggcggacggctacgactgaa tgttaagtgg
28 021 agaggcagag caactgcgcc tgaaacacct ggtccactgtcgccgccaca agtgctttgc
28081 ccgcgactcc ggtgagtttt gctactttga attgcccgaggatcatatcg agggcccggc
28141 gcacggcgtc cggcttaccg cccagggaga gcttgcccgtagcctgattc gggagtttac
28201 ccagcgcccc ctgctagttg agcgggacag gggaccctgtgttctcactg tgatttgcaa
282 61 ctgtcctaac cttggattac atcaagatcc tctagttataactagagtac ccggggatct
28321 tattcccttt aactaataaa aaaaaataat aaagcatcacttacttaaaa tcagttagca
28381 aatttctgtc cagtttattc agcagcacct ccttgccctcctcccagctc tggtattgca
28441 gcttcctcct ggctgcaaac tttctccaca atctaaatggaatgtcagtt tcctcctgtt
28501 cctgtccatc cgcacccact atcttcatgt tgttgcagatgaagcgcgca agaccgtctg
28561 aagatacctt caaccccgtg tatccatatg acacggaaaccggtcctcca actgtgcctt
28621 ttcttactcc tccctttgta tcccccaatg ggtttcaagagagtccccct ggggtactct28681 ctttgcgcct atccgaacct ctagttacct. ccaatggcatgcttgcgctc aaaatgggca
28741 acggcctctc tctggacgag gccggcaacc ttacctcccaaaatgtaacc actgtgagcc
28801 cacctctcaa aaaaaccaag tcaaacataa acctggaaatatctgcaccc ctcacagtta
28861 cctcagaagc cctaactgtg gctgccgccg cacctctaatggtcgcgggc aacacactca
28921 ccatgcaatc acaggccccg ctaaccgtgc acgactccaaacttagcatt gccacccaag
28981 gacccctcac agtgtcagaa ggaaagctag ccctgcaaacatcaggcccc ctcaccacca
29041 ccgatagcag tacccttact atcactgcct caccccctctaactactgcc actggtagct
29101 tgggcattga cttgaaagag cccatttata cacaaaatggaaaactagga ctaaagtacg
29161 gggctccttt gcatgtaaca gacgacctaa acactttgaccgtagcaact ggtccàggtg
29221 tgactattaa taatacttcc ttgcaaacta aagttactggagccttgggt tttgattcac
29281 aaggcaatat gcaacttaat gtagcaggag gactaaggattgattctcaa aacagacgcc
29341 ttatacttga tgttagttat ccgtttgatg ctcaaaaccaactaaatcta agactaggac
29401 agggccctct ttttataaac tcagcccaca acttggatattaactacaac aaaggccttt
294 61 acttgtttac agcttcaaac aattccaaaa agcttgaggttaacctaagc actgccaagg
29521 ggttgatgtt tgacgctaca gccatagcca ttaatgcaggagatgggctt gaatttggtt
29581 cacctaatgc accaaacaca aatcccctca aaacaaaaattggccatggc ctagaatttg
29641 attcaaacaa ggctatggtt cctaaactag gaactggccttagttttgac agcacaggtg
29701 ccattacagt aggaaacaaa aataatgata agctaactttgtggaccaca ccagctccat
29761 ctcctaactg tagactaaat gcagagaaag atgctaaactcactttggtc ttaacaaaat
29821 gtggcagtca aatacttgct acagtttcag ttttggctgttaaaggcagt ttggctccaa
29881 tatctggaac agttcaaagt gctcatctta ttataagatttgacgaaaat ggagtgctac
29941 taaacaattc cttcctggac ccagaatatt ggaactttagaaatggagat cttactgaag
30001 gcacagccta tacaaacgct gttggattta tgcctaacctatcagcttat ccaaaatctc
30061 acggtaaaac tgccaaaagt aacattgtca gtcaagtttacttaaacgga gacaaaacta
30121 aacctgtaac actaaccatt acactaaacg gtacacaggaaacaggagac acaactccaa30181 gtgcatactc tatgtcattt tcatgggact ggtctggccacaactacatt aatgaaatat
30241 ttgccacatc ctcttacact ttttcataca ttgcccaagaataaagaatc gtttgtgtta
30301 tgtttcaacg tgtttatttt tcaattgcag aaaatttcaagtcatttttc attcagtagt
30361 atagccccac caccacatag cttatacaga tcaccgtaccttaatcaaac tcacagaacc
30421 ctagtattca acctgccacc tccctcccaa cacacagagtacacagtcct ttctccccgg
30481 ctggccttaa aaagcatcat atcatgggta acagacatattcttaggtgt tatattccac
30541 acggtttcct gtcgagccaa acgctcatca gtgatattâataaactcccc gggcagctca
30601 cttaagttca tgtcgctgtc cagctgctga gccacaggctgctgtccaac ttgcggttgc
30661 ttaacgggcg gcgaaggaga agtccacgcc tacatgggggtagagtcata atcgtgcatc
30721 aggatagggc ggtggtgctg cagcagcgcg cgaataaactgctgccgccg ccgctccgtc
30781 ctgcaggaat acaacatggc agtggtctcc tcagcgatgattcgcaccgc ccgcagcata
30841 aggcgccttg tcctccgggc acagcagcgc accctgatctcacttaaatc agcacagtaa
30901 ctgcagcaca gcaccacaat attgttcaaa atcccacagtgcaaggcgct gtatccaaag
30961 ctcatggcgg ggaccacaga acccacgtgg ccatcataccacaagcgcag gtagattaag
31021 tggcgacccc tcataaacac gctggacata aacattacctcttttggcat gttgtaattc
31081 accacctccc ggtaccatat aaacctctga ttaaacatggcgccatccac caccatccta
31141 aaccagctgg ccaaaacctg cccgccggct atacactgcagggaaccggg actggaacaa
31201 tgacagtgga gagcccagga ctcgtaacca tggatcatcatgctcgtcat gatatcaatg
31261 ttggcacaac acaggcacac gtgcatacac ttcctcaggattacaagctc ctcccgcgtt
31321 agaaccatat cccagggaac aacccattcc tgaatcagcgtaaatcccac actgcaggga
31381 agacctcgca cgtaactcac gttgtgcatt gtcaaagtgttacattcggg cagcagcgga
314 41 tgatcctcca gtatggtagc gcgggtttct gtctcaaaaggaggtagacg atccctactg
31501 tacggagtgc gccgagacaa ccgagatcgt gttggtcgtagtgtcatgcc aaatggaacg
31561 ccggacgtag tcatatttcc tgaagcaaaa ccaggtgcgggcgtgacaaa cagatctgcg
31621 tctccggtct cgccgcttag atcgctctgt gtagtagttgtagtatatcc actctctcaa31681 agcatccagg cgccccctgg cttcgggttc tatgtaaactccttcatgcg ccgctgccct
317 41 gataacatcc accaccgcag aataagccac acccagccaacctacacatt cgttctgcga
31801 gtcacacacg. ggaggagcgg gaagagctgg aagaaccatgtttttttttt tattccaaaa
31861 gattatccaa aacctcaaaa tgaagatcta ttaagtgaacgcgctcccct ccggtggcgt
31921 ggtcaaactc tacagccaaa gaacagataa tggcatttgtaagatgttgc acaatggctt
31981 ccaaaaggca aacggccctc acgtccaagt ggacgtaaaggctaaaccct tcagggtgaa
32041 tctcctctat aaacattcca gcaccttcaa ccatgcccaaataattctca tctcgccacc
32101 ttctcaatat atctctaagc aaatcccgaa tattaagtccggccattgta aaaatctgct
32161 ccagagcgcc ctccaccttc agcctcaagc agcgaatcatgattgcaaaa attcaggttc
32221 ctcacagacc tgtataagat tcaaaagcgg aacattaacaaaaataccgc gatcccgtag
32281 gtcccttcgc agggccagct gaacataatc gtgcaggtctgcacggacca gcgcggccac
32341 ttccccgcca ggaaccttga caaaagaacc cacactgattatgacacgca tactcggagc
32401 tatgctaacc agcgtagccc cgatgtaagc tttgttgcatgggcggcgat ataaaatgca
324 61 aggtgctgct caaaaaatca ggcaaagcct cgcgcaaaaaagaaagcaca tcgtagtcat
32521 gctcatgcag ataaaggcag gtaagctccg gaaccaccacagaaaaagac accatttttc
32581 tctcaaacat gtctgcgggt ttctgcataa acacaaaataaaataacaaa aaaacattta .
32641 aacattagaa gcctgtctta caacaggaaa aacaacccttataagcataa gacggactac
32701 ggccatgceg gcgtgaccgt aaaaaaactg gtcaccgtgattaaaaagca ccaccgacag.
32761 ctcctcggtc atgtccggag tcataatgta agactcggtaaacacatcag gttgattcat
32821 cggtcagtgc taaaaagcga ccgaaatagc ccgggggaatacatacccgc aggcgtagag
32881 acaacattac agcccccata ggaggtataa caaaattaataggagagaaa aacacataaa
32941 cacctgaaaa accctcctgc ctaggcaaaa tagcaccctcccgctccaga acaacataca
33001 gcgcttcaca gcggcagcct aacagtcagc cttaccagtaaaaaagaaaa cctattaaaa
33061 aaacaccact cgacacggca ccagctcaat cagtcacagtgtaaaaaagg gccaagtgca
33121 gagcgagtat atataggact aaaaaatgac gtaacggttaaagtccacaa aaaacaccca33181 gaaaaccgca cgcgaaccta cgcccagaaa cgaaagccaaaaaacccaca acttcctcaa
33241 atcgtcactt ccgttttccc acgttacgta acttcccattttaagaaaac tacaattccc
33301 aacacataca agttactccg ccctaaaacc tacgtcacccgccccgttcc cacgccccgc
33361 gccacgtcac aaactccacc ccctcattat catattggcttcaatccaaa ataaggtata
33421 ttattgatga tnnnnnttaa t
SEQIDN9: 17 (ND1.1 214)
1 taaggatccn nncctgtcct cgaccgatgc ccttgagagc cttcaacccagtcagcrtcct
61 tccggtgggc gcggggcatg actatcgtcg ccgcacttatgactgtcttc tttatcatgc
121 aactcgtagg acaggtgccg gcagcgctct gggtcattttcggcgaggac cgctttcgct
181 ggagcgcgac gatgatcggc ctgtcgcttg cggtattcggaatcttgcac gccctcgctc
241 aagccttcgt cactggtccc gccaccaaac gtttcggcgagaagcaggcc attatcgccg
301 gcatggcggc cgacgcgctg ggctacgtct tgctggcgttcgcgacgcga ggctggatgg
361 ccttccccat tatgattctt ctcgcttccg gcggcatcgggatgcccgcg ttgcaggcca
421 tgctgtccag gcaggtagat gacgaccatc agggacagcttcaaggatcg ctcgcggctc
481 ttaccagcct aacttcgatc actggaccgc tgatcgtcacggcgatttat gccgcctcgg
541 cgagcacatg gaacgggttg gcatggattg taggcgccgccctatacctt gtctgcctcc
601 ccgcgttgcg tcgcggtgca tggagccggg ccacctcgacctgaatggaa gccggcggca
661 cctcgctaac ggattcacca ctccaagaat tggagccaatcaattcttgc ggagaactgt
721 gaatgcgcaa accaaccctt ggcagaacat atccatcgcgtccgccatct ccagcagccg
781 cacgcggcgc atctcgggca gcgttgggtc ctggccacgggtgcgcatga tcgtgctcct
841 gtcgttgagg acccggctag gctggcgggg ttgccttactggttagcaga atgaatcacc
901 gatacgcgag cgaacgtgaa gcgactgctg ctgcaaaacgtctgcgacct gagcaacaac
961 atgaatggtc ttcggtttcc gtgtttcgta aagtctggaaacgcggaagt cagcgccctg
1021 caccattatg ttccggatct gcatcgcagg atgctgctggctaccctgtg gaacacctac
1081 atctgtatta acgaagcgct ggcattgacc ctgagtgatttttctctggt cccgccgcat1141 ccataccgcc agttgtttac cctcacaacg ttccagtaaccgggcatgtt catcatcagt
1201 aacccgtatc gtgagcatcc tctctcgttt catcggtatcattaccccca tgaacagaaa
1261 ttccccctta cacggaggca tcaagtgacc aaacaggaaaaaaccgccct taacatggcc
1321 cgctttatca gaagccagac attaacgctt ctggagaaactcaacgagct ggacgcggat
1381 gaacaggcag acatctgtga atcgcttcac gaccacgctgatgagcttta ccgcagctgc
14 41 ctcgcgcgtt tcggtgatga cggtgaaáac ctctgacacatgcagctccc ggagacggtc
1501 acagcttgtc tgtaagcgga tgccgggagc agacaagcccgtcagggcgc gtcagcgggt.
1561 gttggcgggt gtcggggcgc agccatgacc cagtcacgtagcgatagcgg agtgtatact
1621 ggcttaacta tgcggcatca gagcagattg tactgagãgtgcaccatatg cggtgtgaaa
1681 taccgcacag atgcgtaagg agaaaatacc gcatcaggcgctcttccgct tcctcgctca
1741 ctgactcgct gcgctcggtc gttcggctgc ggcgagcggtatcagctcac tcaaaggcgg
1801 taatacggtt atccacagaa tcaggggata acgcaggaaagaacatgtga gcaaaaggcc
1861 agcaaaaggc caggaaccgt aaaaaggccg cgttgctggcgtttttccat aggctccgcc
1921 cccctgacga gcatcacaaa aatcgacgct caagtcagaggtggcgaaac ccgacaggac
1981 tataaagata ccaggcgttt ccccctggaa gctccctcgtgcgctctcct gttccgaccc
2041 tgccgcttac cggatacctg tccgcctttc tcccttcgggaagcgtggcg ctttctcaat
2101 gctcacgctg taggtatctc agttcggtgt aggtcgttcgctccaagctg ggctgtgtgc
2161 acgaaccccc cgttcagccc gaccgctgcg ccttatccggtaactatcgt cttgagtcca
2221 acccggtaag acacgactta tcgccactgg cagcagccactggtaacagg attagcagag
2281 cgaggtatgt aggcggtgct acagagttct tgaagtggtggcctaactac ggctacacta
2341 gaaggacagt atttggtatc tgcgctctgc tgaagccagttaccttcgga aaaagagttg
24 01 gtagctcttg atccggcaaa caaaccaccg ctggtagcggtggttttttt gtttgcaagc
2461 agcagattac gcgcagaaaa aaaggatctc aagaagatcctttgatcttt tctacggggt
2521 ctgacgctca gtggaacgaa aactcacgtt aagggattttggtcatgaga ttatcaaaaa
2581 ggatcttcac ctagatcctt ttaaattaaa aatgaagttttaaatcaatc taaagtatat2641 atgagtaaac ttggtcfcgac agttaccaat gcttaatcagtgaggcacct atctcagcga
2701 tctgtctatt tcgttcatcc atagttgcct gactccccgtcgtgtagata actacgatac
2761 gggagggctt accatctggc cccagtgctg caatgataccgcgagaccca cgctcaccgg
2821 ctccagattt atcagcaata aaccagccag ccggaagggocgagcgcaga agtggtcctg
2881 caactttatc cgcctccatc cagtctatta attgttgccgggaagctaga gtaagtagtt
2941 cgccagttaa tagtttgcgc aacgttgttg ccattgctgc agccatgagattatcaaa
aaggatcttc acctagatcc ttttcacgta gaaagccagt ccgcagaaacggtgctgacc
ccggatgaat gtcagctact gggctatctg gacaagggaa aacgcaagcgcaaagagaaa
gcaggtagct tgcagtgggc ttacatggcg atagctagac tgggcggttttatggacagc
aagcgaaccg gaattgccag ctggggcgcc ctctggtaag gttgggaagccctgcaaagt
aaactggatg gctttctcgc cgccaaggat ctgatggcgc aggggatcaagctctgatca
agagacagga tgaggatcgt ttcgcatgat tgaacaagat ggattgcacgcaggttctcc
ggccgcttgg gtggagaggc tattcggcta tgactgggca caacagacaatcggctgctc
tgatgccgcc gtgttccggc tgtcagcgca ggggcgcccg gttctttttgtcaagaccga
cctgtccggt gccctgaatg aactgcaaga cgaggcagcg cggctatcgtggctggccac
gacgggcgtt ccttgcgcag ctgtgctcga cgttgtcact gaagcgggaagggactggct
gctattgggc gaagtgccgg ggcaggatct cctgtcatct caccttgctcctgccgagaa
agtatccatc atggctgatg caatgcggcg gctgcatacg cttgatccggctacctgccc
attcgaccac caagcgaaac atcgcatcga gcgagcacgt actcggatggaagccggtct
tgtcgatcag gatgatctgg acgaagagca tcaggggctc gcgccagccgaactgttcgc
caggctcaag gcgagcatgc ccgacggcga ggatctcgtc gtgacccatggcgatgcctg
cttgccgaat atcatggtgg aaaatggccg cttttctgga ttcatcgactgtggccggct
gggtgtggcg gaccgctatc aggacatagc gttggctacc cgtgatattgctgaagagct
tggcggcgaa tgggctgacc gcttcctcgt gctttacggt atcgccgctcccgattcgca
gcgcatcgcc ttctatcgcc ttcttgacga gttcttctga attttgttaaaatttttgttaaatcagctc attttttaac caataggccg aaatcggcaa catcccttataaatcaaaag
aatagaccgc gatagggttg agtgttgttc cagtttggaa caagagtccactattaaaga
acgtggactc caacgtcaaa gggcgaaaaa ccgtctatca gggcgatggcccactacgtg
aaccatcacc caaatcaagt tttttgcggt cgaggtgccg taaagctctaaatcggaacc
ctaaagggag cccccgattt agagcttgac ggggaaagcc ggcgaacgtggcgagaaagg
aagggaagaa agcgaaagga gcgggcgcta gggcgctggc aagtgtagcggtcacgctgc
gcgtaaccac cacacccgcg cgcttaatgc gccgctacag ggcgcgtccattcgccattc
aggatcgaat taattcttaa ttaacatcatc aataatatac cttattttggattgaagcca atatgataat gagggggtgg agtttgtgac gtggcgcggggcgtgggaac ggggcgggtg acgtagtagt gtggcggaag tgtgatgttgcaagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgtttttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttaggcggatgttg tagtaaattt gggcgtaacc gagtaagatt tggccattttcgcgggaaaa ctgaataaga ggaagtgaaa tctgaataat tttgtgttactcatagcgcg
taatactGCTAGAgatCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTGTAATACGACTCACTATAGGGCGAATTGGGTACTGGCCAcagagct tggcccattgcatacgttgtatccatatcataatatgtacatttatattggctcatgtccaacattaccgccatgttgacattgattattgactagttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccaccccattgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtctatataagcagagctcgtttagtgaaccgtcagatcgcctggagacgccatccacgctgttttgacctccatagaagacaccgggaccgatccagcctgactctagCct AGCTCtgaagttggtggtgaggccctgggcaggttggtatcaaggttacaagacaggtttaaggagaccaatagaaactgggcatgtggagacagagaagactcttgggtttctgataggcactgactctctctgcctattggtc
tattttcccacccttaggctgctggtctgagcctagGAGATCTCTCGAGGTCGACGGTATcgatgcca ccATGGAGAA AATCGTCCTG TTGCTCGCTA TTGTGTCTCTAGTGAAGAGCGATCAAATTT GTATCGGCTA CCATGCCAAT AACTCAACAGAGCAGGTCGATACTATCATG GAGAAAAACG TAACAGTTAC TCATGCCCAA GACATCTTGGAAAAGACCCA CAACGGCAAA CTTTGCGACC TGGATGGAGT GAAGCCCCTGATCCTCCGGG ACTGTTCAGT CGCTGGTTGG CTGCTCGGGA ACCCTATGTGTGATGAGTTT ATCAACGTGC CTGAATGGTC TTACATTGTG GAGAAGGCTAACCCTACCAA TGACCTCTGC TATCCTfSGGT CATTTAACGA TTACGAGGAACTGAAACACC TGTTGTCTAG AATTAACCAC TTTGAAAAGA TACAGATTATACCCAAGTCT AGTTGGAGTG ATCACGAAGC CTCCTCAGGC GTTAGCTCAGCGTGTCCCTA TCTGGGCTCT CCATCCTTCT TTAGAAATGT GGTCTGGTTAATCAAAAAGA ACAGTACCTA CCCAACCATC AAAAAGTCTT ATAACAATACCAATCAGGAG GACCTGCTCG TGTTGTGGGG TATCCATCAC CCGAACGACGCCGCTGAACA GACTAGGCTG TATCAGAACC CCACTACATA CATCAGTATTGGCACGAGTA CTCTGAACCA GCGATTAGTG CCAAAGATTG CAACACGGAGCAAAGTAAAT GGGCAATCTG GCAGGATGGA GTTTTTCTGG ACAATCTTAAAACCCAACGA TGCGATAAAT TTCGAGTCCA ATGGCAATTT CATCGCCCCTGAATACGCCT ATAAGATCGT GAAAAAGGGG GACTCTGCAA TTATGAAGTCCGAATTAGAG TATGGCAATT GCAACACGAA GTGCCAGACA CCAATGGGAGCCAT TAATAG CTCAATGCCC TTCCATAATA TTCATCCATT GACCATTGGGGAGTGCCCAA AGTACGTGAA GTCCAACCGC CTGGTCCTCG CAACCGGTCTAAGAAATAGC CCGCAGAGAG AATCGCGGAG GAAGAAACGT GGCCTGTTTGGCGCGATTGC CGGATTCATC GAGGGAGGCT GGCAGGGTAT GGTCGATGGTTGGTACGGAT ACCACCATAG CAACGAACAG GGGTCCGGCT ATGCAGCAGATAAGGAGAGC ACTCAGAAAG CTATTGACGG AGTTACAAAC AAGGTTAATAGTATTATAGA TAAAATGAAC ACGCAATTCG AGGCCGTTGG GAGGGAGTTTAACAATCTGG AACGCCGGAT CGAAAATCTG AATAAGAAAA TGGAAGACGGCT TCCTTGAC GTGTGGACTT ATAATGCAGA GCTGCTTGTA CTCATGGAGAACGAGAGGAC CCTGGATTTC CACGATAGCA ACGTGAAGAA CCTTTACGACAAGGTGAGAC TTCAGCTCCG AGACAACGCC AAGGAGCTGGGGAATGGATGCTTCGAGTTT TACCACAAAT GTGACAATGA GTGCATGGAAAGTATACGCAACGGGACCTA CAATTACCCT CAGTATAGCG AAGAGGCTCGGCTCAAACGCGAAGAGATAA GCGGGGTGAA ATTGGAATCA ATCGGAACATATCAAATCCTGTCCATCTAT TCCACCGTCG CCTCTTCGCT GGCCCTCGCTATCATGATGG CTGGTCTGTC CCTATGGATG TGTTCCAATGGAAGCCTTCAGTGCCGTATT TGHATATGAg c
GGCCGCCCTATTCTATAGTGTCACCTAAATGCTAGAGCTCGCTGATCAGCCTCGACTGTGCCTT
CTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCAC
TGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGT
GGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCT
CTATGGCTTCTGAGGCGGAAAGAACCAASGCXtaacatcatc aataatataccttattttgg attgaagcca atatgataat gagggggtgg.
agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagtgtggcggaag
tgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaaagtgacgttt
ttggtgtgcg ccggtgtaca caggaagtga caattt-tcgc gcggttttaggcggatgttg
tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaactgaataaga
ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgtaatagtaatca
attacggggt cattagttca tagcccatat atggagttcc gcgttacataacttacggta
aatggcccgc ctggctgacc gcccaacgac ccccgcccat tgacgtcaataatgacgtat
gttcccatag taacgccaat agggactttc cattgacgtc aatgggtggagtatttacggtaaactgccc acttggcagt acatcaagtg tatcatatgcccctattgac
gtcaatgacg gtaaatggcc cgcctggcat tatgcccagtatgggacttt
cctacttggc agtacatcta cgtattagtc atcgctattagcggttttgg
cagtacatca atgggcgtgg atagcggttt gactcacgggtctccacccc
attgacgtca atgggagttt gttttggcac caaaatcaacaaaatgtcgt
aacaactccg ccccattgac gcaaatgggc ggtaggcgtgggtctatata
agcagagctg gtttagtgaa ccgtcagatccgctag AGATCTGGgaaacga ta tgggctgaata cggatccgtattcagccca ta tcgtttcTCT AGA AAT AAA ATA TCT TTA TTT TCA TTA CAT CTG TGT GTT GGTTTT TTG TGT GGC
GG CCGCtcçragcct AAGCTTctag ataagatatc cgatccaccg gatctagataactgatcata
atcagccata ccacatttgt agaggtttta cttgctttaa aaaacctcccacacctcccc
ctgaacctga aacataaaat gaatgcaatt gttgttgtta acttgtttattgcagcttat
aatggttaca aataaagcaa tagcatcaca aatttcacaa ataaagcatttttttcactg
cattctagtt gtggtttgtc caaactcatc aatgtatctt aacgcggatctgggcgtggt
taagggtggg aaagaatata taaggtgggg gtcttatgta gttttgtatctgttttgcag
cagccgccgc cgccatgagc accaactcgt ttgatggaag cattgtgAGCTTgtcgactcg aagatctggg cgtggttaag
ggtgggaaag aatatataag gtgggggtct tatgtagttt tgtatctgttttgcagcagc
cgccgccgcc atgagcacca actcgtttga tggaagcatt gtgagctcatatttgacaac
gcgcatgccc ccatgggccg gggtgcgtca gaatgtgatg ggctccagcattgatggtcg
ccccgtcctg cccgcaaact ctactacctt gacctacgag accgtgtctggaacgccgtt
ggagactgca gcctccgccg ccgcttcagc cgctgcagcc accgcccgcgggattgtgac
tgactttgct ttcctgagcc cgcttgcaag cagtgcagct tcccgttcatccgcccgcga
tgacaagttg acggctcttt tggcacaatt ggattctttg acccgggaacttaatgtcgt
ttctcagcag ctgttggatc tgcgccagca ggtttctgcc ctgaaggcttcctcccctcc
caatgcggtt taaaacataa ataaaaaacc agactctgtt tggatttggatcaagcaagt
gtcttgctgt ctttatttag gggttttgcg cgcgcggtag gcccgggaccagcggtctcg
caagtacgccacatgaccttccatggtgatgatttccaaggggactttcctacggtgggagtcgttgagg gtcctgtgta ttttttccag gacgtggtaa aggtgactctggatgttcag
atacatgggc ataagcccgt ctctggggtg gaggtagcac cactgcagagcttcatgctg
cggggtggtg ttgtagatga tccagtcgta gcaggagcgc tgggcgtggtgcctaaaaat
gtctttcagt agcaagctga ttgccagggg caggcccttg gtgtaagtgtttacaaagcg
gttaagctgg gatgggtgca tacgtgggga tatgagatgc atcttggactgtatttttag
gttggctatg ttcccagcca tatccctccg gggattcatg ttgtgcagaaccaccagcac
agtgtatccg gtgcacttgg gaaatttgtc atgtagctta gaaggaaatgcgtggaagaa
cttggagacg cccttgtgac ctccaagatt ttccatgcat tcgtccataatgatggcaat
gggcccacgg gcggcggcct gggcgaagat atttctggga tcactaacgtcatagttgtg
ttccaggatg agatcgtcat aggccatttt tacaaagcgc gggcggagggtgccagactg
cggtataatg gttccatccg gcccaggggc gtagttaccc tcacagatttgcatttccca
cgctttgagt tcagatgggg ggatcatgtc tacctgcggg gcgatgaagaaaacggtttc
cggggtaggg gagatcagct gggaagaaag caggttcctg agcagctgcgacttaccgca
gccggtgggc ccgtaaatca cacctattac cgggtgcaac tggtagttaagagagct
g cagctgccgt catccctgag caggggggcc
acttcgttaa gcatgtccct gactcgcatg ttttccctga ccaaatccgccagaaggcgc
tcgccgccca gcgatagcag ttcttgcaag gaagcaaagt ttttcaàcggtttgagaccg
tccgccgtag gcatgctttt gagcgtttga ccaagcagtt ccaggcggtcccacagctcg
gtcacctgct ctacggcatc tcgatccagc atatctcctc gtttcgcgggttggggcggc
tttcgctgta cggcagtagt cggtgctcgt ccagacgggc cagggtcatgtctttccacg
ggcgcagggt cctcgtcagc gtagtctggg tcacggtgaa ggggtgcgctccgggctgcg
cgctggccag ggtgcgcttg aggctggtcc tgctggtgct gaagcgctgccggtcttcgc
cctgcgcgtc ggccaggtag catttgacca tggtgtcata gtccagcccctccgcggcgt
ggcccttggc gcgcagcttg cccttggagg aggcgccgca cgaggggcagtgcagacttt
tgagggcgta gagcttgggc gcgagaaata ccgattccgg ggagtaggcatccgcgccgc
aggccccgca gacggtctcg cattccacga gccaggtgag ctctggccgttcggggtcaaaaaccaggtt tcccccatgc tttttgatgc gtttcttacc tctggtttccatgagccggt
gtccacgctc ggtgacgaaa aggctgtccg tgtccccgta tacagacttgagaggcctgt
cctcgagcgg tgttccgcgg tcctcctcgt atagaaactc ggaccactctgagacaaagg
ctcgcgtcca ggccagcacg aaggaggcta agtgggaggg gtagcggtcgttgtccacta
gggggtccac tcgctccagg gtgtgaagac acatgtcgcc ctcttcggcatcaaggaagg
tgattggttt gtaggtgtag gccacgtgac cgggtgttcc tgaaggggggctatiaaaagg
gggtgggggc gcgttcgtcc tcactctctt ccgcatcgct gtctgcgagggccagctgtt
ggggtgagta ctccctctga aaagcgggca tgacttctgc gctaagattgtcagtttcca
6301 aaaacgagga ggatttgata ttcacctggc ccgcggtgatgcctttgagg gtggccgcat
6361 ccatctggtc agaaaagaca atctttttgt tgtcaagcttggtggcaaac gacccgtaga
6421 gggcgttgga cagcaacttg gcgatggagc gcagggtttggtttttgtcg cgatcggcgc
6481 gctccttggc cgcgatgttt agctgcacgt attcgcgcgcaacgcaccgc cattcgggaa
6541 agacggtggt gcgctcgtcg ggcaccaggt gcacgcgccaaccgcggttg tgcagggtga
6601 caaggtcaac gctggtggct acctctccgc gtaggcgctcgttggtccag cagaggcggc
6661 cgcccttgcg cgagcagaat ggcggtaggg ggtctagctgcgtctcgtcc ggggggtctg
6721 cgtccacggt aaagaccccg ggcagcaggc gcgcgtcgaagtagtctatc ttgcatcctt
6781 gcaagtctag cgcctgctgc catgcgcggg cggcaagcgcgcgctcgtat gggttgagtg
6841 ggggacccca tggcatgggg tgggtgagcg cggaggcgtacatgccgcaa atgtcgtaaa
6901 cgtagagggg ctctctgagt attccaagat atgtagggtagcatcttcca ccgcggatgc
6961 tggcgcgcac gtaatcgtat agttcgtgcg agggagcgaggaggtcggga ccgaggttgc
7021 tacgggcggg ctgctctgct cggaagacta tctgcctgaagatggcatgt gagttggatg
7081 atatggttgg acgctggaag acgttgaagc tggcgtctgtgagacctacc gcgtcacgca
7141 cgaaggaggc gtaggagtcg cgcagcttgt tgaccagctcggcggtgacc tgcacgtcta
7201 gggcgcagta gtccagggtt tccttgatga tgtcatacttatcctgtccc ttttttttcc
7261 acagctcgcg gttgaggaca aactcttcgc ggtctttccagtactcttgg atcggaaacc7321 cgtcggcctc cgaacggtaa gagcctagca tgtagaactggttgacggcc tggtaggcgc
7381 agcatccctt ttctacgggt agcgcgtatg cctgcgcggccttccggagc gaggtgtggg
7441 tgagcgcaaa ggtgtccctg accatgactt tgaggtactggtatttgaag tcagtgtcgt
7501 cgcatccgcc ctgctcccag agcaaaaagt ccgtgcgctttttggaacgc ggatttggca
7561 gggcgaaggt gacatcgttg aagagtatct ttcccgcgcgaggcataaag ttgcgtgtga
7621 tgcggaaggg tcccggcacc tcggaacggt tgttaattacctgggcggcg agcacgatct
7681 cgtcaaagcc gttgatgttg tggcccacaa tgtaaagttccaagaagcgc gggatgccct
7741 tgatggaagg caatttttta agttcctcgt aggtgagctcttcaggggag ctgagcccgt
7801 gctctgaaag ggcccagtct gcaagatgag ggttggaagcgacgaatgag ctccacaggt
7861 cacgggccat tagcatttgc aggtggtcgc gaaaggtcctaaactggcga cctatggcca
7921 ttttttctgg ggtgatgcag tagaaggtaa gcgggtcttgttcccagcgg tcccatccaa
7981 ggttcgcggc taggtctcgc gcggcagtca ctagaggctcatctccgccg aacttcatga
8041 ccagcatgaa gggcacgagc tgcttcccaa aggcccccatccaagtatag gtctctacat
8101 cgtaggtgac aaagagacgc tcggtgcgag gatgcgagccgatcgggaag aactggatct.
8161 cccgccacca attggaggag tggctattga tgtggtgaaagtagaagtcc ctgcgacggg
8221 ccgaacactc gtgctggctt ttgtaaaaac gtgcgcagtactggcagcgg tgcacgggct
8281 gtacatcctg cacgaggttg acctgacgac cgcgcacaaggaagcagagt gggaatttga
8341 gcccctcgcc tggcgggttt ggctggtggt cttctacttcggctgcttgt ccttgaccgt
8 4 01 ctggctgctc gaggggagtt acggtggatc ggaccaccacgccgcgcgag cccaaagtcc
84 61 agatgtccgc gcgcggcggt cggagcttga tgacaacatcgcgcagatgg gagctgtcca
8521 tggtctggag ctcccgcggc gtcaggtcag gcgggagctcctgcaggttt acctcgcata
8581 gacgggtcag ggcgcgggct agatccaggt gatacctaatttccaggggc tggttggtgg
8641 cggcgtcgat ggcttgcaag aggccgcatc cccgcggcgcgactacggta ccgcgcggcg
8701 ggcggtgggc cgcgggggtg tccttggatg atgcatctaaaagcggtgac gcgggcgagc
8761 ccccggaggt agggggggct ccggacccgc cgggagagggggcaggggca cgtcggcgcc8821 gcgcgcgggc aggagctggt gctgcgcgcg taggttgctggcgaacgcga cgaegcggcg
8881 gttgatctcc tgaatctggc gcctctgcgt gaagacgacgggcccggtga gcttgagcct
8941 gaaagagagt tcgacagaat caatttcggt gtcgttgacggcggcctggc gcaaaatctc
9001 ctgcacgtct cctgagttgt cttgataggc gatctcggccatgaactgct cgatctcttc
9061 ctcctggaga tctccgcgtc cggctcgctc cacggtggcggcgaggtcgt tggaaatgcg
9121 ggccatgagc tgcgagaagg cgttgaggcc tccctcgttccagacgcggc tgtagaccac
9181 gcccccttcg gcatcgcggg cgcgcatgac cacctgcgcgagattgagct ccacgtgccg
9241 ggcgaagacg gcgtagtttc gcaggcgctg aaagaggtagttgagggtgg tggcggtgtg
9301 ttctgccacg aagaagtaca taacccagcg tcgcaacgtggattcgttga tatcccccaa
9361 ggcctcaagg cgctccatgg cctcgtagaa gtccacggcgaagttgaaaa actgggagtt
9421 gcgcgccgac acggttaact cctcctccag aagacggatgagctcggcga cagtgtcgcg
9481 cacctcgcgc tcaaaggcta caggggcctc ttcttcttcttcaatctcct cttccataag
9541 ggcctcccct tcttcttctt ctggcggcgg tgggggaggggggacacggc ggcgacgacg
9601 gcgcaccggg aggcggtcga caaagcgctc gatcatctccccgcggcgac ggcgcatggt
9661 ctcggtgacg gcgcggccgt tctcgcgggg gcgcagttggaagacgccgc ccgtcatgtc
9721 ccggttatgg gttggcgggg ggctgccatg cggcagggatacggcgctaa cgatgcatct
9781 caacaattgt tgtgtaggta ctccgccgcc gagggacctgagcgagtccg catcgaccgg
98 41 atcggaaaac ctctcgagaa aggcgtctaa ccagtcacagtcgcaaggta ggctgagcac
9901 cgtggcgggc ggcagcgggc ggcggtcggg gttgtttctggcggaggtgc tgctgatgat
9961 gtaattaaag taggcggtct tgagacggcg gatggtcgacagaagcacca tgtccttggg
10021 tccggcctgc tgaatgcgca ggcggtcggc catgccccaggcttcgtttt gacatcggcg
10081 caggtctttg tagtagtctt gcatgagcct ttctaccggcacttcttctt ctccttcctc
10141 ttgtcctgca tctcttgcat ctatcgctgc ggcggcggcggagtttggcc gtaggtggcg
10201 ccctcttcct cccatgcgtg tgaccccgaa gcccctcatcggctgaagca gggctaggtc
10261 ggcgacaacg cgctcggcta atatggcctg ctgcacctgcgtgagggtag actggaagtc10321 atccatgtcc acaaagcggt ggtatgcgcc cgtgttgatggtgtaagtgc agttggccat
10381 aacggaccag ttaacggtct ggtgacccgg ctgcgagagctcggtgtacc tgagacgcga
10441 gtaagccctc gagtcaaata cgtagtcgtt gcaagtccgcaccaggtact ggtatcccac
10501 caaaaagtgc ggcggcggct ggcggtagag gggccagcgtagggtggccg gggctccggg
10561 ggcgagatct tccaacataa ggcgatgata tccgtagatgtacctggaca tccaggtgat
10621 gccggcggcg gtggtggagg cgcgcggaaa gtcgcggacgcggttccaga tgttgcgcag
10681 cggcaaaaag tgctccatgg tcgggacgct ctggccggtcaggcgcgcgc aatcgttgac
10741 gctctaccgt gcaaaaggag agcctgtaag cgggcactcttccgtggtct ggtggataaa
10801 ttcgcaaggg tatcatggcg gacgaccggg gttcgagccccgtatccggc cgtccgccgt
10861 gatccatgcg gttaccgccc gcgtgtcgaa cccaggtgtgcgacgtcaga caacggggga
10921 gtgctccttt tggcttcctt ccaggcgcgg cggctgctgcgctagctttt ttggccactg
10981 gccgcgcgca gcgtaagcgg ttaggctgga aagcgaaagcattaagtggc tcgctccctg
11041 tagccggagg gttattttcc aagggttgag tcgcgggacccccggttcga gtctcggacc
11101 ggccggactg cggcgaacgg gggtttgcct ccccgtcatgcaagaccccg cttgcaaatt
11161 cctccggaaa cagggacgag cccctttttt gcttttcccagatgcatccg gtgctgcggc
11221 agatgcgccc ccctcctcag cagcggcaag agcaagagcagcggcagaca tgcagggcac
11281 cctcccctcc tcctaccgcg tcaggagggg cgacatccgcggttgacgcg gcagcagatg
11341 gtgattacga acccccgcgg cgccgggccc ggcactacctggacttggag gagggcgagg
114 01 gcctggcgcg gctaggagcg ccctctcctg agcggtacccaagggtgcag ctgaagcgtg
114 61 atacgcgtga ggcgtacgtg ccgcggcaga acctgtttcgcgaccgcgag ggagaggagc
11521 ccgaggagat gcgggatcga aagttccacg cagggcgcgagctgcggcat ggcctgaatc
11581 gcgagcggtt gctgcgcgag gaggactttg agcccgacgcgcgaaccggg attagtcccg
11641 cgcgcgcaca cgtggcggcc gccgacctgg "taaccgcatacgagcagacg gtgaaccagg
11701 agattaactt tcaaaaaagc tttaacaacc acgtgcgtacgcttgtggcg cgcgaggagg
11761 tggctatagg actgatgcat ctgtgggact ttgtaagcgcgctggagcaa aacccaaata11821 gcaagccgct catggcgcag ctgttcctta tagtgcagcacagcagggac aacgaggcat
11881 tcagggatgc gctgctaaac atagtagagc ccgagggccgctggctgctc gatttgataa
11941 acatcctgca gagcatagtg gtgcaggagc gcagcttgagcctggctgac aaggtggccg
12001 ccatcaacta ttccatgctt agcctgggca agttttacgcccgcaagata taccataccc
12061 cttacgttcc catagacaag gaggtaaaga tcgaggggttctacatgcgc atggcgctga
12121 aggtgcttac cttgagcgac gacctgggcg tttatcgcaacgagcgcatc cacaaggccg
12181 tgagcgtgag ccggcggcgc gagctcagcg accgcgagctgatgcacagc ctgcaaaggg
12241 ccctggctgg cacgggcagc ggcgatagag aggccgagtcctactttgac gcgggcgctg
12301 acctgcgctg ggccccaagc cgacgcgccc tggaggcagctggggccgga· cctgggctgg
12361 cggtggcacc cgcgcgcgct ggcaacgtcg gcggcgtggaggaatatgac gaggacgatg
12421 agtacgagcc agaggacggc gagtactaag cggtgatgtttctgatcaga tgatgcaaga
12481 cgcaacggac ccggcggtgc gggcggcgct gcagagccagccgtccggcc ttaactccac
12541 ggacgactgg cgccaggtca tggaccgcat catgtcgctgactgcgcgca atcctgacgc
12601 gttccggcag cagccgcagg ccaaccggct ctccgcaattctggaàgcgg tggtcccggc
12661 gcgcgcaaac cccacgcacg agaaggtgct ggcgatcgtaaacgcgctgg ccgaaaacag
12721 ggccatccgg cccgacgagg ccggcctggt ctacgacgcgctgcttcagc gcgtggctcg
12781 ttacaacagc ggcaacgtgc agaccaacct ggaccggctggtgggggatg tgcgcgaggc
12841 cgtggcgcag cgtgagcgcg cgcagcagca gggcaacctgggctccatgg ttgcactaaa
12901 cgccttcctg agtacacagc ccgccaacgt gccgcggggacaggaggact acaccaactt
12961 tgtgagcgca ctgcggctaa tggtgactga gacaccgcaaagtgaggtgt accagtctgg
13021 gccagactat tttttccaga ccagtagaca aggcctgcagaccgtaaacc tgagccaggc
13081 tttcaaaaac ttgcaggggc t.gtgggggg-t gcgggctcccacaggcgacc gcgcgaccgt
13141 gtctagcttg ctgacgccca actcgcgcct gttgctgctgctaatagcgc ccttcacgga
13201 cagtggcagc gtgtcccggg acacatacct aggtcacttgctgacactgt accgcgaggc
13261 cataggtcag gcgcatgtgg acgagcatac tttccaggagattacaagtg tcagccgcgc13321 gctggggcag gaggacacgg gcagcctgga ggcaaccctaaactacctgc tgaccaaccg
13381 gcggcagaag atcccctcgt tgcacagttt aaacagcgaggaggagcgca ttttgcgcta
13441 cgtgcagcag agcgtgagcc ttaacctgat gcgcgacggggtaacgccca gcgtggcgct
13501 ggacatgacc gcgcgcaaca tggaaccggg catgtatgcctcaaaccggc cgtttatcaa
13561 ccgcctaatg gactacttgc atcgcgcggc cgccgtgaaccccgagtatt tcaccaatgc
13621 catcttgaac ccgcactggc taccgccccc tggtttctacaccgggggat tcgaggtgcc
13681 cgagggtaac gatggattcc tctgggacga catagacgacagcgtgtttt ccccgcaacc
13741 gcagaccctg ctagagttgc aacagcgcga gcaggcagaggcggcgctgc gaaaggaaag
13801 cttccgcagg ccaagcagct tgtccgatct aggcgctgcggccccgcggt cagatgctag
13861 tagcccattt ccaagcttga tagggtctct taccagcactcgcaccaccc gcccgcgcct
13921 gctgggcgag gaggagtacc taaacaactc gctgctgcagccgcagcgcg aaaaaaacct
13981 gcctccggca tttcccaaca acgggataga gagcctagtggacaagatga gtagatggaa
14041 gacgtacgcg caggagcaca gggacgtgcc aggcccgcgcccgcccaccc gtcgtcaaag
14101 gcacgaccgt cagcggggtc tggtgtggga ggacgatgactcggcagacg acagcagcgt
14161 cctggatttg ggagggagtg gcaacccgtt tgcgcaccttcgccccaggc tggggagaat
14221 gttttaaaaa aaaaaaagca tgatgcaaaa taaaaaactcaccaaggcca tggcaccgag
14281 cgttggtttt cttgtattcc ccttagtatg cggcgcgcggcgatgtatga ggaaggtcct
14341 cctccctcct acgagagtgt ggtgagcgcg gcgccagtggcggcggcgct gggttctccc
14 401 ttcgatgctc ccctggaccc gccgtttgtg cctccgcggtacctgcggcc taccgggggg
144 61 agaaacagca tccgttactc tgagttggca cccctattcgacaccacccg tgtgtacctg
.14521 gtggacaaca agtcaacgga tgtggcatcc ctgaactaccagaacgacca cagcaacttt
14581 ctgaccacgg tcattcaaaa caatgactac agcccgggggaggcaagcac acagaccatc
14 641 aatcttgacg accggtcgca ctggggcggc gacctgaaaaccatcctgca taccaacatg
14701 ccaaatgtga acgagttcat gtttaccaat aagtttaaggcgcgggtgat ggtgtcgcgc
147 61 ttgcctacta aggacaatca ggtggagctg aaatacgagtgggtggagtt cacgctgccc14821 gagggcaact actccgagac catgaccata gaccttatgaacaacgcgat cgtggagcac
148 81 tacttgaaag tgggcagaca gaacggggtt ctggaaagcgacatcggggt aaagtttgac
14 941 acccgcaact tcagactggg gtttgacccc gtcactggtcttgtcatgcc tggggtatat
15001 acaaacgaag ccttccatcc agacatcatt ttgctgccaggatgcggggt ggacttcacc
15061 cacagccgcc tgagcaactt gttgggcatc cgcaagcggcaacccttcca ggagggcttt
15121 aggatcacct acgatgatct ggagggtggt aacattcccgcactgttgga tgtggacgcc
15181 taccaggcga gcttgaaaga tgacaccgaa cagggcgggggtggcgcagg cggcagcaac
15241 agcagtggca gcggcgcgga agagaactcc aacgcggcagccgcggcaat gcagccggtg
15301 gaggacatga acgatcatgc cattcgcggc gacacctttgccacacgggc tgaggagaag
15361 cgcgctgagg ccgaagcagc ggccgaagct gc.cgcccccgctgcgcaacc cgaggtcgag
15421 aagcctcaga agaaaccggt gatcaaaccc ctgacagaggacagcaagaa acgcagttac
154 81 aacctaataa gcaatgacag caccttcacc cagtaccgcagctggtacct tgcatacaac
15541 tacggcgacc cticagaccgg aatccgctca tggaccctgctttgcactcc tgacgtaacc
15601 tgcggctcgg agcaggtcta ctggtcgttg ccagacatgatgcaagaccc cgtgaccttc
15661 cgctccacgc gccagatcag caactttccg gtggtgggcgccgagctgtt gcccgtgcac
15721 tccaagagct tctacaacga ccaggccgtc tactcccaactcatccgcca gtttacctct
15781 ctgacccacg tgttcaatcg ctttcccgag aaccagattttggcgcgccc gccagccccc
15841 accatcacca ccgtcagtga aaacgttcct gctctcacagatcacgggac gctaccgctg
15901 cgcaacagca tcggaggagt ccagcgagtg accattactgacgccagacg ccgcacctgc
15961 ccctacgttt acaaggccct gggcatagtc tcgccgcgcgtcctatcgag ccgcactttt
16021 tgagcaagca tgtccatcct tatatcgccc agcaataacacaggctgggg cctgcgcttc
16081 ccaagcaaga tgtttggcgg ggccaagaag cgctccgaccaacacccagt gcgcgtgcgc
16141 gggcactacc gcgcgccctg gggcgcgcac aaacgcggccgcactgggcg caccaccgtc
16201 gatgacgcca tcgacgcggt ggtggaggag gcgcgcaactacacgcccac gccgccacca
16261 gtgtccacag tggacgcggc cattcagacc gtggtgcgcggagcccggcg ctatgctaaa16321 atgaagagac ggcggaggcg cgtagcacgt cgccaccgccgccgacccgg cactgccgcc
16381 caacgcgcgg cggcggccct gcttaaccgc gcacgtcgcaccggccgacg ggcggccatg
16441 cgggccgctc gaaggctggc cgcgggtatt gtcactgtgccccccaggtc caggcgacga
16501 gcggccgccg cagcagccgc ggccattagt gctatgactcagggtcgcag gggcaacgtg
16561 tattgggtgc gcgactcggt tagcggcctg cgcgtgcccgtgcgcacccg ccccccgcgc
16621 aactagattg caagaaaaaa ctacttagac tcgtactgttgtatgtatcc agcggcggcg
16681 gcgcgcaacg aagctatgtc caagcgcaaa atcaaagaagagatgctcca ggtcatcgcg
16741 ccggagatct atggcccccc gaagaaggaa gagcaggattacaagccccg aaagctaaag
16801 cgggtcaaaa agaaaaagaa agatgatgat gatgaacttgacgacgaggt ggaactgctg
16861 cacgctaccg cgcccaggcg acgggtacag tggaaaggtcgacgcgtaaa acgtgttttg
16921 cgacccggca ccaccgtagt ctttacgccc ggtgagcgctccacccgcac ctacaagcgc
16981 gtgtatgatg aggtgtacgg cgacgaggac ctgcttgagcaggccaacga gcgcctcggg
17041 gagtttgcct acggaaagcg gcataaggac atgctggcgttgccgctgga cgagggcaac
17101 ccaacaccta gcctaaagcc cgtaacactg cagcaggtgctgcccgcgct tgcaccgtcc
17161 gaagaaaagc gcggcctaaa gcgcgagtct ggtgacttggcacccaccgt gcagctgatg
17221 gtacccaagc gccagcgact ggaagatgtc ttggaaaaaatgaccgtgga acctgggctg
17281 gagcccgagg tccgcgtgcg gccaatcaag caggtggcgccgggactggg cgtgcagacc
17341 gtggacgttc agatacccac taccagtagc accagtattgccaccgccac agagggcatg
17401 gagacacaaa cgtccccggt tgcctcagcg gtggcggatgccgcggtgca ggcggtcgct
174 61 gcggccgcgt ccaagacctc tacggaggtg caaacggacccgtggatgtt tcgcgtttca
17521 gccccccggc gcccgcgcgg ttcgaggaag tacggcgccgccagcgcgct actgcccgaa
17581 tatgccctac atccttccat tgcgcctacc cccggctatcgtggctacac ctaccgcccc
17641 agaagacgag càactacccg acgccgaacc accactggaacccgccgccg ccgtcgccgt
17701 cgccagcccg tgctggcccc gatttccgtg cgcagggtggctcgcgaagg aggcaggacc
17761 ctggtgctgc caacagcgcg ctaccacccc agcatcgtttaaaagccggt ctttgtggtt17821 cttgcagata tggccctcac ctgccgcctc cgtttcccggtgccgggatt ccgaggaaga
17881 atgcaccgta ggaggggcat ggccggccac ggcctgacgggcggcatgcg tcgtgcgcac
17 941 caccggcggc ggcgcgcgtc gcaccgtcgc atgcgcggcggtatcctgcc cctccttatt
18001 ccactgatcg ccgcggcgat tggcgccgtg cccggaattgcatccgtggc cttgcaggcg
18061 cagagacact gattaaaaac aagttgcatg tggaaaaatcaaaataaaaa gtctggactc
18121 tcacgctcgc ttggtcctgt aactattttg tagaatggaagacatcaact ttgcgtctct
18181 ggccccgcga cacggctcgc gcccgttcat gggaaactggcaagatatcg gcaccagcaa
18241 tatgagcggt ggcgccttca gctggggctc gctgtggagcggcattaaaa atttcggttc
18 301 caccgttaag aactatggca gcaaggcctg gaacagcagcacaggccaga tgctgaggga
18361 taagttgaaa gagcaaaatt tccaacaaaa ggtggtagatggcctggcct ctggcattag
18421 cggggtggtg gacctggcca accaggcagt gcaaaataagattaacagta agcttgatcc
184 81 ccgccctccc gtagaggagc ctccaccggc cgtggagacagtgtctccag aggggcgtgg
18 541 cgaaaagcgt ccgcgccccg acagggaaga aactctggtgacgcaaatag'acgagcctcc
18 601 ctcgtacgag gaggcactaa agcaaggcct gcccaccacccgtccca.tcg cgcccatggc
18 661 taccggagtg ctgggccagc acacacccgt aacgctggacctgcctcccc ccgccgacac
18721 ccagcagaaa cctgtgctgc caggcccgac cgccgttgttgtaacccgtc ctagccgcgc
18781 gtccctgcgc cgcgccgcca gcggtccgcg atcgttgcggcccgtagcca gtggcaactg
18841 gcaaagcaca ctgaacagca tcgtgggtct gggggtgcaatccctgaagc gccgacgatg
18901 cttctgaata gctaacgtgt cgtatgtgtg tcatgtatgcgtccatgtcg ccgccagagg
18961 agçtgctgag ccgccgcgcg cccgctttcc aagatggctaccccttcgat gatgccgcag
19021 tggtcttaca tgcacatctc gggccaggac gcctcggagtacctgagccc cgggctggtg
19081 cagtttgccc gcgccaccga gacgtacttc agcctgaataacaagtttag aaaccccacg
19141 gtggcgccta cgcacgacgt gaccacagac cggtcccagcgtttgacgct gcggttcatc
19201 cctgtggacc gtgaggatac tgcgtactcg tacaaggcgcggttcaccct agctgtgggt
19261 gataaccgtg tgctggacat ggcttccacg tactttgacatccgcggcgt gctggacagg19321 ggccctactt ttaagcccta ctctggcact gcctacaacgccctggctcc caagggtgcc
19381 ccaaatcctt gcgaatggga tgaagctgct actgctcttgaaataaacct agaagaagag
19441 gacgatgaca acgaagacga agtagacgag caagctgagcagcaaaaaac tcacgtattt
.19501 gggcaggcgc cttattctgg tataaatatt acaaaggagggtattcaaat aggtgtcgaa
19561 ggtcaaacac ctaaatatgc cgataaaaca tttcaacctgaacctcaaat aggagaatct
19621 cagtggtacg aaactgaaat taatcatgca gctgggagagtccttaaaaa gactacccca
19681 atgaaaccat gttacggttc atatgcaaaa cccacaaatgaaaatggagg gcaaggcatt
19741 cttgtaaagc aacaaaatgg aaagctagaa agtcaagtggaaatgcaatt tttctcaact
19801 actgaggcga ccgcaggcaa tggtgataac ttgactcctaaagtggtatt gtacagtgaa
19861 gatgtagata tagaaacccc agafcactcat atttcttacatgcccactat taaggaaggt
19921 aactcacgag aactaatggg ccaacaatct atgcccaacaggcctaatta cattgctttt
19981 agggacaatt ttattggtct aatgtattac aacagcacgggtaatatggg tgttctggcg
20041 ggccaagcat cgcagttgaa tgctgttgta gatttgcaagacagaaacac agagctttca
20101 taccagcttt tgcttgattc cattggtgat agaaccaggtacttttctat gtggaatcag
20161 gctgttgaca gctatgatcc agatgttaga attattgaaaatcatggaac tgaagatgaa
20221 cttccaaatt. actgctttcc actgggaggt gtgattaatacagagactct taccaaggta
20281 aaacctaaaa caggtcagga aaatggatgg gaaaaagatgctacagaatt ttcagataaa
20341 aatgaaataa gagttggaaa taattttgcc atggaaatcaatctaaatgc caacctgtgg
204 01 agaaatttcc tgtactccaa catagcgctg tatttgcccgacaagctaaa gtacagtcct
204 61 tccaacgtaa aaatttctga taacccaaac acctacgactacatgaacaa gcgagtggtg
20521 gctcccgggt tagtggactg ctacattaac cttggagcacgctggtccct tgactatatg
20581 gacaacgtca acccatttaa ccaccaccgc aatgctggcctgcgctaccg ctcaatgttg
20641 ctgggcaatg gtcgctatgt gcccttccac atccaggtgcctcagaagtt ctttgccatt.
20701 aaaaacctcc ttctcctgcc gggctcatac acctacgagtggaacttcag gaaggatgtt
207 61 aacatggttc tgcagagctc cctaggaaat gaçctaagggttgacggagc cagcattaag20821 tttgatagca tttgccttta cgccaccttc ttccccatggcccacaacac cgcçtccacg
20881 cttgaggcca tgcttagaaa cgacaccaac gaecagtcctttaacgacta tctctccgcc
20941 gccaacatgc tctaccctat acccgccaac gctaccaacgtgcccatatc catcccctcc
21001 cgcaactggg cggctttccg cggctgggcc ttcacgcgccttaagactaa ggaaacccca
21061 tcactgggct cgggctacga cccttattac acctactctggctctatacc ctacctagat
21121 ggaacctttt acctcaacca cacctttaag aaggtggccattacctttga ctcttctgtc
21181 agctggcctg gcaatgaccg cctgcttacc cccaacgagtttgaaattaa gcgctcagtt
21241 gacggggagg gttacaacgt tgcccagtgt aacatgaccaaagactggtt cctggtacaa
21301 atgctagcta actacaacat tggctaçcag ggcttctatatcccagagag ctacaaggac
21361 cgcatgtact ccttctttag aaacttccag cccatgagccgtcaggtggt ggatgatact
21421 aaatacaagg actaccaaca ggtgggcatc ctacaccaacacaacaactc tggatttgtt
21481 ggctaccttg cccccaccat gcgcgaagga caggcctaccctgctaactt cccctatccg
21541 cttataggca agaccgcagt tgacagcatt acccagaaaaagtttctttg cgatcgcacc
21601 ctttggcgca tcccattctc cagtaacttt atgtccatgggcgcactcac agacctgggc
21661 caaaaccttc tctacgccaa ctccgcccac gcgctagacatgacttttga ggtggatccc
21721 atggacgagc ccacccttct ttatgttttg tttgaagtctttgacgtggt ccgtgtgcac
21781 cggccgcacc gcggcgtcat cgaaaccgtg tacctgcgcacgcccttctc ggccggcaac
21841 gccacaacat aaagaagcaa gcaacatcaa caacagctgccgccatgggc tccagtgagc
21901 aggaactgaa agccattgtc aaagatcttg gttgtgggccatattttttg ggcacctatg
21961 acaagcgctt tccaggcttt gtttctccac acaagctcgcctgcgccata gtcaatacgg
22021 ccggtcgcga gactgggggc gtacactgga tggcctttgcctggaacccg cactcaaaaa
22081 catgctacct ctttgagccc tttggctttt ctgaccagcgactcaagcag gtttaccagt
22141 ttgagtacga gtcactcctg cgccgtagcg ccattgcttcttcccccgac cgctgtataa
22201 cgctggaaaa gtccacccaa agcgtacagg ggcccaactcggccgcctgt ggactattct
222 61 gctgcatgtt tctccacgcc tttgccaact ggccccaaactcccatggat cacaacccca22321 ccatgaacct tattaccggg gtacccaact ccatgctcaacagtccccag gtacagccca
22381 ccctgcgtcg caaccaggaa cagctctaca gcttcctggagcgccactcg ccctacttcc
22441 gcagccacag tgcgcagatt aggagcgcca cttctttttgtcacttgaaa aacatgtaaa
22501 aataatgtac tagagacact ttcaataaag gcaaatgcttttatttgtac actctcgggt
22561 gattatttac ccccaccctt gccgtctgcg ccgtttaaaaatcaaagggg ttctgccgcg ·
22621 catcgctatg cgccactggc agggacacgt tgcgatactggtgtttagtg ctccacttaa
22681 actcaggcac aaccatccgc ggcagctcggf tgaagttttcactccacagg ctgcgcàcca
22741 tcaccaacgc gtttagcagg tcgggcgccg atatcttgaagtcgcagttg gggcctccgc
22801 cctgcgcgcg cgagttgcga tacacagggt tgcagcactggaacactatc agcgccgggt
228 61 ggtgcacgct ggccagcacg ctcttgtcgg agatcagatccgcgtccagg tcctccgcgt
22921 tgctcagggc gaacggagtc aactttggta gctgccttcccaaaaagggc gcgtgcccag
22981 gctttgagtt .gcactcgcac cgtagtggca tcaaaaggtgaccgtgcccg gtctgggcgt
23041 taggatacag cgcctgcata aaagccttga tctgcttaaaagccacctga gcctttgcgc
23101 cttcagagaa gaacatgccg caagacttgc cggaaaactgattggccgga caggccgcgt
23161 cgtgcacgca gcaccttgcg tcggtgttgg agatctgcaccacatttcgg ccccaccggt
23221 tcttcacgat cttggccttg ctagactgct ccttcagcgcgcgctgcccg ttttcgctcg
23281 tcacatccat ttcaatcacg tgctccttat ttatcataatgcttccgtgt agacacttaa
23341 gctcgccttc gatctcagcg cagcggtgca gccacaacgcgcagcccgtg ggctcgtgat
23401 gcttgtaggt cacctctgca aacgactgca ggtacgcctgcaggaatcgc cccatcatcg
234 61 tcacaaaggt cttgttgctg gtgaaggtca gctgcaacccgcggtgctcc tcgttcagcc
23521 aggtcttgca tacggccgcc agagcttcca cttggtcaggcagtagtttg aagttcgcct
23581 ttagatcgtt atccacgtgg tacttgtcca tcagcgcgcgcgcagcctcc atgcccttct
23641 cccacgcaga cacgatcggc acactcagcg ggttcatcaccgtaatttca ctttccgctt
23701 cgctgggctc ttcctct-tcc tcttgcgtcc gcataccacgcgccactggg tcgtcttcat
23761 tcagccgccg cactgtgcgc ttacctcctt tgccatgcttgattagcacc ggtgggttgc23821 tgaaacccac catttgtagc gccacatctt ctctttcttcctcgctgtcc acgattacct
23881 ctggtgatgg cgggcgctcg ggcttgggag aagggcgcttctttttcttc ttgggcgcaa
23941 tggccaaatc cgccgccgag gtcgatggcc gcgggctgggtgtgcgcggc accagcgcgt
24001 cttgtgatga gtcttcctcg tcctcggact cgatacgccgcctçatccgc ttttttgggg
24061 gcgcccgggg aggcggcggc gacggggacg gggacgacacgtcctccatg gttgggggac
24121 gtcgcgccgc accgcgtccg cgctcggggg tggtttcgcgctgctcctct tcccgactgg
24181 ccatttcctt ctcctatagg cagaaaaaga tcatggagtcagtcgagaag aaggacagcc
24241 taaccgcccc ctctgagttc gccaccaccg cctccaccgatgccgccaac gcgcctacca
24301 ccttccccgt cgaggcaccc ccgcttgagg aggaggaagtgattatcgag caggacccag
24361 gttttgtaag cgaagacgac gaggaccgct cagtaccaacagaggataaa aagcaagacc
24421 aggacaacgc agaggcaaac gaggaacaag tcgggcggggggacgaaagg catggcgact
24481 acctagatgt gggagacgac gtgctgttga agcatctgcagcgceagtgc gccattatct
24541 gcgacgcgtt gcaagagcgc agcgatgtgc ccctcgccatagcggatgtc agccttgcct
24601 acgaacgcca cctattctca ccgcgcgtac cccccaaacgccaagaaaac ggcacatgcg
24661 agcccaaccc gcgcctcaac ttctaccccg tatttgccgtgccagaggtg cttgccacct
24721 atcacatctt tttccaaaac tgcaagatac ccctatcctgccgtgccaac cgcagccgag
24 781 cggacaagca gctggccttg cggcagggcg ctgtcatacctgatatcgcc tcgctcaacg .
24841 aagtgccaaa aatctttgag ggtcttggac gcgacgagaagcgcgcggca aacgctctgc
24901 aacaggaaaa cagcgaaaat gaaagtcact ctggagtgttggtggaactc gagggtgaca
24961 acgcgcgcct agccgtacta aaacgcagca tcgaggtcacccactttgcc tacccggcac
25021 ttaacctacc ccccaaggtc atgagcacag tcatgagtgagctgatcgtg cgccgtgcgc
25081 agcccctgga gagggatgca aatttgcaag aacaaacagaggagggccta cccgcagttg
25141 gcgacgagca gctagcgcgc tggcttcaaa cgcgcgagcctgccgacttg gaggagcgac
25201 gcaaactaat gatggccgca gtgctcgtta ccgtggagcttgagtgcatg cagcggttct
25261 ttgctgaccc ggagatgcag' cgcaagctag aggaaacattgcactacacc tttcgacagg25321 gctacgtacg ccaggcctgc aagatctcca acgtggagctctgcaácctg gtctcctacc
25381 ttggaatttt gcacgaaaac cgccttgggc aaaacgtgcttcattccacg ctcaagggcg
25441 aggcgcgccg cgactacgtc cgcgactgcg tttacttatttctatgctac acçtggcaga
25501 cggccatggg cgtttggcág cagtgcttgg aggagtgcaacctcaaggag ctgcagaaac
25561 tgctaaagca aaacttgaag gacctatgga cggccttcaacgagcgctcc gtggccgcgc
25621 acctggcgga catcattttc cccgaacgcc tgcttaaaaccctgcaacag ggtctgccag
25681 acttcaccag tcaaagcatg ttgcagaact ttaggaactttatcctagag cgctcaggaa
25741 tcttgcccgc cacctgctgt gcacttccta gcgactttgtgcccattaag taccgcgaat
25801 gccctccgcc gctttggggc cactgctacc ttctgcagctagccaactac cttgcctacc
25861 actctgacat. aatggaagac gtgagcggtg acggtctactggagtgtcac tgtcgctgca
25921 acctatgcac cccgcaccgc tccctggttt gcaattcgcagctgcttaac gaaagtcaaa
25981 ttatcggtac ctttgagctg cagggtccct cgcctgacgaaaagtccgcg gctccggggt
2 6041 tgaaactcac tccggggctg tggacgtcgg cttaccttcgcaaatttgta cctgaggact
26101 açcacgccca cgagattagg ttctacgaag accaatcccgcccgccaaat gcggagctta
26161 ccgcctgcgt cattacccag ggccacattc ttggccaattgcaagccatc aacaaagccc
26221 gccaagagtt tctgctacga aagggacggg gggtttacttggacccccag tccggcgagg
26281 agctcaaccc aatccccccg ccgccgcagc cctatcagcagcagccgcgg gcccttgctt
26341 cccaggatgg cacccaaaaa gaagctgcag ctgccgccgccacccacgga cgaggaggaa
26401 tactgggaca gtcaggcaga ggaggttttg gacgaggaggaggaggacat gatggaagac
264 61 tgggagagcc tagacgagga agcttccgag gtcgaagaggtgtcagacga aacaccgtca
26521 ccctcggtcg cattcccctc gccggcgccc cagaaatcggcaaccggttc cagcatggct
26581 acaacctccg ctcctcaggc gccgccggca ctgcccgttcgccgacccaa ccgtagatgg
26641 gacaccactg gaaccagggc cggtaagtcc aagcagccgccgccgttagc ccaagagcaa
26701 caacagcgcc aaggctaccg ctcatggcgc gggcacaagaacgccatagt tgcttgcttg
26761 caagactgtg ggggcaacat ctccttcgcc cgccgctttcttctctacca tcacggcgtg26821 gccttccccc gtaacatcct gcattactac cgtcatctctacagcccata ctgcaccggc
26881 ggcagcggca gcggcagcaa cagcagcggc cacacagaagcaaaggcgac cggatagcaa
26941 gactctgaca aagcccaaga aatccacagc ggcggcagcagcaggaggag gagcgctgcg
27001 tctggcgccc aacgaacccg tatcgacccg cgagcttagaaacaggattt ttcccactct
27061 gtatgctata tttcaacaga gcaggggcca agaacaagagctgaaaataa aaaacaggtc
27121 tctgçgatcc ctcacccgca gctgcctgta tcacaaaagcgaagatcagc ttcggcgcac
27181 gctggaagac gcggaggctc tcttcagtaa atactgcgcgctgactctta aggactagtt
27241 tcgcgccctt tctcaaattt aagcgcgaaa actacgtcatctccagcggc cacacccggc
27301 gccagcacct gtcgtcagcg ccattatgag caaggaaattcccacgccct acatgtggag
27361 ttaccagcca caaatgggac ttgcggctgg agctgcccaagactactcaa cccgaataaa
27421 ctacatgagc gcgggacccc acatgatatc ccgggtcaacggaatccgcg cccaccgaaa
27481 ccgaattctc ttggaacagg cggctattac caccacacctcgtaataacc ttaatccccg
27541 tagttggccc gctgccctgg tgtaccagga aagtcccgctcccaccactg tggtacttcc
27 601 cagagacgcc caggccgaag ttcagatgac taactcaggggcgcagcttg cgggcggctt
27661 tcgtcacagg gtgcggtcgc ccgggcaggg tàtaactcacctgacaatca gagggcgagg
27721 tattcagctc aacgacgagt cggtgagctc ctcgcttggtctccgtccgg acgggacatt
27781 tcagatcggc ggcgccggcc gtccttcatt cacgcctcgtcaggcaatcc taactctgca
27841 gacctcgtcc tctgagccgc gctctggagg cattggaactctgcaattta ttgaggagtt
27901 tgtgccatcg gtctacttta accccttctc gggacctcccggccactatc cggatcaatt
27961 tattcctaac tttgacgcgg taaaggactc ggcggacggctacgactgaa tgttaagtgg
28021 agaggcagag caactgcgcc tgaaacacct ggtccactgtcgccgccaca agtgctttgc
28081 ccgcgactcc ggtgagtttt gctactttga attgcccgaggatcatatcg agggcccggc
28141 gcacggcgtc cggcttaccg çccagggaga gcttgcccgtagcctgattc gggagtttac
28201 ccagcgcccc ctgctagttg agcgggacag gggaccctgtgttctcactg tgatttgcaa
28261 ctgtcctaac cttggattac atcaagatcc tctagttataactagagtac ccggggatct28321 tattcccttt aactaataaa aaaaaataat aaagcatcacttacttaaaa tcagttagca
28381 aatttctgtc cagtttattc agcagcacct ccttgccctcctcccagctc tggtattgca
28441 gcttcctcct ggctgcaaac tttctccaca atctaaatggaatgtcagtt tcctcctgtt
28501 cctgtccatc cgcacccact atcttcatgt tgttgcagatgaagcgcgca agaccgtctg
28561 aagatacctt caaccccgtg tatccatatg acacggaaaccggtcctcca actgtgcctt
28621 ttcttactcc tccctttgta tcccccaatg ggtttcaagagagtccccct ggggtactct
28681 ctttgcgcct atccgaacct ctagttacct ccaatggcatgcttgcgctc aaaatgggca
28741 acggcctctc tctggacgag gccggcaacc ttacctcccaaaatgtaacc actgtgagcc
28801 cacctctcaa aaaaaccaag tcaaacataa acctggaaatatctgcaccc ctcacagtta
288 61 cctcagaagc cctaactgtg gctgccgccg cacctctaatggtcgcgggc aacacactca
28921 ccatgcaatc acaggccccg ctaaccgtgc acgactccaaacttagcatt gccacccaag
28981 gacccctcac agtgtcagaa ggaaagctag ccctgcaaacatcaggcccc ctcaccacca
29041 ccgatagcag tacccttact atcactgcct caccccctctaactactgcc actggtagct
29101 tgggcattga cttgaaagag cccatttafca cacaaaatggaaaactagga ctaaagtacg
29161 gggctccttt gcatgtaaca gacgacctaa acactttgaccgtagcaact ggtccaggtg
29221 tgactattaa taatacttcc ttgcaaacta aagttactggagccttgggt tttgattcac
29281 aaggcaatat gcaacttaat gtagcaggag gactaaggattgattctcaa aacagacgcc
29341 ttatacttga tgttagttat ccgtttgatg ctcaaaaccaactaaatcta agactaggac
29401 agggccctct ttttataaac tcagcccaca acttggatattaactacaac aaaggccttt
29461 acttgtttac agcttcaaaç aattccaaaa agcttgaggttaacctaagc actgccaagg
29521 ggttgatgtt tgacgctaca gccatagcca ttaatgcaggagatgggctt gaatttggtt
29581 cacctaatgc accaaacaca aatcccctca aaacaaaaattggccatggc ctagaatttg
29641 attcaaacaa ggctatggtt cctaaactág gaactggccttagttttgac agcacaggtg
29701 ccattacagt aggaaacaaa aataatgata agctaactttgtggaccaca ccagctccat
29761 ctcctaactg tagactaaat gcagagaaag atgctaaactcactttggtc ttaacaaaat29821 gtggcagtca aatacttgct acagtttcag ttttggctgttaaaggcagt ttggctccaa
29881 tatctggaac agttcaaagt gctcatctta ttataagatttgacgaaaat ggagtgctac
29941 taaacaattc cttcctggac ccagaatatt ggaactttagaaatggagat cttactgaag
30001 gcacagccta tacaaacgct gttggattta tgcctaacctatcagcttãt ccaaaatctc
30061 acggtaaaac.tgccaaaagt aacattgtca gtcaagtttacttaaacgga gacaaaacta
30121 aacctgtaac actaaccatt acactaaacg gtacacaggaaacaggagac acaactccaa
30181 gtgcatactc tatgtcattt tcatgggact ggtctggccacaactacatt aatgaaatat
30241 ttgccacatc ctcttacact ttttcataca ttgcccaagaataaagaatc gtttgtgtta
30301 tgtttcaacg tgtttatttt tcaattgcag aaaatttcaagtcatttttc attcagtagt
30361 atagccccac caccacatag cttatacaga tcaccgtaccttaatcaaac tcacagaacc
30421 ctagtattca acctgccacc tccctcccaa cacacagagtacacagtcct ttctccccgg
30481 ctggccttaa aaagcatcat atcatgggta acagacatattcttaggtgt tatattccac
30541 acggtttcct gtcgagccaa acgctcatca gtgatattaataaactcccc gggcagctca
30601 cttaagttca tgtcgctgtc cagctgctga gccacaggctgctgtçcaac ttgcggttgc
30661 ttaacgggcg gcgaaggaga agtccacgcc tacatgggggtagagtcata atcgtgcatc
30721 aggatagggc ggtggtgctg cagcagcgcg cgaataaactgetgccgccg ccgctccgtc
30781 ctgcaggaat acaacatggc agtggtctcc tcagcgatgattcgcaccgc ccgcagcata
30841 aggcgccttg tcctccgggc acagcagcgc accctgatctcacttaaatc agcacagtaa
30901 ctgcagcaca gcaccacaat attgttcaaa atcccacagtgcaaggcgct gtatccaaag
30961 ctcatggcgg ggaccacaga acccacgtgg ccãtcataccacaagcgcag gtagattaag
31021 tggcgacccc tcataaacac gctggacata aacattacctcttttggcat gttgtaattc
31081 accacctccc ggtaccatat aaacctctga ttaaacatggcgccatccac caccatccta
31141 aaccagctgg ccaaaacctg cccgccggct atacactgcagggaaccggg actggaacaa
31201 tgacagtgga gagcccagga ctcgtaacca tggatcatcatgctcgtcat gatatcaatg
31261 ttggcacaac acaggcacac gtgcatacac ttcctcaggattacaagctc ctcccgcgtt31321 agaaccatat cccagggàac aacccattcc tgaatcagcgtaaatcccac actgcâggga
31381 agacctcgca cgtaactcac gttgtgcatt gtcaaagtgttacattcggg cagcagcgga
31441 tgatcctcca gtatggtagc gcgggtttct gtctcaaaaggaggtagacg atccctactg
31501 tacggagtgc gccgagacaa ccgagatcgt gttggtcgtagtgtcatgcc aaatggaacg
31561 ccggacgtag tcatatttcc tgaagcaaaa ccaggtgcgggcgtgacaaa cagatctgcg
31621 tctccggtct cgccgcttag atcgctctgt gtagtagttgtagtatatcc actctctcaa
31681 agcatccagg cgccccctgg cttcgggttc tatgtaaactccttcatgcg ccgctgccct
31741 gataacatcc accaccgcag aataagccac acccagccaacctacacatt cgttctgcga
31801 gtcacacacg ggaggagcgg gaagagctgg aagaaccatgtttttttttt tattccaaaa
31861 gattatccaa aacctcaaaa tgaagatcta ttaagtgaacgcgctcccct ccggtggcgt
31921 ggtcaaactc tacagccaaa gaacagataa tggcatttgtaagatgttgc acaatggctt
31981 ccaaaaggca aacggccctc acgtccaagt ggacgtaaaggctaaaccct tcagggtgaa
32041 tctcctctat aaacattcca gcaccttcaa ccatgcccaaataattctca tctcgccacc
32101 ttctcaatat atctctaagc aaatcccgaa ta-ttaagtccggccattgta aaaatctgct
32161 ccagagcgcc ctccaccttc agcctcaagc agcgaatcatgattgcaaaa attcaggttc
32221 ctcacagacc tgtataagat tcaaaagcgg aacattaacaaaaataccgc gatcccgtag
32281 gtcccttcgc agggccagct gaacataatc gtgcaggtctgcacggacca gcgcggccac
32341 ttccccgcca ggaaccttga caaaagaacc cacactgattatgacacgca tactcggagc
32401 tatgctaacc agcgtagccc cgatgtaagc tttgttgcatgggcggcgat ataaaatgca
324 61 aggtgctgct caaaaaatca ggcaaagcct cgcgcaaaaaagaaagcaca tcgtagtcat
32521 gctcatgcag ataaaggcag gtaagctccg gaaccaccacagaaaaagac accatttttc
32581 tctcaaacat gtctgcgggt ttctgcataa acacaaaataaaataacaaa aaaacattta
32641 aacattagaa gcctgtctta caacaggaaa aacaacccttataagcataa gacggactac
32701 ggccatgccg gcgtgaccgt aaaaaaactg gtcaccgtgattaaaaagca ccaccgacag
32761 ctcctcggtc atgtccggag tcataatgta agactcggtaaacacatcag gttgattcat32821 cggtcagtgc taaaaagcga ccgaaatagc ccgggggaatacatacccgc aggcgtagag
32881 acaacattac agcccccata ggaggtataa caaaattaataggagagaaa aacacataaa
32941 cacctgaaaa accctcctgc ctaggcaaaa tagcaccctcccgctccaga acaacataca
33001 gcgcttcaca gcggtíagcct aacagtcagc cttaccagtaaaaaagaaaa cctattaaaa
33061 aaacaccact cgacacggca ccagctcaat cagtcacagtgtaaaaaagg gccaagtgca
33121 gagcgagtat atataggact aaaaaatgac gtaacggttaaagtccacaa aaaacaccca
33181 gaaaaccgca cgcgaaccta cgcccagaaa cgaaagccaaaaaacccaca acttcctcaa
33241 atcgtcactt ccgttttccc acgttacgta acttcccattttaagaaaac tacaattccc
33301 aacacataca agttactccg ccctaaaacc tacgtcacccgccccgttcc cacgccccgc
33361 gccacgtcac aaactccacc ccctcattat catattggcttcaatccaaa ataaggtata
33421 ttattgatga tnnnnnttaa tListagem de Seqüência
<110> Tuckerv Sean N.
West Coast Biologicals<120> Vetores adenovirais quiméricos<130> 026163-000IlOPC
<140> WO PCT/US07/05386<141> 2007-02-28
<150> US 60/778,026<151> 2006-02-28
<150> US 60/801,64 5<151> 2006-05-19
<150> US 60/802,992<151> 2006-05-22
<150> ÜS 60/821,492<151> 2006-08-04
<150> US 60/846,658<151> 2006-09-22
<150> ÜS 60/848,195<151> 2006-09-28
<160> 17<170> FastSEQ for Windows Version 4.0
<210> 1<211 > 11025
<212> DNA<213> Seqüência artificial
<220> vetor adenoviral quimérico DSl<400> 1
taacatcatc aataatatac cttattttgg attgaagcca atatgataat gagggggtgg 60agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagt gtggcggaag 120tgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgttt 180ttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttag gcggatgttg 240tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataaga 300ggaagtgaaa tctgaátaat tttgtgttac tcatagcgcg taatactggt accgcggccg 360cctcgagtct agagatctgg cgaaaggggg atgtgctgca aggcgattaa gttgggtaac 420gccagggttt tcccagtcac gacgttgtaa aacgacggcc agtgaattgt aatacgactc 480actatagggc gaattgggta ctggccacag agcttggccc attgcatacg ttgtatccat 540atcataatat gtacatttat attggctcat gtccaacatt accgccatgt tgacattgat 600tattgactag ttattaatag taatcaatta cgçggtcatt agttcatagc ccatatatgg 660agttccgcgt tacataactt acggtaaatg gcccgcctgg ctgaccgccc aacgaccccc 720gcccattgac gtcaataatg acgtatgttc ccatagtaac gccaataggg actttccatt 780gacgtcaatg ggtggagtat ttacggtaaa ctgcccactt ggcagtacat caagtgtatc 840atatgccaag tacgccccct attgacgtca atgacggtaa atggcccgcc tggcattatg 900cccagtacat gaccttatgg gactttccta cttggcagta catctacgta ttagtcatcg 960ctattaccat ggtgatgcgg ttttggcagt acatcaatgg gcgtggatag cggtttgact 1020cacggggatt tccaagtctc caccccattg acgtcaatgg gagtttgttt tggcaccaaa 1080atcaacggga ctttccaaaa tgtcgtaaca actccgcccc attgacgcaa atgggcggta 1140ggcgtgtacg gtgggaggtc tatataagca gagctcgttt agtgaaccgt cagatcgcct 1200ggagacgcca tccacgctgt tttgacctcc atagaagaca ccgggaccga tccagcctga 1260ctctagccta gctctgaagt tggtggtgag gccctgggca ggttggtatc aaggttacaa 1320gacaggttta aggagaccaa tagaaactgg gcatgtggag acagagaaga ctcttgggtt 1380tctgataggc actgactctc tctgcctatt ggtctatttt cccaccctta ggctgctggt 1440ctgagcctag gagatctctc gaggtcgacg gtatagcttc tagagatccc tcgacctcga 1500gatccattgt gctctaaagg agatacccgg ccagacaccc tcacctgcgg tgcccagctg 1560cccaggctga ggcaagagaa ggccagaaac catgcccatg gggtctctgc aaccgctggc 1620caccttgtac ctgctgggga tgctggtcgc ttccgtgcta gctgtggaga agctgtgggt 1680gactgtatac tatggggtgc ctgtgtggaa ggaggccacc accacçctgt tctgtgcctc 1740tgatgccaag gcctatgaca ctgaggtcca caatgtctgg gccacccatg cctgtgtgcc 1800cactgacccc aaccctcagg aggtggtgct ggagaatgtg actgagcact tcaacatgtg 1860gaagaacaac atggtggagc agatgcagga ggacatcatc agcctgtggg accagagcct 1920gaagccctgt gtgaagctga cccccctgtg tgtgaccctg aactgcaagg atgtgaatgc 1980caccaacacc accaatgact ctgagggcac tatggagagg ggtgagatca agaactgcag 2040cttcaacatc accaccagca tcagggatga ggtgcagaag gagtatgccc tgttctacaa 2100gctggatgtg gtgcccattg acaacaacaa caccagctac aggctgatca gctgtgacac 2160ctctgtgatc acccaggcct gccccaagat cagctttgag cccatcccca tccactactg 2220tgcccctgct ggctttgcca tcctgaagtg caatgacaag accttcaatg gcaaaggccc 2280ttgcaagaat gtgagcactg tgcagtgcac tcatggcatc aggcctgtgg tgagcaccca 2340gctgctgctg aatggcagcc tggctgagga ggaggtggtg atcaggtctg acaacttcac 2400caacaatgcc aagaccatca ttgtgcagct gaaggagtct gtggagatca actgcaccag 2460gcccaacaac aacaccagga agagcattca cattggccct ggcagggcct tctacaccac 2520tggggagatc attggggaca tcaggcaggc ccactgcaac atcagcaggg ccaagtggaa 2580tgacaccctg aagcagattg tgatcaagct gagggagcag tttgagaaca agaccattgt 2640gttcaatcac agctctggtg gtgatcctga gattgtgatg cacagcttca actgtggtgg 2700tgagttcttc tactgcaaca gcacccagct gttcaacagc acctggaaca acaacactga 2760gggcagcaac aacactgagg gcaacaccat caccctgcct tgcaggatca agcagatcat 2820caacatgtgg caggaggtgg gcaaggccat gtatgctcct cccatcaggg gccagatcag 2880gtgcagcagc aacatcactg gcctgctgct gaccagggat ggtggcatca atgagaatgg 2940cactgagatt ttcaggcctg gtggtgggga catgagggac aactggaggt ctgagctgta 3000caagtacaag gtggtgaaga ttgagcccct tggtgtggct cccaccaagg ctaagcgcag 3060ggtggtgcag agggagaagc gcgctgtggg ctgaggatcc cgagggtgag tgctcctgcc 3120tggacgcatc ccggctatgc agccccagtc cagggcagca aggcaggccc cgtctgcctc 3180ttcacccgga gcctctgccc gccccactca tgctcaggga gagggtcttc tggctttttc 3240ccaggctctg ggcaggcaca ggctaggtgc ccctaaccca ggccctgcac acaaaggggc 3300aggtgctggg ctcagacctg ccaagagcca tatccgggag gaccctgccc ctgacctaag 3360cccaccccaa aggccaaact ctccactccc tcagctcgga caccttctct cctcccagat 3420tccàgtaact cccaatcttc tctctgcaga gcccaaatct tgtgacaaaa ctcacacatg 3480cccaccgtgc ccaggtaagc cagcccaggc ctcgccctcc agctcaaggc gggacaggtg 3540ccctagagta gcctgcatcc agggacaggc cccagccggg tgctgacacg tccacctcca 3600tctcttcctc agcacctgaa ctcctggggg gaccgtcagt cttcctcttc cccccaaaac 3660ccaaggacac cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga 3720gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag gtgcataatg 3780ccaagacaaa gccgcgggag gagcagtaca ãcagcacgta ccgggtggtc agcgtcctca 3840ccgtcctgca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag 3900ccctcccagc ccccatcgag aaaaccatct ccaaagccaa aggtgggacc cgtggggtgc 3960gagggccaca tggacagagg ccggctcggc ccaccctctg ccctgagagt gaccgctgta 4020ccaacctctg tcctacaggg cagccccgag aaccacaggt gtacaccctg cccccatccc 4080gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc ttctatccca 4140gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac aagaccacgc 4200ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc gtggacaaga 4260gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct ctgcacaacc 4320actacacgca gaagagcctc tccctgtctc cgggtaaatg agtgcgacgg ccgcaggtaa 4380gccagcccag gcctcgccct ccagctcaag gcgggacagg tgccctagag tagcctgcat 444 0ccagggacag gccccagccg ggtgctgaca cgtccacctc catctcttcc tcaggtctgc 4500ccgggtggca tccctgtgac ccctccccag tgcctctcct ggccctggaa gttgccactc 4 560cagtgcccac cagccttgtc ctaataaaat taagttgcat cattttgtct gactaggtgt 4 620ccttctataa tattatgggg tggagggggg tggtatggag caaggggccc aagttaactt 4680gtttattgca gcttataatg gttacaaata aagcaatagc atcacaaatt tcacaaataa 4740agcatttttt tcactgcatt ctagttgtgg tttgtccaaa ctcatcaatg tatcttatca 4800tgtctggatc tgggcgtggt taagggtggg aaagaatata taaggtgggg gtcttatgtà 4860gttttgtatc tgttttgcag caigccgccgc cgccatgagc accaactcgt ttgatggaag 4920cattgtgagc tcatatttga caacgcgcat gcccccatgg gccggggtgc gtcagaatgt 4980gatgggctcc agcattgatg gtcgccccgt cctgcccgca aactctacta ccttgaccta 5040cgagaccgtg tctggaacgc cgttggagac tgcagcctcc gccgccgctt cagccgctgc 5100agccaccgcc cgcgggattg tgactgactt tgctttcctg agcccgcttg caagcagtgc 5160agcttcccgt tcatccgccc gcgatgacaa gttgacggct cttttggcac aattggattc 5220tttgacccgg gaacttaatg tcgtttctca gcagctgttg gatctgcgcc agcaggtttc 5280tgccctgaag gcttcctccc ctcccaatgc ggtttaaaac ataaataaaa aaccagactc 5340tgtttggatt tggatcaagc aagtgtcttg ctgtctttat ttaggggttt tgcgcgcgcg 5400gtaggcccgg gaccagcggt ctcggtcgtt gagggtcctg tgtatttttt ccaggacgtg 5460gtaaaggtga ctctggatgt tcagatacat gggcataagc ccgtctctgg ggtggaggta 5520gcaccactgc agagcttcat gctgcggggt ggtgttgtag atgatccagt cgtagcagga 5580gcgctgggcg tggtgcctaa aaatgtcttt cagtagcaag ctgattgcca ggggcaggcc 5640cttggtgtaa gtgtttacaa agcggttaag ctgggatggg tgcatacgtg gggatatgag 5700atgcatcttg gactgtattt ttaggttggc tatgttccca gccatatccc tccggggatt 5760catgttgtgc agaaccacca gcacagtgta tccggtgcac ttgggaaatt tgtcatgtag 5820cttagaagga aatgcgtgga agaacttgga gacgcccttg tgacctccaa gattttccat 5880gcattcgtcc ataatgatgg caatgggccc acgggcggcg gcctgggcga agatatttct 5940gggatcacta acgtcatagt tgtgttccag gatgagatcg tcataggcca tttttacaaa 6000gcgcgggcgg agggtgccag actgcggtat aatggttcca tccggcccag gggcgtagtt 6060accctcacag atttgcattt cccacgcttt gagttcagat ggggggatca tgtctacctg 6120cggggcgatg aagaaaacgg tttccggggt aggggagatc agctgggaag aaagcaggtt 6180cctgagcagc tgcgacttac cgcagccggt gggcccgtaa atcacaccta ttaccgggtg 6240caactggtag ttaagagagc tgcagctgcc gtcatccctg agcagggggg ccacttcgtt 6300aagcatgtcc ctgactcgca tgttttccct gaccaaatcc gccagaaggc gctcgccgcc 6360- cagcgatagc agttcttgca aggaagcaaa gtttttcaac ggtttgagac cgtccgcçgt 6420aggcatgctt ttgagcgttt gaccaagcag ttccaggcgg tcccacagct cggtçacctg 6480ctctacggca tctcgatcca gcatatctcc tcgtttcgcg ggttggggcg gctttcgctg 6540tacggcagta gtcggtgctc gtccagacgg gccagggtca tgtctttcca cgggcgcagg 6600gtcctcgtca gcgtagtctg ggtcacggtg aaggggtgcg ctccgggctg cgcgctggcc 6660agggtgcgct tgaggctggt cctgctggtg ctgaagcgct gccggtcttc gccctgcgcg 6720tcggccaggt agcatttgac catggtgtca tagtccagcc cctccgcggc gtggcccttg 6780gcgcgcagct tgcccttgga ggaggcgccg cacgaggggc agtgcagact tttgagggcg 6840tagagcttgg gcgcgagaaa taccgattcc ggggagtagg catccgcgcc gcaggccccg 6900cagacggtct cgcattccac gagccaggtg agctctggcc gttcggggtc aaaaaccagg 6960tttcccccat gctttttgat gcgtttctta cctctggttt ccatgagccg gtgtccacgc 7020tcggtgacga aaaggctgtc cgtgtccccg tatacagact tgagagggag tttaaacgaa 7080ttcaatagct tgttgcatgg gcggcgatat aaaatgcaag gtgctgctca aaaaatcagg 7140caaagcctcg cgcaaaaaag aaagcacatc gtagtcatgc tcatgcagat aaaggcaggt 7200aagctccgga accaccacag aaaaagacac· catttttctc tcaaacatgt ctgcgggttt 7260ctgcataaac acaaaataaa ataacaaaaa aacatttaaa cattagaagc ctgtcttaca 7320acaggaaaaa caacccttat aagcataaga cggactacgg ccatgccggc gtgaccgtaa 7380aaaaactggt caccgtgatt aaaaagcacc accgacagct cctcggtcat gtccggagtc 7440ataatgtaag actcggtaaa cacatcaggt tgattcatcg gtcagtgcta aaaagcgacc 7500gaaatagccc gggggaatac atacccgcag gcgtagagac aacáttacag cccccatagg 7560aggtataaca aaattaatag gagagaaaaa cacataaaca cctgaaaaac cctcctgcct 7620aggcaaaata gcaccctccc gctccagaac aacatacagc gcttcacagc ggcagçctaa; 7680cagtcagcct taccagtaaa aaagaaaacc tattaaaaaa acaccactcg acacggcacc 7740agctcaatca gtcacagtgt aaaaaagggc caagtgcaga gcgagtatat ataggactaa 7800aaaatgacgt aacggttaaa gtccacaaaa aacacccaga aaaccgcacg cgaacctacg 7860cccagaaacg aaagccaaaa aacccacaac ttcctcaaat cgtcacttcc gttttcccac 7920gttacgtaac ttcccatttt aagaaaacta caattcccaa cacatacaag ttactccgcc 7980ctaaaaccta cgtcacccgc cccgttccca cgccccgcgc cacgtcacaa actccacccc 8040ctcattatca tattggcttc aatccaaaat aaggtatatt attgatgatg ttaattaaca 8100tgcatggatc catatgcggt gtgaaatacc gcacagatgc gtaaggagaa aataccgcat 8160caggcgctct tccgcttcct cgctcactga ctcgctgcgc tcggtcgttc ggctgcggcg 8220agcggtatca gctcactcaa aggcggtaat acggttatcc acagaatcag gggataacgc 8280aggaaagaac atgtgagcaa aaggccagca aaaggccagg aaccgtaaaa aggccgcgtt 8340gctggcgttt ttccataggc tccgcccccc tgacgagcat cacaaaaatc gacgctcaag 84 00tcagaggtgg cgaaacccga caggactata aagataccag gcgtttcccc ctggaagctc 8460cctcgtgcgc tctcctgttc cgaccctgcc gcttaccgga tacctgtccg cctttctccc 8520ttcgggaagc gtggcgcttt ctcatagctc acgctgtagg tatctcagtt cggtgtaggt 8580cgttcgctcc aagctgggct gtgtgcacga accccccgtt cagcccgacc gctgcgcctt 8640atccggtaac tatcgtcttg agtccaaccc ggtaagacac gacttatcgc cactggcagc 8700agccactggt aacaggatta gcagagcgag gtatgtaggc ggtgctacag agttcttgaa 8760gtggtggcct aactacggct acactagaag gacagtattt ggtatctgcg ctctgctgaa 8820gccagttacc ttcggaaaaa gagttggtag ctcttgatcc ggcaaacaaa ccaccgctgg 8880tagcggtggt ttttttgttt gcaagcagca gattacgcgc agaaaaaaag gatctcaaga 8940agatcctttg atcttttcta cggggtctga cgctcagtgg aacgaaaact cacgttaagg 9000gattttggtc atgagattat caaaaaggat cttcacctag atccttttaa attaaaaatg 9060aagttttaaa tcaatctaaa gtatatatga gtaaacttgg tctgacagtt accaatgctt 9120aatcagtgag gcacctatct cagcgatctg tctatttcgt tcatccatag ttgcctgact 9180ccccgtcgtg tagataacta cgatacggga gggcttacca tctggcccca gtgctgcaat 9240gataccgcga gacccacgct caccggctcc agatttatca gcaataaacc agccagccgg 9300aagggccgag cgcagaagtg gtcctgcaac tttatccgcc tccatccagt ctattaattg 9360ttgccgggaa gctagagtaa gtagttçgcc agttaatagt ttgcgcaacg ttgttgccat 9420tgctgcagcc atgagattat caaaaaggat cttcacctag atccttttca cgtagaaagc 9480cagtccgcag aaacggtgct gaccccggát gaatgtcagc tactgggcta tctggacaag 9540ggaaaacgca agcgcaaaga gaaagcaggt agcttgcagt gggcttacat ggcgatagct 9600agactgggcg gttttatgga cagcaagcga accggaattg ccagctgggg cgccctctgg 9660taaggttggg aagccctgca aagtaaactg gatggctttc tcgccgccaa ggatctgatg 9720gcgcagggga tcaagctctg atcaagagac aggatgagga tcgtttcgca tgattgaaca 9780agatggattg cacgcaggtt ctccggccgc ttgggtggag aggctattcg gctatgactg 9840ggcaçaacag acaatcggct gctctgatgc cgccgtgttc cggctgtcag cgcaggggcg 9900cccggttctt tttgtcaaga ccgacctgtc cggtgccctg aatgaactgc aagaçgaggc 9960agcgcggcta tcgtggctgg ccacgacggg cgttccttgc gcagctgtgc tcgacgttgt 10020cactgaagcg ggaagggact ggctgctatt gggcgaagtg ccggggcagg atctcctgtc 10080atctcacctt gctcctgccg agaaagtatc catcatggct gatgcaatgc ggcggçtgca 10140tacgcttgat ccggctacct gcccattcga ccaccaagcg aaacatcgca tcgágcgagc 10200acgtactcgg atggaagccg gtcttgtcga tcaggatgat ctggacgaag agcatcaggg 10260gctcgcgcca gccgaactgt tcgccaggct caaggcgagc atgcccgacg gcgaggatct 10320cgtcgtgacc catggcgatg cctgcttgcc gaatatcatg gtggaaaatg gccgcttttc 10380tggattcatc gactgtggcc ggctgggtgt ggcggaccgc tatcaggaca tagcgttggc 10440tacccgtgat attgctgaag agcttggcgg cgaatgggct gaccgcttcc tcgtgcttta 10500cggtatcgcc gctcccgatt cgcagcgcat cgccttctat cgccttcttg acgagttctt 10560ctgaattttg ttaaaatttt tgttaaatca gctcattttt taaccaatag gccgaaatcg 10620gcaacatccc ttataaatca aaagaataga ccgcgatagg gttgagtgtt gttccagttt 10680ggaacaagag tccactatta aagaacgtgg actccaacgt caaagggcga aaaaccgtct 10740atcagggcga tggcccacta cgtgaaccat cacccaaatc aagttttttg cggtcgaggt 10800gccgtaaagc tctaaatcgg aaccctaaag ggagcccccg atttagagct tgacggggaa 10860agccggcgaa cgtggcgaga aaggaaggga agaaagcgaa aggagcgggc gctagggcgc 10920tggcaagtgt agcggtcacg ctgcgcgtaa ccaccacacc cgcgcgctta atgcgccgct 10980acagggcgcg tccattcgcc attcaggatc gaattaattc ttaat 11025
<210> 2<211> 11933<212> DNA<213> Seqüência artificial<220><223> Vetor adenoviral quimérico DS2<400> 2
taacátcatc aataatatac cttattttgg attgaagcca atatgataat gagggggtgg 60agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagt gtggcggaag 120tgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgttt 180ttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttag gcggatgttg 240tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataaga 300ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgct agagatctgg 360cgaaaggggg atgtgctgca aggcgattaa gttgggtaac gccagggttt tcccagtcac 420gacgttgtaa aacgacggcc agtgaattgt aatacgactc actatagggc gaattgggta 480ctggccacag agcttggccc attgcatacg ttgtatccat atcataatat gtacatttat 540attggctcat gtccaacatt accgccatgt tgacattgat tattgactag ttattaatag 600taatcaatta cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt 660acggtaaatg gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg 720acgtatgttc ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat 780ttacggtaaa ctgcccactt ggcagtacat caagtgtatc atatgccaag tacgccccct 840attgacgtca atgacggtaa atggcccgcc tggcattatg cccagtacát gaccttatgg 900gactttccta cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg 960ttttggcagt acatcaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc 1020caccccattg acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa 1080tgtcgtaaca actccgcccc attgacgcaa atgggcggta ggcgtgtacg gtgggaggtc 1140tatataagca gagctcgttt agtgaaccgt cagatcgcct ggagacgcca tcçacgctgt 1200tttgacctcc atagaagaca ccgggaccga tccagcctga ctctagccta gctctgaagt 1260tggtggtgag gccctgggca ggttggtatc aaggttacaa gacaggttta aggagaccaa 1320tagaaactgg gcatgtggag acagagaaga ctcttgggtt tctgataggc actgactctc 1380tctgcctatt ggtctatttt cccaccctta ggctgctggt ctgagcctag gagatctctc 1440gaggtcgacg gtatcgatgg gtacagcttc tagagatccc tcgacctcga gatccattgt 1500gctctaaagg agatacccgg ccagacaccc tcacctgcgg tgcccagctg cccaggctga 1560ggçaagagaa ggccagaaac catgcccatg gggtctctgc aaccgctggc caccttgtac 1620ctgctgggga tgctggtcgc ttccgtgcta gctgtggaga agctgtgggt gactgtatac 1680tatggggtgc ctgtgtggaa ggaggccacc accaccctgt tctgtgcctc tgatgccaag 1740gcctatgaca ctgaggtcca caatgtctgg gccacccatg cctgtgtgec cactgacccc 1800aaccctcagg aggtggtgct ggagaatgtg actgagcact tcaacatgtg gaagaacaac 1860atggtggagc agatgcagga ggacatcatc agcctgtggg accagagcct gaagccctgt 1920gtgaagctga cccccctgtg tgtgaccctg aactgcaagg atgtgaatgc caccaacacc 1980accaatgact ctgagggcac tatggagagg ggtgagatca agaactgcag cttcaacatc 2040accaccagca tcagggatga ggtgcagaag gagtatgccc tgttctaeaa gctggatgtg 2100gtgcccattg acaacaacaa caccagctac aggctgatca gctgtgacac ctctgtgatc 2160acccaggcct gccccaagat cagctttgag cccatcccca tccactactg tgcccctgct 2220ggctttgcca tcctgaagtg caatgacaag accttcaatg gcaaaggccc ttgcaagaat 2280gtgagcactg tgcagtgcac tçatggcatc aggcctgtgg tgagcaccca gctgctgctg 234 0aatggcagcc tggetgagga ggaggtggtg atcaggtctg acaacttcac caacaatgcc 2400aagaccatca ttgtgcagct gaaggagtct gtggagatca actgcaccag gcccaacaac 2460aacaçcagga agagcattca cattggccct ggcagggcct tctacaccac tggggagatc 2520attggggaca tcaggcaggc ccactgcaac atcagcaggg ccaágtggaa tgacaccctg 2580aagcagattg tgatcaagct gagggagcag tttgagaaca agaccattgt gttcaatcac 2640agctctggtg gtgatcctga gattgtgatg cacagcttca actgtggtgg tgagttcttc 2700tactgcaaca gcacccagct gttcaacagc acctggaaca acaacactga gggcagcaac 2760aacactgagg gcaacaccat caccctgcct tgcaggatca agcagatcat caacâtgtgg 2820caggaggtgg gcaaggccat gtatgctcct cccatcaggg gccagatcag gtgcagcagc 2880aâcatcactg gcctgctgct gaccagggat ggtggcatca atgagaatgg cactgagatt 2940ttcaggcctg gtggtgggga catgagggac aactggaggt ctgagctgta caagtacaag 3000gtggtgaaga ttgagcccct tggtgtggct cccaccaagg ctaagcgcag ggtggtgcag 3060agggagaagc gcgctgtggg ctgaggatcc cgagggtgag tgctcctgcc tggacgcatc 3120ccggctatgc agccccagtc cagggcagca aggcaggccc cgtctgcctc ttcacccgga 3180gcctctgccc gccccactca tgctcaggga gagggtcttc tggctttttc ccaggctctg 3240ggcaggcaca ggctaggtgc ccctaaccca ggccctgcac acaaaggggc aggtgctggg 3300ctcagacctg ccaagagcca tatccgggag gaccctgccc ctgacctaag cccaccccaa 3360aggccaaact ctccactccc tcagctcgga caccttctct cctcccagat tccagtaact 3420cccaatcttc tctctgcaga gcccaaatct tgtgacaaaa ctcacacatg cccaccgtgc 3480ccaggtaagc cagcccaggc ctcgccctcc agctcaaggc gggacaggtg ccctagagta 3540gcctgcatcc agggacaggc cccagccggg tgctgacacg tccacctcca tctcttcctc 3600agcacctgaa ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac 3660cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga 3720ccctgaggtc aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa 3780gccgcgggag gagcagtaca acagcacgta ccgggtggtc agcgtcctca ccgtcctgca 3840ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc 3900ccccatcgag aaaaccatct ccaaagccaa aggtgggacc cgtggggtgc gagggccaca 3960tggacagagg ccggctcggc ccaccctctg ccctgagagt gaccgctgta ccaacctctg 4020tcctacaggg cagccccgag aaccacaggt gtacaccctg cccccatccc gggatgagct 4080gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc 414 0cgtggagtgg gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct 4200ggactccgac ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca 4260gcaggggaac gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca 4320gaagagcctc tccctgtctc cgggtaaatg agtgcgacgg ccgcaggtaa gccagcccag 4380gcctcgccct ccagctcaag gcgggacagg tgccctagag tagcctgcat ccagggaçag 4440gccccagccg ggtgctgaca cgtccacctc catctcttcc tcaggtctgc ccgggtggca 4500tccctgtgac ccctccccag tgcctctcct ggccctggaa gttgccactc cagfcgcccac 4560cagccttgtc ctaataaaat taagttgcat cattttgtct gactaggtgt ccttctataa 4620tattatgggg tggagggggg tggtatggag caaggggccc aagttàactt gtttattgca 4680gcttataatg gttacaaata aagcaatagc atcacaaatt tcaçaaataa agcatttttt 4740tcactgcatt ctagttgtgg tttgtccaaa ctcatcaatg tatcttatca tgtctggatc 4800tgggcgtggt taagggtggg aaagaatata taaggtgggg gtcttatgta gttttgtatc 4860tgttttgcag cagccgccgc cgccatgagc accaactcgt ttgatggaag cattgtgagc 4920tcatcggcgg ccgccctatt ctatagtgtc acctaaatgc tagagctcgc tgatcagcct 4980cgactgtgcc ttctagttgc cagccatctg ttgtttgccc ctcccccgtg ccttccttga 5040ccctggaagg tgccactccc actgtccttt cctaataaaa tgaggaaatt gcatcgcatt 5100gtctgagtag gtgtcattct attctggggg gtggggtggg gcaggacagc aagggggagg 5160attgggaaga caatagcagg catgctgggg atgcggtggg ctctatggct tctgaggcgg 5220aaagaaccta tggcttctga ggcggaaaga accaaccacc gcggtggcgg ccgccacaca 5280aaaaaccaac acacagatgt aatgaaaata aagatatttt atttctagag aaacgatatg 5340ggçtgaatac ggatccgtat tcagcccata tcgtttcctg caggaattcg ccctttagat 5400atcatcgatg tctcggcggt ggtggcgcgt cgcgccgctg ggttttatag ggcgccgccg 5460cggccgctcg agccataaaa ggcaactttc ggaacggcgc acgctgattg gccccgcgcc 5520gctcactcac cggcttcgcc gcacagtgca gcattttttt accccctctc ccctcctttt 5580gcgaaaaaaa aaaagagcga gagcgagatt gaggaagagg aggagggaga gttttggcgt 5640tggccgcctt ggggtgctgg gcgtcgacga tatctaaggg cgaattcgat atcáagctag 5700cttgtcgact cgaagatctg ggcgtggtta agggtgggaa agaatatata aggtgggggt 5760cttatgtagt tttgtatctg ttttgcagca gccgccgccg ccatgagcac caactcgttt 5820gatggaagca ttgtgagctc atatttgaca acgcgcatgc ccccatgggc cggggtgcgt 5880cagaatgtga tgggctccag cattgatggt cgccccgtcc tgcccgcaaa ctctactacc 5940ttgacctacg agaccgtgtc tggaacgccg ttggagactg cagcctccgc cgccgcttca 6000gccgctgcag ccaccgcccg cgggattgtg actgactttg ctttcctgag cccgcttgca 6060agcagtgcag cttcccgttc atccgcccgc gatgacaagt tgacggctct tttggcacaa 6120ttggattctt tgacccggga acttaatgtc gtttctcagc agctgttgga tctgcgccag 6180caggtttctg ccctgaaggc ttcctcccct cccaatgcgg tttaaaacat aaataaaaaa 6240ccagactctg tttggatttg gatcaagcaa gtgtcttgct gtctttattt aggggttttg 6300cgcgcgcggt aggcccggga ccagcggtct cggtcgttga gggtcctgtg tattttttcc 6360aggacgtggt aaaggtgact ctggatgttc agatacatgg gcataagccc gtctctgggg 6420tggaggtagc accactgcag agcttcatgc tgcggggtgg tgttgtagat gatccagtcg 6480tagcaggagc gctgggcgtg gtgcctaaaa atgtctttca gtagcaagct gattgccagg 6540ggcaggccct tggtgtaagt gtttacaaag cggttaagct gggatgggtg catacgtggg 6600gatatgagat gcatcttgga ctgtattttt aggttggcta tgttcccagc -catatccctc 6660cggggattca tgttgtgcag aaccaccagc acagtgtatc cggtgcactt gggaaatttg 6720tcatgtagct tagaaggaaa tgcgtggaag aaçttggaga cgcccttgtg acctccaaga 6780ttttccatgc attcgtccat aatgatggca atgggcccac gggcggcggc ctgggcgaag 6840atatttctgg gatcactaac gtcatagttg tgttccagga tgagatcgtc ataggccatt 6900tttacaaagc gcgggcggag ggtgccagac tgcggtataa tggttccatc cggcccaggg 6960gcgtagttac cctcacagat ttgcatttcc cacgctttga gttcagatgg ggggatcatg 7020tctacctgcg gggcgatgaa gaaaacggtt tccggggtag gggagatcag ctgggaagaa 7080agcaggttcc tgagcagctg cgacttaccg cagccggtgg gcccgtaaat cacacctatt 7140accgggtgca actggtagtt aagagagctg cagctgccgt catccctgag caggggggcc 7200acttcgttaa gcatgtccct gactcgcatg ttttccctga ccaaatccgc cagaaggcgc 7260tcgccgccca gcgatagcag ttcttgcaag gaagcaaagt ttttcaacgg tttgagaccg 7320tccgccgtag gcatgctttt gagcgtttga ccaagcagtt ccaggcggtc ccacagctcg 7380gtcacctgct ctacggcatc tcgatccagc atatctcctc gtttcgcggg ttggggcggc 7440tttcgctgta cggcagtagt cggtgctcgt ccagacgggc cagggtcatg tctttccacg 7500ggcgcagggt cctcgtcagc gtagtctggg tcacggtgaa ggggtgcgct ccgggctgcg 7560cgctggccag ggtgcgcttg aggctggtcc tgctggtgct gaagcgctgc cggtcttcgc 7620cctgcgcgtc ggccaggtag catttgacca tggtgtcata gtccagcccc tccgcggcgt 7 680ggcccttggc gcgcagcttg cccttggagg aggcgccgca cgaggggcag tgcagacttt 7740tgagggcgta gagcttgggc gcgagaaata ccgattccgg ggagtaggca tccgcgccgc 7800aggcçccgca gacggtctcg cattccacga gccaggtgag ctctggccgt tcggggtcaa 7860aaaccaggtt tcccccatgc tttttgatgc gtttcttacc tctggtttcc atgagccggt 7920gtccacgctc ggtgacgaaa aggctgtccg tgtccccgta tacagacttg agagggagtt 7980taaacgaatt caatagcttg ttgcatgggc ggcgatataa aatgcaaggt gctgctcaaa 8040aaatcaggca aagcctcgcg caaaaaagaa agcacatcgt agtcatgctc atgcagataa 8100aggcaggtaa gctccggaac caccacagaa aaagacacca tttttctctc aaacatgtct 8160gcgggtttct gcataaacac aaaataáaat aacaaaaaaa catttaaaca ttagaagcct 8220gtcttacaac aggaaaaaca acccttataa gcataagacg gactacggcc atgccggcgt 8280gaccgtaaaa aaactggtca ccgtgattaa aaagcaccac cgacagctcc tcggtcatgt 8340ccggagtcat aatgtaagac tcggtaaaca catcaggttg attcatcggt cagtgctaaa 8400aagcgaccga aatagcccgg gggaatacat acccgcaggc gtagagacaa cattacagcc 8460cccataggag gtataacaaa attaatagga gagaaaaaca cataaacacc tgáaaaaccc 8520tcctgcctag gcaaaatagc accctcccgc tccagaacaa catacagcgc ttcacagcgg 8580cagcctaaca gtcagcctta ccagtaaaaa agaaaaccta ttaaaaaaac accactcgac 8640acggcaccag cteaatcagt cacagtgtaa aaaagggcca agtgcagagc gagtatatat 8700aggactaaaa aatgacgtaa cggttaaagt ccacaaaaaa cacccagaaa accgcacgcg 8760áacctacgcc cagaaacgaa agccaaaaaa cccacaactt cctcaaatcg tcacttccgt 8820tttCGcacgt tacgtaactt cccattttaa gaaaactaca attcccaaca catacaagtt 8880actccgccct aaáacctacg tcacccgccc cgttcccacg ccccgcgcca cgtcacaaac 8940tccaccccct cattatcata ttggcttcaa tccaaaataa ggtatattat tgatgatgtt 9000aattaacatg catggatcca tatgcggtgt gaaataccgc acagatgcgt aaggagaaaa 9060taccgcatca ggcgctcttc cgcttcctcg ctcactgact cgctgcgctc ggtcgttcgg 9120ctgcggcgag cggtatcagc tcactcaaag gcggtaatac ggttatccac agaatcaggg 9180gataacgcag gaaagaacat gtgagcaaaa ggccagcaaa aggccaggaa ccgtaaaaag 9240gccgcgttgc tggcgttttt ccataggctc cgcccccctg acgagcatca caaaaatcga 9300cgctcaagtc agaggtggcg aaaçccgaca ggactataaa gataccaggc gtttccccct 9360ggaagctccc tcgtgcgctc tcctgttccg accctgccgc ttaccggatá cctgtccgcc 9420tttctccctt cgggaagcgt ggcgctttct catagctcac gctgtaggta tctcagttcg 9480gtgtaggtcg ttcgctccaa gctgggctgt gtgcacgaac cccccgttca gcccgaccgc 9540tgcgccttat ccggtaacta tcgtcttgag tccaacccgg taagacacga cttatcgcca 9600ctggcagcag ccactggtaa caggattagc agagcgaggt atgtaggcgg tgctacagag 9660ttcttgaagt ggtggcctaa ctacggctac actagaagga cagtatttgg tàtctgcgct 9720ctgctgaagc cagttacctt cggaaaaaga gttggtagct cttgatccgg caaacaaacc 9780accgctggta gcggtggttt ttttgtttgc aagcagcaga ttacgcgcag aaaaaaagga 9840tctcaagaag atcctttgat cttttctacg gggtctgacg ctcagtggaa cgaaaactca 9900cgttaaggga ttttggtcat gagattatca aaaaggatct tcacctagat ccttttaaat 9960taaaaatgaa gttttaaatc aatctaaagt atatatgagt aaacttggtc tgacagttac 10020caatgcttaa tcagtgaggc acctatctca gcgatctgtc tatttcgttc atccatagtt 10080gcctgactcc ccgtcgtgta gataactacg atacgggagg gcttaccatc tggccccagt 10140gctgcaatga taccgcgaga cccacgctca ccggctccag atttatcagc aataaaccag 10200ccagccggaa gggccgagcg cagaagtggt cctgcaactt tatccgcctc catccagtct 10260attaattgtt gccgggaagc tagagtaagt agttcgccag ttaatagttt gcgcaacgtt 10320gttgccattg ctgcagccat gagattatca aaaaggatct tcacctagat ccttttcacg 10380tagaaagcca gtccgcagaa acggtgctga ccccggatga atgtcagcta ctgggctatc 10440tggacaaggg aaaacgcaag cgcaaagaga aagcaggtag cttgcagtgg gcttacatgg 10500cgatagctag actgggcggt tttatggaca gcaagcgaac cggaattgcc agctggggcg 10560ccctctggta aggttgggaa gccctgcaaa gtaaactgga tggctttctc gccgccaagg 10620atctgatggc gcaggggatc aagctctgat caagagacag gatgaggatc gtttcgcatg 10680attgaacaag atggattgca cgcaggttct ccggccgctt gggtggagag gctattcggc 10740tatgactggg cacaacagac aatcggctgc tctgatgccg ccgtgttccg gctgtcagcg 10800caggggcgcc cggttctttt tgtcaagacc gacctgtccg gtgccctgaa tgaactgcaa 10860gacgaggcag cgcggctatc gtggctggcc acgacgggcg ttccttgcgc agctgtgctc 10920gacgttgtea ctgaagcggg aagggactgg ctgctattgg gcgaagtgcc ggggcaggat 10980ctcctgtcat ctcaccttgc tcctgccgag aaagtatcca tcatggctga tgcaatgcgg 11040cggctgcata cgcttgatcc ggctacctgc ccattcgacc accaagcgaa acatcgcatc 11100gagcgagcac gtactcggat ggaagccggt cttgtcgatc aggatgatct ggacgaagag 11160catcaggggc tcgcgccagc cgaactgttc gccaggctca aggcgagcat gcccgacggc 11220gaggatctcg tcgtgaccca tggcgatgcc tgcttgccga atatcatggt ggaaaatggc 11280cgcttttctg gattcatcga ctgtggccgg ctgggtgtgg cggaccgcta tcaggacata 11340gcgttggcta cccgtgatat tgctgaagag cttggcggcg aatgggctga ccgcttcctc 11400gtgctttacg gtatcgccgc tcccgattcg cagcgcatcg ccttctatcg ccttcttgac 11460gagttcttct gaattttgtt aaaatttttg ttaaatcagc tcatttttta accaataggc 11520cgaaatcggc aacatccctt ataaatcaaa agaatagacc gcgatagggt tgagtgttgt 11580tccagtttgg aacaagagtc cactattaaa gaacgtggac tccaacgtca aagggcgaaa 11640aaccgtctat cagggcgatg gcccactacg tgaaccatca cccaaatcaa gttttttgcg 11700gtcgaggtgc cgtaaagctc taaatcggaa ccctaaaggg agcccccgat ttagagcttg 11760acggggaaag ccggcgaacg tggcgagaaa ggaagggaag aaagcgaaag gagcgggcgc 11820tagggcgctg gcaagtgtag cggtcacgct gcgcgtaacc accacacccg cgcgcttaat 11880gcgccgctac agggcgcgtc cattcgccat tcaggatcga attaattctt aat 11933
<210> 3<211> 46<212> DNA<213> Seqüência artificial<220><223> agonista do receptor toll-like 3 (TLR-3)<400> 3
gaaacgatat gggctgaata cttaagtatt cagcccatat cgtttc 46
<210> 4<2U> 1190<212> DNA<213> Seqüência artificial<220><223> agonista do receptor toll-like 3 (TLR-3)<400> 4
cgggcccccc ctcgaggtcg acggtatcga taagcttgat atcgaattcg cccttagata 60tcgtcgacgc ccagcacccc aaggcggcca acgccaaaac tctccctcct cctcttcctc 120aatctcgctc tcgctctttt tttttttcgc aaaaggaggg gagagggggt aaaaaaatgc 180tgcactgtgc ggcgaagccg gtgagtgagc ggcgcggggc caatcagcgt gcgccgttcc 240gaaagttgcc ttttatggct cgagcggccg cggcggcgcc ctataaaacc cagcggcgcg 300acgcgccacc accgccgaga catcgatgat atctaaaggg cgaattcctg cagcccgggg 360gatccactag tctagatgca tgctcgagcg gccgccagtg tgatggatat ctgcagaatt 420cgcccttcag ctgcggatcc attcgccatt caggctgcgc aactgttggg aagggcgatc 480ggtgcgggcc tcttcgctat tacgccagct ggcgaaaggg ggatgtgctg caaggcgatt 540aagttgggta acgccagggt tttcccagtc acgacgttgt aaaacgacgg ccagtgaatt 600gtaatacgac tcactatagg gcgaattggg taccgggccc cccctcgagg tcgacggtat 660cgataagctt gatatcgaat tcctgcagcc cgggggatcc actagtttct agaaataaaa 720tatctttatt ttcattacat ctgtgtgttg gttttttgtg tggcggccgc caccgcggtg 780gagctatcga attcaagctt gtcgactcga agatcctaga ctagtggatc ccccgggctg 840caggaattcg ccctttagat atcatcgatg tctcggcggt ggtggcgcgt cgcgccgctg 900ggttttatag ggcgccgccg cggccgctcg agccataaaa ggcaactttc ggaacggcgc 960acgctgattg gccccgcgcc gçtcactcac cggcttcgcc gcacagtgca gcattttttt 1020accccctctc ccctcctttt gcgaaaaaaa aaaagagcga gagcgagatt gaggaagagg 1080aggagggaga gttttggcgt tggccgcctt ggggtgctgg gcgtcgacga tatctaaggg 1140cgaattcgat atcaagctta tcgataccgt cgacctcgag ggggggcccg 1190
<210> 5<211> 1757<212> DNA<213> Seqüência artificial<220>
<223> agonista do receptor toll-like 3 (TLR-3)<400> 5
cgggcccccc ctcgaggtcg acggtatcga taagcttgat atcgaattcg cccttagata 60tcgtcgacgc ccagcacccc aaggcggcca acgccaaaac tctccctcct cctcttcctc 120aatctcgctc tcgctctttt tttttttcgc aaaaggaggg gagagggggt aaaaaaatgc 180tgcactgtgc ggcgaagccg gtgagtgagc ggcgcggggc caatcagcgt gcgccgttcc 240gaaagttgcc ttttatggct cgagcggccg cggcggcgcc ctataaaacc cagcggcgcg 300acgcgccacc accgccgaga catcgatgat atctaaaggg cgaattcctg cagcccgggg 360gatccactag tctagatgca tgctcgagcg gccgccagtg tgatggatat ctgcagaatt 420cgcccttcag ctgcggatcc attcgccatt caggctgcgc aactgttggg aagggcgatc 480ggtgcgggcc tcttcgctat tacgccagct ggcgaaaggg ggatgtgctg caaggcgatt 540aagttgggta acgccagggt tttcccagtc acgacgttgt aaaacgacgg ccagtgaatt 600gtaatacgac tcactatagg gcgaattggg taccgggccc cccctcgagg tcgacggtat 660cgataagctt gatatcgaat tcctgcagcc cgggggatcc actagtttct agaaataaaa 720tatctttatt ttcattacat ctgtgtgttg gttttttgtg tggcggccgc caccgcggtg 780gagctatcga attcaagctt gtcgactcga agatcgtaca caggaagtga caattttcgc 840gcggttttag gcggatgttg tagtaaattt gggcgtaacc gagtaagatt tggccatttt 900cgcgggaaaa ctgaataaga ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg 960taatactggt accgggcccc ccctcgaggt cgacggtatc gataagcttg atatcgaatt 1020cgcccttaga tatcgtcgac gcccagcacc ccaaggcggc caacgccaaa actctccctc 1080ctcctcttcc tcaatctcgc tctcgctctt tttttttttc gcaaaaggag gggagagggg 1140gtaaaaaaat gctgcactgt gcggcgaagc cggtgagtga gcggcgcggg gccaatcagc 1200gtgcgccgtt ccgaaagttg ccttttatgg ctcgagcggc cgcggcggcg ccctataaaa 1260cccagcggcg cgacgcgcca ccaccgccga gacatcgatg atatctaaag ggcgaattcc 1320tgcagcccgg gggatccact agtctagaac tagtggatcc cccgggctgc aggaattcga 1380tatcaagctt atcgataccg tcgacctcga gggggggccc ggtacccaat tcgccctata 14 40gtgagtcgta ttacaattca ctggccgtcg ttttacaacg tcgtgactgg gaaaaccctg 1500gcgttaccca acttaatcgc cttgcagcac atcccccttt cgccagctgg cgtaatagcg 1560aagaggcccg caccgatcgc ccttcccaac agttgcgcag cctgaatggc gaatggatcc 1620gcagctgaag ggcgaattct gcagatatcc atcacactgg cggccgctcg agcatgcatc 1680tagaaataáa atatctttat tttcattaca tctgtgtgtt ggttttttgt gtggcggccg 1740ccaccgcggt ggagcta 1757
<210> 6<211> 10153<212> ONA<213> Seqüência artificial<220>
<223> vetor adenoviral quimérico que codifica hemaglutinina (HA) de influenza e agonista doRNA TLR-3 Iuc na mesma orientação<400> 6
taacatcatc aataatatac cttattttgg attgaagcca atatgataat gagggggtgg 60agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagt gtggcggaag 120tgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgttt 180ttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttag gcggatgttg 240tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataaga 300ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgct agagatctgg 360cgaaaggggg atgtgctgca aggcgattaa gttgggtaac gccagggttt tcccagtcac 420gacgttgtaa aacgacggcc agtgaattgt aatacgactc actatagggc gaattgggta 480ctggccacag agcttggccc attgcatacg ttgtatccat atcataatat gtacatttat 540attggctcat gtccaacatt accgccatgt tgacattgat tattgactag ttattaataa 600taatcaatta cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt 660acggtaaatg gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg 720acgtatgttc ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat 780ttacggtaaa ctgcccactt ggcagtacat caagtgtatc atatgccaag tacgccccct 840attgacgtca atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttatgg 900gactttccta cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg 960ttttggcagt acatcaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc 1020caccccattg acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa 1080tgtcgtaaca actccgcccc attgacgcaa atgggcggta ggcgtgtacg gtgggaggtc 1140tatataagca gagctcgttt agtgaaccgt cagatcgcct ggagacgcca tccacgctgt 1200tttgacctcc atagaagaca ccgggaccga tccagcctga ctctagccta gctctgaagt 1260tggtggtgag gccctgggca ggttggtatc aaggttacaa gacaggttta aggagaccaa 1320tagaaactgg gcatgtggag acagagaaga ctcttgggtt tctgataggc actgactctc 1380tctgcctatt ggtctatttt cccaccctta ggctgctggt ctgagcctag gagatctctc 1440gaggtcgacg gtatcgatgc caccatggag aaaatcgtcc tgttgctcgc tattgtgtct 1500ctagtgaaga gcgatcaaat ttgtatcggc taccatgcca ataactcaac agagcaggtc 1560gatactatca tggagaaaaa cgtaacagtt actcatgccc aagacatctt ggaaaagacc 1620cacaacggca aactttgcga cctggatgga gtgaagcccc tgatcctccg ggactgttca 1680gtcgctggtt ggctgctcgg gaaccctatg tgtgatgagt ttatcaacgt gcctgaatgg 1740tcttacattg tggagaaggc taaccctacc aatgacctct gctatcctgg gtcatttaac 1800gattacgagg aactgaaaca cctgttgtct agaattaacc actttgaaaa gatacagatt 1860atacccaagt ctagttggag tgatcacgaa gcctcctcag gcgttagctc agcgtgtccc 1920tatctgggct ctccatcctt ctttagaaat gtggtctggt taatcaaaaa gaacagtacc 1980tacccaacca tcaaaaagtc ttataacaat accaatcagg aggacctgct cgtgttgtgg 2040ggtatccatc acccgaacga cgccgctgaa cagactaggc tgtatcagaa ccccactaca 2100tacatcagta ttggcacgag tactctgaac cagcgattag tgccaaagat tgcaacacgg 2160agcaaagtaa atgggcaatc tggcaggatg gagtttttct ggacaatctt aaaacccaac 2220gatgcgataa atttcgagtc caatggcaat ttcatcgccc ctgaatacgc ctataagatc 2280gtgaaaaagg gggactctgc aattatgaag tccgaattag agtatggcaa ttgcaacacg 2340aagtgccaga caccaatggg agcçattaat agctcaatgc ccttccataa tattcatcca 2400ttgaccattg gggagtgccc aaagtacgtg aagtccaacc gcctggtcct cgcaaccggt 2460ctaagaaata gcccgcagag agaatcgcgg aggaagaaac gtggcctgtt tggcgcgatt 2520gccggattca tcgagggagg ctggcagggt atggtcgatg gttggtacgg ataccaccat 2580agcaacgaac aggggtccgg ctatgcagca gataaggaga gcactcagaa agctattgac 2640ggagttacaa acaaggttaa tagtattata gataaaatga acacgcaatt cgaggccgtt 2700gggagggagt ttaacaatct ggaacgccgg atcgaaaatc tgaataagaa aatggaagac 2760ggcttccttg acgtgtggac ttataatgca gagctgcttg tactcatgga gaacgagagg 2820accctggatt tccacgatag caacgtgaag aacctttacg acaaggtgag acttcagctc 2880cgagacaacg ccaaggagct ggggaatgga tgcttcgagt tttaccacaa atgtgacaat 2940gagtgcatgg aaagtatacg caacgggacc tácaattacc ctcagtatag cgaagaggct 3000cggctcaaac gcgaagagat aagcggggtg aaattggaat caatcggaac atatcaaatc 3060ctgtcçatct attccaccgt cgcctcttcg ctggccctcg ctatcatgat ggctggtctg 3120tccctatgga tgtgttccaa tggaagcctt cagtgccgta tttgtatatg agcggccgcc 3180ctattctata gtgtcaccta aatgctagag ctcgctgatc agcctcgact gtgccttcta 3240gttgccagcc atctgttgtt tgcccctccc ccgtgccttc cttgaccctg gaaggtgcca 3300ctcccactgt cctttcctaa taaaatgagg aaattgcatc gcattgtctg agtaggtgtc 3360attctattct ggggggtggg gtggggcagg acagcaaggg ggaggattgg gaagacaata 3420gcaggcatgc tggggatgcg gtgggçtcta tggcttctga ggcggaaaga accaaccacc 3480gcggtggcgg ccgccacaca aaaaaccaac acacagatgt aatgaaaata aagatatttt 3540atttctagag aaacgatatg ggctgaatac ggatccgtat tcagcccata tcgtttcctg 3600caggaattcg ccctttagat atcatcgatg tctcggçggt ggtggcgcgt cgcgccgctg 3660ggttttatag ggcgccgccg cggccgctcg agccataaaa ggcaactttc ggaacggcgc 3720acgctgattg gccccgcgcc gctcactcac cggcttcgcc gcacagtgca gcattttttt 3780accccctctc ccctcctttt gcgaaaaaaa aaaagagcga gagcgagatt gaggaagagg 3840aggagggaga gttttggcgt tggccgcctt ggggtgctgg gcgtcgacga tatctaaggg 3900cgaattcgat atcaagctag cttgtcgact cgaagatctg ggcgtggtta agggtgggaa 3960agaatatata aggtgggggt cttatgtagt tttgtatctg ttttgcagca gccgccgccg 4020ccatgagcac caactcgttt gatggaagca ttgtgagctc atatttgaca acgcgcatgc 4080ccccatgggc cggggtgcgt cagaatgtga tgggctccag cattgatggt cgccccgtcc 4140tgcccgcaaa ctctactacc ttgacctacg agaccgtgtc tggaacgccg ttggagactg 4200cagcctccgc cgccgcttca gccgctgcag ccaccgcccg cgggattgtg actgactttg 4260ctttcçtgag cccgcttgca agcagtgcag cttcccgttc atccgcccgc gatgacaagt 4320tgacggctct tttggcacaa ttggattctt tgacccggga acttaatgtc gtttctcagc 4380agctgttgga tctgcgccag caggtttctg ccctgaaggc ttcctcccct cccaatgcgg 4440tttaaaacat aaataaaaaa ccagactctg tttggatttg gatcaagcaa gtgtcttgct 4500gtctttattt aggggttttg cgcgcgcggt aggcccggga ccagcggtct cggtcgttga 4560gggtcctgtg tattttttcc aggacgtggt aaaggtgact ctggatgttc agatacatgg 4620gcataagccc gtctctgggg tggaggtagc accactgcag agcttcatgc tgcggggtgg 4680tgttgtagat gatccagtcg tagcaggagc gctgggcgtg gtgcctaaaa atgtctttca 4740gtagcaagct gattgccagg ggcaggccct tggtgtaagt gtttacaaag cggttaagct 4800gggatgggtg catacgtggg gatatgagat gcatcttgga ctgtattttt aggttggcta 4860tgttcccagc catatccctc cggggattca tgttgtgcag aaccaccagc acagtgtatc 4920cggtgcactt gggaaatttg tcatgtagct tagaaggaaa tgcgtggaag aacttggaga 4 980cgcccttgtg acctccaaga ttttccatgc attcgtccat aatgatggca atgggcccac 5040gggcggcggc ctgggcgaag atatttctgg gatcactaac gtcatagttg tgttçcagga 5100tgagatcgtc ataggccatt tttacaaagc gcgggcggag ggtgccagac tgcggtataa 5160tggttccatc cggcccaggg gcgtagttac cctcacagat ttgcatttcc cacgctttga 5220gttcagatgg ggggatcatg tctacctgcg gggcgatgaa gaaaacggtt tccggggtag 5280gggagatcag ctgggaagaa agcaggttcc tgagcagctg cgacttaccg cagccggtgg 5340gcccgtaaat cacacctatt accgggtgca actggtagtt aagagagctg cagctgccgt 5400catccctgag caggggggcc acttcgttaa gcatgtccct gactcgcatg ttttccctga 5460ccaaatccgc cagaaggcgc tcgccgccca gcgatagcag ttcttgcaag gaagcaaagt 5520ttttcaacgg tttgagaccg tccgccgtag gcatgctttt gagcgtttga ccaagcagtt 5580ccaggcggtc ccacagctcg gtcacctgct ctacggcatc tcgatccagc atatctcctc 5640gtttcgcggg ttggggcggc tttcgctgta cggcagtagt cggtgctcgt ccagacgggc 5700cagggtcatg tctttccacg ggcgcagggt cctcgtcagc gtagtctggg tcacggtgaa 5760ggggtgcgct ccgggctgcg cgctggccag ggtgcgcttg aggctggtcc tgctggtgct 5820gaagcgctgc cggtcttcgc cctgcgcgtc ggccaggtag catttgacca tggtgtcata 5880gtccagcccc tccgcggcgt ggcccttggc gcgcagcttg cccttggagg aggcgccgca 5940cgaggggcag tgcagacttt tgagggcgta gagcttgggc gcgagaaata ccgattccgg 6000ggagtaggca tccgcgccgc aggccccgca gacggtctcg cattccacga gccaggtgag 6060ctctggccgt tcggggtcaa aaaccaggtt tcccccatgc tttttgatgc gtttcttacc 6120tctggtttcc atgagccggt gtccacgctc ggtgacgaaa aggctgtccg tgtccccgta 6180tacagacttg agagggagtt taaacgaatt caatagcttg ttgcatgggc ggcgatataa 6240aatgcaaggt gctgctcaaa aaatcaggca aagcctcgcg caaaaaagaa agçacatcgt 6300agtcatgctc atgcagataa aggcaggtaa gctccggaac caccacagaa aaagacacca 6360tttttctctc aaacatgtct gcgggtttct gcataaacac aaaataaaat aacaaaaaaa 6420catttaaaca ttagaagcct gtcttacaac aggaaaaaca acccttataa gcataagacg 6480gactacggcc atgccggcgt gaccgtaaaa aaactggtca ccgtgattaa aaagcaccac 6540cgacagctcc tcggtcatgt ccggagtcat aatgtaagac tcggtaaaca catcaggttg 6600attcatcggt cagtgctaaa aagcgaccga aatagcccgg gggaatacat acccgcaggc 6660gtagagacaa cattacagcc cccataggag gtataacaaa attaatagga gagaaaaaca 6720cataaacacc tgaaaaaccc tcctgcctag gcaaaatagc accctcccgc tccagaacaa 6780catacagcgc ttcacagcgg cagcctaaca gtcagcctta ccagtaaaaa agaàaaccta 6840ttáaaaaaac accactcgac acggcaccag ctcaatcagt cacagtgtaa aaaagggcca 6900agtgcagagc gagtatatat aggactaaaa aatgacgtaa cggttaaagt ccacaaaaaa 6960cacccagaaa accgcacgcg aacctacgcc cagaaacgaa agccaaaaaa cccacaactt 7020cctcaaatcg tcacttccgt tttcccacgt tacgtaactt cccattttaa gaaaactaca 7080attcccaaca catacaagtt actccgccct aaaacctacg tcacccgccc cgttcccacg 7140ccccgcgcca cgtcacaaac tccàccccct cattatcata ttggcttcaa tccaaaataa 7200ggtatattat tgatgatgtt aattaacatg catggatcca tatgcggtgt gaaataccgc 7260acagatgcgt aaggagaaaa taccgcatca ggcgctcttc cgcttcctcg ctcactgact 7320cgctgcgctc ggtcgttcgg ctgcggcgag cggtatcagc tcactcaaag gcggtaatac 7380ggttatccac agaatcaggg gataacgcag gaaagaacat gtgagcaaaa ggccagcaaa 7440aggccaggaa ccgtaaaaag gccgcgttgc tggcgttttt ccataggctc cgcccccctg 7500acgagcatca caaaaatcga cgctcaagtc agaggtggcg aaacccgaca ggactataaa 7560gataccaggc gtttccccct ggaagctccc tcgtgcgctc tcctgttccg accctgccgc 7620ttaccggata cctgtccgcc tttctccctt cgggaagcgt ggcgctttct catagctcac 7680gctgtaggta tctcagttcg gtgtaggtcg ttcgctccaa gctgggctgt gtgcacgaac 7740cccccgttca gcccgaccgc tgcgccttat ccggtaacta tcgtcttgag tccaacccgg 7800taagacacga cttatcgcca ctggcagcag ccactggtaa caggattagc agagcgaggt 7860atgtaggcgg tgctacagag ttcttgaagt ggtggcctaa ctacggctac actagaagga 7920cagtatttgg tatctgcgct ctgctgaagc cagttacctt cggaaaaaga gttggtagct 7980cttgatccgg caaacaaacc accgctggta gcggtggttt ttttgtttgc aagcagcaga 8040ttacgcgcag aaaaaaagga tctcaagaag atcctttgat cttttctacg gggtctgacg 8100ctcagtggaa cgaaaactca cgttaaggga ttttggtcat gagattatca aaaaggatct 8160tcacctagat ccttttaaat taaaaatgaa gttttaaatc aatctaaagt atatatgagt 8220aaacttggtc tgacagttac caatgcttaa tcagtgaggc acctatctca gcgatctgtc 8280tatttcgttc atccatagtt gcctgactcc ccgtcgtgta gataactacg atacgggagg 8340gcttaccatc tggccccagt gctgcaatga taccgcgaga cccacgctca ccggctccag 8400atttatcagc aataaaccag ccagccggaa gggccgagcg cagaagtggt cctgcaactt 8460tatccgcctc catccagtct attaattgtt gccgggaagc tagagtaagt agttcgccag 8520ttaatagttt gcgcaacgtt gttgccattg ctgcagccat gagattatca aaaaggatct 8580tcacctagat ccttttcacg tagaaagcca gtccgcagaa acggtgctga ccccggatga 864 0atgtcagcta ctgggctátc tggacaaggg aaaacgcaag cgcaaagaga aagcaggtag 8700cttgcagtgg gcttacatgg cgatagctag actgggcggt tttatggaca gcaagcgaac 8760cggaattgcc agctggggcg ccctctggta aggttgggaa gccctgcaaa gtaaactgga 8820tggctttctc gccgccaagg atctgatggc gcaggggatc aagctctgat caagagacag 8880gatgaggatc gtttcgcatg attgaacaag atggattgca cgcaggttct ccggccgctt 8940gggtggagag gctattcggc tatgactggg cacaacagac aatcggctgc tctgatgccg 9000ccgtgttccg gctgtcagcg caggggcgcc cggttctttt tgtcaagacc gacctgtccg 9060gtgccctgaa tgaactgcaa gacgaggcag cgcggctatc gtggctggcç acgacgggcg 9120ttccttgcgc agctgtgctc gacgttgtca ctgaagcggg aagggactgg ctgctattgg 9180gcgaagtgcc ggggcaggat ctcctgtcat ctcaccttgc tcctgccgag aaagtatcca 9240tcatggctga tgcaatgcgg cggctgcata cgcttgatcc ggctacctgc ccattcgacc 9300accaagcgaa acatcgcatc gagcgagcac gtactcggat ggaàgccggt cttgtcgatc 9360aggatgatct ggacgaagag catcaggggc tcgcgccagc cgaactgttc gccaggctca 9420aggcgagcat gcccgacggc gaggatctcg tcgtgacçca tggcgatgcc tgcttgccga 9480atatcatggt ggaaaatggc cgcttttctg gattcatcga ctgtggccgg ctgggtgtgg 9540cggaccgcta tcaggacata gcgttggcta cccgtgatat tgctgaagag cttggcggcg 9600aatgggctga ccgcttcctc gtgctttacg gtatcgccgc tcccgattcg cagcgcatcg 9660ccttctatcg ccttcttgac gagttcttct gaattttgtt aaaatttttg ttaaatcagc 9720tcatttttta accaataggc cgaaatcggc aacatccctt ataaatcaaa agaatagacc 9780gcgatagggt tgagtgttgt tccagtttgg aacaagagtc cactattaaa gaacgtggac 9840tccaacgtca aagggcgaaa aaccgtctat cagggcgatg gcccactacg tgaaccatca 9900cccaaatcaa gttttttgcg gtcgaggtgc cgtaaagctc taaatcggaa ccctaaaggg 9960agcccccgat ttagagcttg acggggaaag ccggcgaacg tggcgagaaa ggaagggaag 10020aaagcgaaag gagcgggcgc tagggcgctg gcaagtgtag cggtcacgct gcgcgtaacc 10080accacacccg cgcgcttaat gcgccgctac agggcgcgtc cattcgccat tcaggatcga 10140attaattctt aat 10153
<210> 7<211> 10153<212> DNA
<213> Seqüência artificial<220>
<223> vetor adenoviral quimérico que codifica hemaglutinina (HA) de influenza e agonista do
RNA TLR-3 Iuc na orientação oposta. (DS2b-for)<400> 7
taacatcatc aataatatac cttattttgg attgaagcca atatgataat gagggggtgg 60
agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagt gtggcggaag 120
tgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgttt 180
ttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttag gcggatgttg 240
tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataagá 300
ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgct agagatctgg 360
cgaaaggggg atgtgctgca aggcgattaa gttgggtaac gccagggttt tcccagtcac 420
gacgttgtaa aacgacggcc agtgaattgt aatacgactc actatagggc gaattgggta 480
ctggccacag agcttggccc attgcatacg ttgtatccat atcataatat gtacatttat 540
attggctcat gtccaacatt accgccatgt tgacattgat tattgactag ttattaatag 600
taatcaatta cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt 660
acggtaaatg gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg 720
acgtatgttc ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat 780
ttacggtaaa ctgcccactt ggcagtacat caagtgtatc atatgccaag tacgccccct 840
attgacgtca atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttatgg 900
gactttccta cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg 960
ttttggcagt acatcaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc 1020
caccccattg acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa 1080
tgtcgtaaca actccgcccc attgacgcaa atgggcggta ggcgtgtacg gtgggaggtc 1140tatataagca gagctcgttt agtgaaccgt cagatcgcct ggagacgcca tccacgctgt 120Ctttgacctcc atagaagaca ccgggaccga tccagcctga ctctagccta gctctgaagt 126Ctggtggtgag gccctgggca ggttggtatc aaggttacaa gacaggttta aggagaccaa 1320tagaaactgg gcatgtggag acagagaaga ctcttgggtt tctgataggc actgactctc 1380tctgcetatt ggtctatttt cccaccctta ggctgctggt ctgagcctag gagatctctc 1440gaggtcgacg gtatcgatgc caccatggag aaaatcgtcc tgttgctcgc tattgtgtct 1500ctagtgaaga gcgatcaaat ttgtatcggc taccatgcca ataactcaac agagcaggtc 1560gatactatca tggagaaaaa cgtaacagtt actcatgccc aagacatctt ggaaaagacc 1620cacaacggca aactttgcga cctggatgga gtgaagcccc tgatcctccg ggactgttca 1680gtcgctggtt ggctgctcgg gaaccctatg tgtgatgagt ttatcaacgt gcctgaatgg 1740tcttacattg tggagaaggc taaccctacc aatgacctct gctatcctgg gtcatttaâc 1800gattacgagg aactgaaaca cctgttgtct agaattaacc actttgaaaa gatacagatt 1860atacccaagt ctagttggag tgatcacgaa gcctcctcag gcgttagctc agcgtgtccc 1920tatctgggct ctccatcctt ctttagaaat gtggtctggt taatcaaaaa gaacagtacc 1980tacccaacca tcaaaaagtc ttataacaat accaatcagg aggacctgct cgtgttgtgg 2040ggtatccatc acccgaacga cgccgctgaa cagactaggc tgtatcagaa ccccactaca 2100tacatcagta ttggcacgag tactctgaac cagcgattag tgccaaagat tgcaacacgg 2160agcaaagtaa atgggcaatc tggcaggatg gagtttttct ggacaatctt aaaacccaac 2220gatgcgataa atttcgagtc caatggcaat ttcatcgccc ctgaatacgc ctataagatc 2280gtgaaaaagg gggactctgc aattatgaag tccgaattag agtatggcaa ttgcaacacg 2340aagtgccaga caccaatggg agccattaat agctcaatgc ccttccataa tattcatcca 2400ttgaccattg gggagtgccc aaagtacgtg aagtccaacc gcctggtcct cgcaaccggt 2460ctaagaaata gcccgcagag agaatcgcgg aggaagaaac gtggcctgtt tggcgcgatt 2520gccggattca tcgàgggagg ctggcagggt atggtcgatg gttggtacgg ataccaccat 2580agcaacgaac aggggtccgg ctatgcagca gataaggaga gcactcagaa agctattgac 2640ggagttacaa acaaggttaa tagtattata gataaaatga acacgcaatt cgaggccgtt 2700gggagggagt ttaacaatct ggaacgccgg atcgaaaatc tgaataagaa aatggaagac 2760ggcttccttg acgtgtggac ttataatgca gagctgcttg tactcatgga gáacgagagg 2820- accctggatt tccacgatag caacgtgaag aacctttacg acaaggtgag acttcagctc 2880cgagacaacg ccaaggagct ggggaatgga tgcttcgagt tttaccacaa atgtgacaat 2940gagtgcatgg aaagtatacg caacgggacc tacaattacc ctcagtatag cgaagaggct 3000cggctcaaac gcgaagagat aagcggggtg aaattggaat caatcggaac atatcaaatc 3060ctgtccatct attccaccgt cgcctcttcg ctggccctcg ctatcatgat ggctggtctg 3120tccctatgga tgtgttccaa tggaagcctt cagtgccgta tttgtatatg agcggccgcc 3180ctattctata gtgtcaccta aatgctagag ctcgctgatc agcctcgact gtgccttcta 3240gttgccagcc atctgttgtt tgcccctccc ccgtgccttc cttgaccctg gaaggtgcca 3300ctcccactgt cctttcctaa taaaatgagg aaattgcatc gcattgtctg agtaggtgtc 3360attctattct ggggggtggg gtggggcagg acagcaaggg ggaggattgg gaagacaata 3420gcaggcatgc tggggatgcg gtgggctcta tggcttctga ggcggaaaga accaaccacc 3480gcggtggcgg ccgccacaca aaaaaccaac acacagatgt aatgaaaata aagatatttt 3540atttctagag aaacgatatg ggctgaatac ggatccgtat tcagcccata tcgtttcctg 3600caggaattcg ccctttagat atcatcgatg tctcggcggt ggtggcgcgt cgcgccgctg 3660ggttttatag ggcgccgccg cggccgctcg agccataaaa ggcaactttc ggaacggcgc 3720acgctgattg gccccgcgcc gctcactcac cggcttcgcc gcacagtgca gcattttttt 3780accccctctc ccctcctttt gcgaaaaaaa aaaagagcga gagcgagatt gaggaagagg 3840aggagggaga gttttggcgt tggccgcctt ggggtgctgg gcgtcgacga tatctaaggg 3900cgaattcgat atcaagctag cttgtcgact cgaagatctg ggcgtggtta agggtgggaa 3960agaatatata aggtgggggt cttatgtagt tttgtatctg ttttgcagca gccgccgccg 4020ccatgagcac caactcgttt gatggaagca ttgtgagctc atatttgaca acgcgcatgc 4080ccccatgggc cggggtgcgt cagaatgtga tgggctccag cattgatggt cgccccgtcc 4140tgcccgcaaa ctctactacc ttgacctacg agaccgtgtc tggaacgccg ttggagactg 4200cagcctccgc cgccgcttca gccgctgcag ccaccgcccg cgggattgtg actgactttg 4260ctttcctgag cccgcttgca agcagtgcag cttcccgttc atccgcccgc gatgacaagt 4320tgacggctct tttggcacaa ttggattctt tgacccggga acttaatgtc gtttctcagc 4380agctgttgga tctgcgccag caggtttctg ccctgaaggc ttcctcccct cccaatgcgg 4440tttaaaacat aaataaaaaa ccagactctg tttggatttg gatcaagcaa gtgtcttgct 4 500gtctttattt aggggttttg cgcgcgcggt aggcccggga ccagcggtct cggtcgttga 4560gggtcctgtg tattttttcc aggacgtggt aaaggtgact ctggatgttc agatacatgg 4620gcataagccc gtctctgggg tggaggtagc accactgcag agcttcatgc tgcggggtgg 4 680tQttgtagat gatccagtcg tagcaggagc gctgggcgtg gtgcctaaaa atgtctttca 4740gtagcaagct gattgccagg ggcaggccct tggtgtaagt gtttacaaag cggttaagct 4800gggatgggtg catacgtggg gatatgagat gcatcttgga ctgtattttt aggttggcta 4860tgttcccagc catatccctc cggggattca tgttgtgcag aaccaccagc acagtgtatc 4920cggtgcactt gggaaatttg tcatgtagct tagaaggaaa tgcgtggaag aacttggaga 4 980cgcccttgtg acctccaaga ttttccatgc attcgtccat aatgatggca atgggcccac 5040gggcggcggc ctgggcgaag atatttctgg gatcactaac gtcatagttg tgttccagga 5100tgagatcgtc ataggccatt tttacaaagc gcgggcggag ggtgccagac tgcggtataa 5160tggttccatc cggcccaggg gcgtagttac cctcacagat ttgcatttcc cacgctttga 5220gttcagatgg ggggatcatg tctacctgcg gggcgatgaa gaaaacggtt tccggggtag 5280gggagatcag ctgggaagaa agcaggttcc tgagcagctg cgacttaccg cagccggtgg 5340gcccgtaaat cacacctatt accgggtgca actggtagtt aagagagctg cagctgccgt 5400catccctgag caggggggcc acttcgttaa gcatgtccct gactcgcatg ttttccctga 5460ccaaatccgc cagaaggcgc tcgccgccca gcgatagcag ttcttgcaag gaagcaaagt 5520ttttcaacgg tttgagaccg tccgccgtag gcatgctttt gagcgtttga ccaagcagtt 5580ccaggcggtc ccacagctcg gtcacctgct ctacggcatc tcgatccagc atatctcctc 564 0gtttcgcggg ttggggcggc tttcgctgta cggcagtagt cggtgctcgt ccagacgggc 5700cagggtcatg tctttccacg ggcgcagggt cctcgtcagc gtagtctggg tcacggtgaa 5760ggggtgcgct ccgggctgcg cgctggccag ggtgcgcttg aggctggtcc tgctggtgct 5820gaagcgctgc cggtcttcgc cctgcgcgtc ggccaggtag catttgacca tggtgtcata 5880gtccagcccc tccgcggcgt ggcccttggc gcgcagcttg cccttggagg aggcgccgca 5940cgaggggcag tgcagacttt tgagggcgta gagcttgggc gcgagaaata ccgattccgg 6000ggagtaggca tccgcgccgc aggccccgca gacggtctcg cattccacga gccaggtgag 6060ctctggccgt tcggggtcaa aaaccaggtt tcccccatgc tttttgatgc gtttcttacc 6120tctggtttcc atgagccggt gtccacgctc ggtgacgaaa aggctgtccg tgtccccgta 6180tacagacttg agagggagtt taaacgaatt caatagcttg ttgcatgggc ggcgatataa 6240aatgcaaggt gctgctcaaa aaatcaggca aagcctcgcg caaaaaagaa agcacatcgt 6300agtcatgctc atgcagataa aggcaggtaa gctccggaac caccacagaa aaagacacca 6360tttttctctc aaacatgtct gcgggtttct gcataaacac aaaataaaat aacaaaaaaa 6420catttaaaca ttagaagcct gtcttacaac aggaaaaaca acccttataa gcataagacg 64 80gactacggcc atgccggcgt gaccgtaaaa aaactggtca ccgtgattaa aaagcaccac 6540cgacagctcc tcggtcatgt ccggagtcat aatgtaagac tcggtaaaca catcaggttg 6600attcatcggt cagtgctaaa aagcgaccga aatagcccgg gggaatacat acccgcaggc 6660gtagagacaa cattacagcc cccataggag gtataacaaa attaatagga gagaaaaaca 6720cataaacacc tgaaaaaccc tcctgcctag gcaaaatagc accctcccgc tccagaacaa 6780catacagcgc ttcacagcgg cagcctaaca gtcagcctta ccagtaaaaa agaaaaccta 6840ttaaaaaaac accactcgac acggcaccag ctcaatcagt cacagtgtaa aaaagggcca 6900agtgcagagc gagtatatat aggactaaaa aatgacgtaa cggttaaagt ccacaaaaaa 6960cacccagaaa accgcacgcg aacctacgcc cagaaacgaa agccaaaaaa occacaactt 7020cctcaaatcg tcacttccgt tttcccacgt tacgtaactt cccattttaa gaaaactaca 7080attcccaaca catacaagtt actccgccct aaaacctacg tcacccgccc cgttcccacg 7140ccccgcgcca cgtcacaaac tccaccccct cattatcata ttggcttcaa tccaaaataa 7200ggtatattat tgatgatgtt aattaacatg catggatcca tatgcggtgt gaaâtaccgc 7260acagatgcgt aaggagaaaa taccgcatca ggcgctcttc cgcttcctcg ctcactgact 7320cgctgcgctc ggtcgttcgg ctgcggcgag cggtatcagc tcactcaaag gcggtaatac 7380ggttatccac agaatcaggg gataacgcag gaaagaacat gtgagcaaaa ggccagcaaa 74 40aggccaggaa ccgtaaaaag gccgcgttgc tggcgttttt ccataggctc cgcccccçtg 7500acgagcatca caaaaatcga cgctcaagtc agaggtggcg aaacccgaca ggactataaa 7560gataccaggc gtttccccct ggaagctccc tcgtgcgctc tcctgttccg accctgccgc 7620ttaccggata cctgtccgcc tttctccctt cgggaagcgt ggcgctttct catagctcac 7680gctgtaggta tctcagttcg gtgtaggtcg ttcgctccaa gctgggctgt gtgcacgaac 7740cccccgttca gcccgaccgc tgcgccttat ccggtaacta tcgtcttgag tccaacccgg 7800taagacacga cttatcgcca ctggcagcag ccactggtaa caggattagc agagcgaggt 7860atgtaggcgg tgctacagag ttcttgaagt ggtggcctaa ctacggctac actagaagga 7920cagtatttgg tatctgcgct ctgctgaagc cagttacctt cggaaaaaga gttggtagct 7980cttgatccgg caaacaaacc accgctggta gcggtggttt ttttgtttgc aagcagcaga 8040ttacgcgcag aaaaaaagga tctcaagaag atcctttgat cttttctacg gggtctgacg 8100ctcagtggaa cgaaaactca cgttaaggga ttttggtcat gagattatca aaaaggatct 8160tcacctagat ccttttaaat taaaaatgaa gttttaaatc aatctaaagt atatatgagt 8220aaacttggtc tgacagttac caatgcttaa tcagtgaggc acctatctca gcgatctgtc 8280tatttcgttc atccatagtt gcctgactcc ccgtcgtgta gataactacg atacgggagg 8340gcttaccatc tggccccagt gctgcaatga taccgcgaga cccacgctca ccggctccag 8400atttatcagc aataaaccag ccagccggaa gggccgagcg cagaagtggt cctgcaactt 8460tatccgcctc catccagtct attaattgtt gccgggaagc tagagtaagt agttcgccag 8520ttaatagttt gcgcaacgtt gttgccattg ctgcagccat gagattatca aaaaggatct 8580tcacctagat ccttttcacg tagaaagcca gtccgcagaa acggtgctga ccccggatga 8640atgtcagcta ctgggctatc tggacaaggg aaaacgcaag cgcaaagaga aagcaggtag 8700cttgcagtgg gcttacatgg cgatagctag actgggcggt tttatggaca gcaagcgaac 8760cggaattgcc agctggggcg ccctctggta aggttgggaa gccctgcaaa gtaaactgga 8820tggctttctc gccgccaagg atctgatggc gcaggggatc aagctctgat caagagacag 8880gatgaggatc gtttcgcatg attgaacaag atggattgca cgcaggttct ccggccgctt 8940gggtggagag gctattcggc tatgactggg cacaacagac aatcggctgc tctgatgccg 9000ccgtgttccg gctgtcagcg caggggcgcc cggttctttt tgtcaagacc gacctgtccg 9060gtgccctgaa tgaactgcaa gacgaggcag cgcggctatc gtggctggcc acgacgggçg 9120ttccttgcgc agctgtgctc gacgttgtca ctgaagcggg aagggactgg ctgctattgg 9180gcgaagtgcc ggggcaggat ctcctgtcat ctcaccttgc tcctgccgag aaagtatcca 9240tcatggctga tgcaatgcgg cggctgcata cgcttgatcc ggctacctgc ccattcgacc 9300accaagcgaa acatcgcatc gagcgagcac gtactcggat ggaagccggt cttgtcgatc 9360aggatgatct ggacgaagag catcaggggc tcgcgccagc cgaactgttc gccaggctca 9420aggcgagcat gcccgacggc gaggatctcg tcgtgaccca tggcgatgcc tgcttgccga 9480atatcatggt ggaaaatggc cgcttttctg gattcatcga ctgtggccgg ctgggtgtgg 9540cggaccgcta tcaggacata gcgttggcta cccgtgatat tgctgaagag cttggcggcg 9600aatgggctga ccgcttcctc gtgctttacg gtatcgccgc tcccgattcg cagçgcatcg 9660ccttctatcg ccttcttgac gagttcttct gaattttgtt aaaatttttg ttaaatcagc 9720tcatttttta accaataggc cgaaatcggc aacatccctt ataaatcaaa agaatagacc 9780gcgatagggt tgagtgttgt tccagtttgg aacaagagtc cactattaaa gaacgtggac 9840tccaacgtca aagggcgaaa aaccgtctat cagggcgatg gcccactacg tgaaccatca 9900cccaaatcaa gttttttgcg gtcgaggtgc cgtaaagctc taaatcggaa ccctaaaggg 9960agcccccgat ttagagcttg acggggaaag ccggcgaacg tggcgagaaa ggaagggaag 10020aaagcgaaag gagcgggcgc tagggcgctg gcaagtgtag cggtcacgct gcgcgtaacc 10080accacacccg cgcgcttaat gcgccgctac agggcgcgtc cattcgccat tcaggatcga 10140attaattctt aat 10153
<210> 8<211> 46<212> DNA
<213> Seqüência artificial<220>
<223> agonista do RNA TLR-3 grampo curto<400> 8
gatggtgctt caagctagta cttaagtact agcttgaagc accatc 46
<210> 9<211> 48<212> DNA
<213> Seqüência artificial<220>
<223> agonista do RNA TLR-3 grampo curto (gl)<400> 9
gaitggtgctt caagctagta cggatccgta ctagcttgaa gcaccatc 48
<210> 10
<211> 48
<212> DNA
<213> Seqüência artificial<220>
<223> agonista do RNA TLR-3 grampo curto (luc), segmento wcl de DNA formado para umgrampo curto com duplo filamento de RNA
<400> 10
gaaacgatat gggctgaata cggatccgta ttcagcccat atcgtttc 48
<210> 11<211> 46<212> DNA<213> Seqüência artificial
<220>
<223> agonista do RNA TLR-3 grampo curto (ml), grampo dsRNA<400> 11
cctaataatt atcaaaatgt ggatccacat tttgataatt attagg 46
<210> 12<211> 44<212> DNA
<213> Seqüência artificial<220>
<223> agonista do RNA TLR-3 grampo curto<4 00> 12
cctaataatt atcaaaatgt aattacattt tgataattat tagg 44
13
9387DNA
Seqüência artificial
vetor adenoviral quimérico DSlc codificando hemaglutinina (HA) de influenzaA/PR/8/34 em vetor pShuttle-CMV (Ad-CMV-HA + agonista TLR-3)
13
taacatcatc aataatatac cttattttgg attgaagcca atatgataát gagggggtgg 60agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagt gtggcggaag 120tgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgttt 180ttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttag gcggatgttg 240tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataaga 300ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgta atagtaatca 360attacggggt cattagttca tagcccatat atggagttcc gcgttacata acttacggta 420aatggcccgc ctggctgacc gcccaacgac ccccgcccat tgacgtcaat aatgacgtat 480gttcccatag taacgccaat agggactttc cattgacgtc aatgggtgga gtatttacgg 540taaactgccc acttggcagt acatcaagtg tatcatatgc caagtacgcc ccctattgac 600gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt acatgacctt atgggacttt 660cctacttggc agtacatcta cgtattagtc átcgctatta ccatggtgat gcggttttgg 720cagtacatca atgggcgtgg atagcggttt gactcacggg gatttccaag tctccacccc 780attgacgtca atgggagttt gttttggcac caaaatcaac gggactttcc aaaatgtcgt 840aacaactccg ccccattgac gcaaatgggc ggtaggcgtg tacggtggga ggtctatata 900agcagagctg gtttagtgaa ccgtcagatc cgctagagat ctggtaccga gctcggatcc 960gccaccatgg aggcaaacct actggtcctg ttatgtgcac ttgcagctgc agatgcagac 1020acaatatgta taggctacca tgcgaacaat tcaaccgaca ctggtgacac agtactcgag 1080aagaatgtga cagtgacaca ctctgttaac ctgctcgaag acagccacaa cggaaaacta 1140tgtagattaa aaggaatagc cccactacaa ttggggaaat gtaacatcgc cggatggctc 1200ttgggaaacc cagaatgcga cccactgctt ccagtgagat catggtccta cattgtagaa 1260acaccaaact ctgagaatgg aatatgttat ccaggagatt tcatcgacta tgaggagctg 1320agggagcaat tgagctcagt gtcatcattc gaaagattcg aaatatttcc caaagaaagc 1380tcatggccca accacaacac aaccaaagga gtaacggcag catgctccca tgcggggaaa 1440
<210><211><212><213><220><223>
<400>agcagttttt acagaaattt gctatggctg acggagaagg agggctcata cccaaagctg 1500aaaaattctt atgtgaacaa gaaagggaaa gaagtccttg tactgtgggg tattcatcac 1560ccgtctaaca gtaaggatca acagaatatc tatcagaatg aaaatgctta tgtctctgta 1620gtgacttcaa attataacag gagatttacc ccggaaatag cagaaagacc caaagtaaga 1680gatcaagctg ggaggatgaa ctattactgg accttgctaa aacccggaga cacaataata 1740tttgaggcaa atggaaatct aatagcacca aggtatgctt tcgcactgag tagaggcttt 1800gggtccggca tcatcacctc aaacgcatca atgcatgagt gtaacacgaa gtgtcaaaca 1860cccctgggag ctataaacag cagtctccct ttccagaata tacacccagt cacaataggã 1920gagtgcccaa aatacgtcag gagtgccaaa ttgaggatgg ttacaggact aaggaacatt 1980ccgtccattc aatccagagg tctatttgga gccattgccg gttttattga agggggatgg 2040actggaatga tagatggatg gtacggttat catcatcaga atgaacaggg atcaggctat 2100gcagcggatc aaaaaagcac acaaaatgcc attaacggga ttacaaacâa ggtgaactct 2160gttatcgaga aaatgaacat tcaattcaca gctgtgggta aagaattcaa caaattagaa 2220aaaaggatgg aaaatttaaa taaaaaagtt gatgatggat ttctggacat ttggacatat 2280aatgcagaat tgttagttct actggaaaat gaaaggactc tggatttcca tgactcaaat 2340gtgaagaatc tgtatgagaa agtaaaaagc caattaaaga ataatgccaa agaaatcgga 2400aatggatgtt ttgagttcta ccacaagtgt gacaatgaat gcatggaaag· tgtaagaaat 24 60gggacttatg attatcccaa atattcagaa gagtcaaagt tgaacaggga aaaggtagat 2520ggagtgaaat tggaatcaat ggggatctat cagattotgg cgatctactc aactgtcgcc 2580agttcactgg tgcttttggt ctccctgggg gcaatcagtt tctggatgtg ttctaatgga 2640tctttgcagt gcagaatatg catctgagat tagaatttca gagatatgag gaaaaacacc 2700cttgtttcta ctcccaagct ttaatgcggt agtttatcac agttaaattg ctaacgcagt 2760caggcaccgt gtatgaaatc taacaatgcg ctcatcgtca tcctcggcac cgtcaccctg 2820gatgctgtag gcataggctt ggttatgccg gtactgccgg gcctcttgcg ggatgggcgg 2880ccgctegagc ctaagcttct agataagata tccgatccac cggatctaga taactgatca 2940taatcagcca taccacattt gtagaggttt tacttgcttt aaaaaacctc ccacacctcc 3000ccctgaacct gaaacataaa atgaatgcaa ttgttgttgt taacttgttt attgcagctt 3060ataatggtta caaataaagc aatagcatca caaatttcac aaataaagca tttttttcac 3120tgcattctag ttgtggtttg tccaaactca tcaatgtatc ttaacgcgga tctgggcgtg 3180gttaagggtg ggaaagaata tataaggtgg gggtcttatg tagttttgta tctgttttgc 3240agcagccgcc gccgccatga gcaccaactc gtttgatgga agdattgtga gctcatattt 3300gacaacgcgc atgcccccat gggccggggt gcgtcagaat gtgatgggct ccagcattga 3360tggtcgcccc gtcctgcccg caaactctac taccttgacc tacgagaccg tgtctggaac 3420gccgttggag actgcagcct ccgccgccgc ttcagccgct gcagccaccg cccgcgggat 3480tgtgactgac tttgctttcc tgagcccgct tgcaagcagt gcagcttccc gttcatccgc 3540ccgcgatgac aagttgacgg ctcttttggc acaattggat tctttgaccc gggaacttaa 3600tgtçgtttct cagcagctgt tggatctgcg ccagcaggtt tctgccctga aggcttcctc 3660ccctcccaat gcggtttaaa acataaátaa aaaaccagac tctgtttgga tttggatcaa 3720gcaagtgtct tgctgtcttt atttaggggt tttgcgcgcg cggtaggccc gggaccagcg 3780gtctcggtcg ttgagggtcc tgtgtatttt ttccaggacg tggtaaaggt gactctggat 3840gttcagatac atgggcataa gcccgtctct ggggtggagg tagcaccact gcagagcttc 3900atgctgcggg gtggtgttgt agatgatcca gtcgtagcag gagcgctggg cgtggtgcct 3960aaaaatgtct ttcagtagca agctgattgc caggggcagg cccttggtgt aagtgtttac 4020aaagcggtta agctgggatg ggtgcatacg tggggatatg agatgcatct tggactgtat 4080ttttaggttg gctatgttcc cagccatatc cctccgggga ttcatgttgt gcagaaccac 4140cagcacagtg tatccggtgc acttgggaaa tttgtcatgt agcttagaag gaaatgcgtg 4200gaagaacttg gagacgccct tgtgacctcc aagattttcc atgcattcgt ccataatgat 4260ggcaatgggc ccacgggcgg cggcctgggc gaagatattt ctgggatcac taacgtcata 4320gttgtgttcc aggatgagat cgtcataggc catttttaca aagcgcgggc ggagggtgcc 4 380agactgcggt ataatggttc catccggccc aggggcgtag ttaccctcac agatttgcat 4440ttcccacgct ttgagttcag atggggggat catgtctacc tgcggggcga tgaagaaaac 4500ggtttccggg gtaggggaga tcagctggga agaaagcagg ttcctgagca gctgcgactt 4560accgcagccg gtgggcccgt aaatcacacc tattaccggg tgcaactggt agttaagaga 4 620gctgcagctg ccgtcatccc tgagcagggg ggccacttcg ttaagcatgt ccctgactcg 4680catgttttcc ctgaccaaat ccgccagaag gcgctcgccg cccagcgata gcagttcttg 4740caaggaagca aagtttttca acggtttgag accgtccgcc gtaggcatgc ttttgagcgt 4800ttgaccaagc agttccaggc ggtcccacag ctcggtcacc tgctctacgg catctcgatc 4860cagcatatct cctcgtttcg cgggttgggg cggctttcgc tgtacggcag tagtcggtgc 4 920tcgtccagac gggccagggt catgtctttc cacgggcgca gggtcctcgt cagcgtagtc 4 980tgggtcacgg tgaaggggtg cgctccgggc tgcgcgctgg ccagggtgcg cttgaggctg 5040gtcctgctgg tgctgaagcg ctgccggtct tcgccctgcg cgtcggccag gtagcatttg 51Ό0accatggtgt catagtccag cccctccgcg gcgtggccct tggcgcgcag cttgcccttg 5160gaggaggcgc cgcacgaggg gcagtgcaga cttttgaggg cgtagagctt gggcgcgaga 5220aataccgatt ccggggagta ggcatccgcg ccgcaggccc cgcagacggt ctcgcattcc 5280acgagccagg tgagctctgg ccgttcgggg tcaaaaacca ggtttccccc atgctttttg 5340atgcgtttct tacctctggt ttccatgagc cggtgtccac gctcggtgac gaaaaggctg 5400tccgtgtccc cgtatacaga cttgagaggg agtttaaacg aattcaatag cttgttgcat 5460gggcggcgat ataaaatgca aggtgctgct caaaaaatca ggcaaagcct cgcgcaaaaa 5520agaaagcaca tcgtagtcat gctcatgcag ataaaggcag gtaagctccg gaaccaccac 5580agaaaaagac accatttttc tctcaaacat gtctgcgggt ttctgcataa acacaaaata 5640aaataacaaa aaaacattta aacattagaa gcctgtctta caacaggaaa aacaaccctt 5700ataagcataa gàcggactac ggccatgccg gcgtgaccgt aaaaaaactg gtcaccgtga 5760ttaaaaagca ccaccgacag ctcctcggtc atgtccggag tcataatgta agactcggta 5820aacacatcag gttgattcat cggtcagtgc taaaaagcga ccgaaatagc ccgggggaat 5880acatacccgc aggcgtagag acaacattac agcccccata ggaggtataa caaaattaat 5940aggagagaaa aacacataaa cacctgaaaa accctcctgc ctaggcaaaa tagcaccctc 6000ccgctccaga acaacataca gcgcttcaca gcggcagcct aacagtcagc cttaccagta 6060aaaaagaaaa cctattaaaa aaacaccact cgacacggca ccagctcaat cagtcacagt 6120gtaaaaaagg gccaagtgca gagcgagtat atataggact aaaaaatgac gtaacggtta 6180aagtccacaa aaaacaccca gaaaaccgca cgcgaaccta cgcccagaaa cgaaagccaa 6240aaaacccaca acttcctcaa atcgtcactt ccgttttccc acgttacgta acttcccatt 6300ttaagaaaac tacaattccc aacacataca agttactccg ccctaaaacc tacgtcaccc 6360gccccgttcc cacgccccgc gccacgtcac aaactccacc ccctcattat catattggct 6420tcaatccaaa ataaggtata ttattgatga tgttaattaa catgcatgga tccatatgcg 6480gtgtgaaata ccgcacagat gcgtaaggag aaaataccgc atcaggcgct cttccgcttc 6540ctcgctcact gactcgctgc gctcggtcgt tcggctgcgg cgagcggtat cagctcactc 6600aaaggcggta atacggttat ccacagaatc aggggataac gcaggaaaga acatgtgagc 6660aaaaggccag caaaaggcca ggaaccgtaa aaaggccgcg ttgctggcgt ttttccatag 6720gctcçgccçc cctgaçgagc atcacaaaaa tcgacgctca agtcagaggt ggcgaaaccc 6780gacaggacta taaagatacc aggcgtttcc ccctggaagc tccctcgtgc gctctcctgt 6840tccgaccctg ccgcttaccg gatacctgtc cgcctttctc ccttcgggaa gcgtggcgct 6900ttctcatagc tcacgctgta ggtatctcag ttcggtgtag gtcgttcgct ccaagctggg 6960ctgtgtgcac gaaccccccg ttcagcccga ccgctgcgcc ttatccggta actatcgtct 7020tgagtccaac ccggtaagac acgacttatc gccactggca gcagccactg gtaacaggat 7080tagcagagcg aggtatgtag gcggtgctac agagttcttg aagtggtggc ctaactacgg 7140ctacâctaga aggacagtat ttggtatctg cgctctgctg aagccagtta ccttcggaaa 7200aagagttggt agctcttgat ccggcaaaca aaccaccgct ggtagcggtg gtttttttgt 7260ttgcaagcag cagattacgc gcagaaaaaa aggatctcaa gaagatcctt tgatcttttc 7320tacggggtct gacgctcagt ggaacgaaaa ctcacgttaa gggattttgg tcatgagatt 7380atcaaaaagg atcttcacct agatcctttt aaattaaaaa tgaagtttta aatcaatcta 7440aagtatatat gagtaaactt ggtctgacag ttaccaatgç ttaatcagtg aggcacctat 7500ctcagcgatc tgtctatttc gttcatccat agttgcctga ctccccgtcg tgtagataac 7560tacgatacgg gagggcttac catctggccc cagtgctgca atgataccgc gagacccacg 7620ctcaccggct ccagatttat cagcaataaa ccagccagcc ggaagggccg agcgcagaag 7 680tggtcctgca actttatccg cctccatcca gtctattaat tgttgccggg aagctagagt 7740aagtagttcg ccagttaata gtttgcgcaa cgttgttgcc attgctgcag ccatgagatt 7800atcaaaaagg atcttcacct agatcctttt cacgtagaaa gccagtccgc agaaacggtg 7860ctgaccccgg atgaatgtca gctactgggc tatctggaca agggaaaacg caagcgcaaa 7920gagaaagcag gtagcttgca gtgggcttac atggcgatag ctagactggg cggttttatg 7980gacagcaagc gaaccggaat tgccagctgg ggcgccctct ggtaaggttg ggaagecctg 8040caaagtaaac tggatggctt tctcgccgcc aaggatctga tggcgcaggg gatcaagctc 8100tgatcaagag acaggatgag gatcgtttcg catgattgaa caagatggat tgcacgcagg 8160ttctccggcc gcttgggtgg agaggctatt cggctatgac tgggcacaac agacaatcgg 8220ctgctctgat gccgccgtgt tccggctgtc agcgcagggg cgcccggttc tttttgtcaa 8280gaccgaicctg tccggtgccc tgaatgaact gcaagacgag gcagcgcggc tatcgtggct 8340ggccacgacg ggcgttcctt gcgcagctgt gctcgacgtt gtcactgaag cgggaaggga 8400ctggctgcta ttgggcgaag tgccggggca ggatctcctg tcatctcacc ttgctcctgc 8460cgagaaagta tccatcatgg ctgatgcaat gcggcggctg catacgcttg atccggctac 8520ctgcccattc gaccaccaag cgaaacatcg catcgagcga gcacgtactc ggatggaagc 8580cggtcttgtc gatcaggatg atctggacga agagcatcag gggctcgcgc cagccgaact 8640gttcgccagg ctcaaggcga gcatgcccga cggcgaggat ctcgtcgtga cccatggcga 8700tgcctgcttg ccgaatatca tggtggaaaa tggccgcttt tctggattca tcgactgtgg 8760ccggctgggt gtggcggacc gctatcagga catagcgttg gctacccgtg atattgctga 8820agagcttggc ggcgaatggg ctgaccgctt cctcgtgctt tacggtatcg ccgctcccga 8880ttcgcagcgc atcgccttct atcgccttct tgacgagttc ttctgaattt tgttaaaatt 8940tttgttaaat cagctcattt tttaaccaat aggccgaaat cggcaacatc ccttataaat 9000caaaagaata gaccgcgata gggttgagtg ttgttccagt ttggaacaag agtccactat 9060taaagaacgt ggactccaac gtcaaagggc gaaaaaccgt ctatcagggc gatggcccac 9120tacgtgaacc atcacccaaa tcaagttttt tgcggtcgag gtgccgtaaa gctctaaatc 9180ggaaccctaa agggagcccc cgatttagag cttgacgggg aaagccggcg aacgtggcga 9240gaaaggaagg gaagaaagcg aaaggagcgg gcgctagggc gctggcaagt gtagcggtca 9300cgctgcgcgt aaccaccaca cccgcgcgct taatgcgccg ctacagggcg cgtccattcg 9360ccattcagga tcgaattaat tcttaat 9387
<210> 14<211> 8473<212> DNA
<213> Seqüência artificial<220>
<223> vetor adenoviral quimérico DS2beta-luc codificando agonista Iuc TLR-3 e promotor da
Ibeta actina humana, vetor shuttle genérico, vetor de clonagem rápido<400> 14
taacatcatc aataatatac cttattttgg attgaagcca atatgataat gagggggtgg 60agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagt gtggcggaag 120tgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgttt 180ttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttag gcggatgttg 240tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataaga 300ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgct agagatctgg 360cgaaaggggg atgtgctgca aggcgattaa gttgggtaac gccagggttt tcccagtcac 420gacgttgtaa aacgacggcc agtgaattgt aatacgactc actatagggc gaattgggta 480ctggccacag agcttggccc attgcatacg ttgtatccat atcataatat gtacatttat 540attggctcat gtccaacatt accgccatgt tgacattgat tattgactag ttattaatag 600taatcaatta cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt 660acggtaaatg gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg 720acgtatgttc ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat 780ttacggtaaa ctgcccactt ggcagtacat caagtgtatc atatgccaag tacgccccct 840attgacgtca atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttatgg 900gactttccta cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg 960ttttggcagt acatcaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc 1020caccccattg acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa 1080tgtcgtaaca actccgccçc attgacgcaa atgggcggta ggcgtgtacg gtgggaggtc 1140tatataagca gagctcgttt agtgaaccgt cagatcgcct ggagacgcca tccacgctgt 1200tttgacctcc atagaagaca ccgggaccga tccagcctga ctctagccta gctctgaagt 1260tggtggtgag gccctgggca ggttggtatc aaggttacaa gacaggttta aggagaccaa 1320tagaaactgg gcatgtggag acagagaaga ctcttgggtt tctgataggc actgactctc 1380tctgcctatt ggtctatttt cccaccctta ggctgctggt ctgagcctag gagatctctc 1440gaggtcgacg gtatcgatgg gtaccggcgg ecgccctatt ctatagtgtc acctaaatgc 1500tagagctcgc tgatcagcct cgactgtgcc ttctagttgc cagccatctg ttgtttgccc 1560ctcccccgtg ccttccttga ccctggaagg tgccactccc actgtccttt cctaataaaa 1620tgaggaaatt gcatcgcatt gtctgagtag gtgtcattct attctggggg gtggggtggg 1680gcaggacagc aagggggagg attgggaaga caatagcagg catgctgggg atgcggtggg 1740ctctatggct tctgaggcgg aaagaaccta tggcttctga ggcggaaaga accaaccacc 1800gcggtggcgg ccgccacaca aaaaaccaac acacagatgt aatgaaaata aagatatttt 1860atttctagag aaacgatatg ggctgaatac ggatccgtat tcagcccata tcgtttcctg 1920caggaattcg ccctttagat atcatcgatg tctcggcggt ggtggcgcgt cgcgccgctg 1980ggttttatag ggcgccgccg cggccgctcg agccataaaa ggcaactttc ggaacggcgc 2040acgctgattg gccccgcgcc gctcactcac cggcttcgcc gcacagtgca gcattttttt 2100accccctctc ccctcctttt gcgaaaaaaa aaaagagcga gagcgagatt gaggaagagg 2160aggagggaga gttttggcgt tggccgcctt ggggtgctgg gcgtcgacga tatctaaggg 2220cgaattcgat atcaagctag cttgtcgact cgaagatctg ggcgtggtta agggtgggaa 2280agaatatata aggtgggggt cttatgtagt tttgtatctg ttttgcagca gccgccgccg 2340ccatgagcac caactcgttt gatggaagca ttgtgagctc atatttgaca acgcgcatgc 2400ccccatgggc cggggtgcgt cagaatgtga tgggctccag cattgatggt cgccccgtcc 2460tgcccgcaaa ctctactacc ttgacctacg agaccgtgtc tggaacgccg ttggagactg 2520cagcctccgc cgccgcttca gccgctgcag ccaccgcccg cgggattgtg actgactttg 2580ctttcctgag cccgcttgca agcagtgcag cttcccgttc atccgcccgc gatgacaagt 2640tgacggctct tttggcacaa ttggattctt tgacccggga acttaatgtc gtttctcagc 2700agctgttgga tctgcgccag caggtttctg ccctgaaggc ttcctcccct cccaatgcgg 2760tttaaaacat aaataaaaaa ccagactctg tttggatttg gatcaagcaa gtgtcttgct 2820gtctttattt aggggttttg cgcgcgcggt aggcccggga ccagcggtct cggtcgttga 2880gggtcctgtg tattttttcc aggacgtggt aaaggtgact ctggatgttc agatacatgg 2940gcataagccc gtctctgggg tggaggtagc accactgcag agcttcatgc tgcggggtgg 3000tgttgtagat gatccagtcg tagcaggagc gctgggegtg gtgcctaaaa atgtctttca 3060gtagcaagct gattgccagg ggcaggccct tggtgtaagt gtttacaaag cggttaagct 3120gggatgggtg catacgtggg gatatgagat gcatcttgga ctgtattttt aggttggcta 3180tgttcccagc catatccctc cggggattca tgttgtgcag aaccaccagc acagtgtatc 3240cggtgcactt gggaaatttg tcatgtagct tagaaggaaa tgcgtggaag aacttggaga 3300cgcccttgtg acctccaaga ttttccatgc attcgtccat aatgatggca atgggcccac 3360A gggcggcgge etgggcgaag atatttctgg gatcactaac gtcatagttg tgttccagga 3420Mtgagatcgtc ataggccatt tttacaaagc gegggcggag ggtgccagac tgcggtataa 3480^ tggttccatc cggeccaggg gcgtagttac cetcacagat ttgcatttcc cacgctttga 3540gttcagatgg ggggatcatg tctacctgcg gggcgatgaa gaaaacggtt tccggggtag 3600gggagatcag ctgggaagaa agcaggttcc tgagcagctg çgacttacçg cagccggtgg 3660gcccgtaaat cacacctatt accgggtgca actggtagtt aagagagctg cagctgecgt 3720catccctgag caggggggcc acttcgttaa gcatgtccct gactcgcatg ttttccctga 3780çcaaatccgc cagaaggcgc tcgccgccca gcgatagcag ttcttgcaag gaagcaaagt 3840ttttcaacgg tttgagaccg tccgccgtag gcatgctttt gagcgtttga ecaagcagtt 3900ccaggcggtc ccacagctcg gtcacctgct ctacggcatc tcgatccagc atatctcctc 3960gtttcgcggg ttggggcggc tttcgctgta cggcagtagt cggtgctcgt ccagacgggc 4020cagggtcatg tctttccacg ggcgeagggt ectcgtcagc gtagtctggg tcaçggtgaa 4080ggggtgcgct ccgggctgcg cgetggccag ggtgcgcttg aggctggtcc tgctggtgct 4140gaagcgctgc cggtcttcgc cctgcgcgtc ggccaggtag catttgacca tggtgtcata 4200gtccagcccc tccgcggcgt ggcccttggc gcgcágcttg cccttggagg aggcgccgca 4260cgaggggcag tgcagacttt tgagggcgta gagcttgggc gcgagaaata ccgattccgg 4 320ggagtaggca tccgcgccgc aggccecgca gacggtctcg cattceacga gccaggtgag 4380ctctggccgt tcggggteaa aaaccaggtt tcccccatgc tttttgatgc gtttcttacc 44 40tctggtttcc atgagccggt gtccacgctc ggtgacgaaa aggctgtccg tgtccccgta 4500tacagacttg agagggagtt taaacgaatt caàtagcttg ttgcatgggc ggcgatataa 4560aatgcaaggt gctgctcaaa aaatcaggca aagcctcgcg caaaaaagaa agcacatcgt 4 620agtcatgctc atgcagataa aggcaggtaa gctcçggaac caccacagaa aaagacacca 4680tttttctctc aaacatgtct gcgggtttct gcataaacac aaaataaaat aacaaaaaaa 4740catttaaaca ttagaagcct gtcttacaac aggaaaaaca acccttataa gcataagacg 4800gactacggcc atgccggcgt gaccgtaaaa aaactggtca ccgtgattaa aaagcaccac 4860cgacagctcc tcggtcatgt ccggagtcat aatgtaagac tcggtaaaca catcaggttg 4920attcatcggt cagtgctaaa aagcgaccga aatagcccgg gggaatacat acccgcaggc 4980gtagagacaa cattacagcc cccataggag gtataacaaa attaatagga gagaaaaaca 5040cataaacacc tgaaaaaccc tcctgcctag gcaaaatagc accctcccgc tccagaacaa 5100catacagcgc ttcacagcgg cagcctaaca gtcagcctta ccagtaaaaa agaaaaccta 5160ttaaaaaaac aceactcgac acggcaccag ctcaatcagt cacagtgtaa aaaagggcca 5220agtgcagagc gagtatatat aggactaaaa aatgacgtaa cggttaaagt ecacaaaaaa 5280cacccagaaa accgcacgcg aacctacgcc cagaaacgaa agccaaaaaa cccacaactt 534 0cctcaaatcg tcacttccgt tttcccacgt tacgtaactt cccattttaa gaaaactaca 5400attcccaaca catacaagtt actccgccct aaaacetacg tcaccegccc cgttcccacg 5460cccegcgcca cgtcacaaac tccaccccct cattatcata ttggcttcaa tccaaaataa 5520ggtatattat tgatgatgtt aattaacatg catggatcca tatgcggtgt gaaataccgc 5580acagatgcgt aaggagaaaa taccgcatca ggcgctcttc cgcttcctcg ctcactgact 5640cgctgcgctc ggtcgttcgg ctgcggcgag cggtatcagc tcactcaaag gcggtaatac 5700ggttatccac agaatcaggg gataacgcag gaaagaacat gtgagcaaaa ggccagcaaa 5760aggccaggaa ccgtaaaaag gccgcgttgc tggcgttttt ccataggctc cgcccccctg 5820acgagcatca caaaaatcga cgctcaagtc agaggtggcg aaacccgaca ggactataaa 5880gataccaggc gtttccccct ggaagctccc tcgtgcgctc tcctgttccg accctgccgc 5940ttaccggata cctgtccgcc tttctccctt cgggaagcgt ggcgctttct catagctcac 6000gctgtaggta tctcagttcg gtgtaggtcg ttcgctccaa gctgggctgt gtgcacgaac 6060cccccgttca gcccgaccgc tgcgccttat ccggtaacta tcgtcttgag tccaacccgg 6120taagacacga cttatcgcca ctggcagcag ccactggtaa caggattagc agagcgaggt 6180atgtaggcgg tgctacagag ttcttgaagt ggtggcctaa ctacggctac actagaagga 6240cagtatttgg tatctgcgct ctgctgaagc cagttacctt cggaaaaaga gttggtagct 6300cttgatccgg caaacaaacc accgctggta gcggtggttt ttttgtttgc aagcagcaga 6360ttacgcgcag aaaaaaagga tctcaagaag atcctttgat cttttctacg gggtctgacg 6420ctcagtggaa cgaaaactca cgttaaggga ttttggtcat gagattatca aaaaggatct 6480tcacctagat ccttttaaat taaaaatgaa gttttaaatc aatctaaagt atatatgagt 6540aaacttggtc tgacagttac caatgcttaa tcagtgaggc acctatctca gcgatctgtc 6600tatttcgttc atccatagtt gcctgactcc ccgtcgtgta gataactacg atacgggagg 6660gcttaccatc tggccccagt gctgcaatga taccgcgaga cccacgctca ccggctccag 6720atttatcagc aataaaccag ccagccggaa gggccgagcg cagaagtggt cctgcàactt 6780tatccgcctc catccagtct attaattgtt gccgggaagc tagagtaagt agttcgccag 6840ttaatagttt gcgcaacgtt gttgccattg ctgcagccat gagattatca aaaaggatct 6900tcacctagat ccttttcacg tagaaagcca gtccgcagaa acggtgctga ccccggatga 6960atgtcagcta ctgggctatc tggacaaggg aaaacgcaag cgcaaagaga aagcaggtag 7020cttgcagtgg gcttacatgg cgatagctag actgggcggt tttatggaca gcaagcgaac 7080cggaattgcc agctggggcg ccctctggta aggttgggaa gccctgcaaa gtaaactgga 7140tggctttctc gccgccaagg atctgatggc gcaggggatc aagctctgat caagagacag 7200gatgaggatc gtttcgcatg attgaacaag atggattgca cgcaggttct ccggccgctt 7260gggtggagag gctattcggc tatgactggg cacaacagac aatcggctgc tctgatgccg 7320ccgtgttccg gctgtcagcg caggggcgcc cggttctttt tgtcaagacc gacctgtccg 7380gtgccctgaa tgaactgcaa gacgaggcag cgcggctatc gtggctggcc acgacgggcg 7440ttccttgcgc agctgtgctc gacgttgtca ctgaagcggg aagggactgg ctgctattgg 7500gcgaagtgcc ggggcaggat ctcctgtcat ctcaccttgc tcctgccgag aaagtatcca 7560tcatggctga tgcaatgcgg cggctgcata cgcttgátcc ggctacctgc ccattcgacc 7620accaagcgaa acatcgcatc gagcgagcac gtactcggat ggaagccggt cttgtcgatc 7680aggatgatct ggacgaagag catcaggggc tcgcgccagc cgaactgttc gccaggctca 7740aggcgagcat gcccgacggc gaggatctcg tcgtgaccca tggcgatgcc tgcttgccga 7800atatcatggt ggaaaatggc cgcttttctg gattcatcga ctgtggccggctgggtgtgg 7860cggaccgcta tcaggacata gcgttggcta cccgtgatat tgctgaagag cttggcggcg 7920aatgggctga ccgcttcctc gtgctttacg gtátcgccgc tcccgattcg cagcgcàtcg 7980ccttctatcg ccttcttgac gagttcttct gaattttgtt aaaatttttg ttaaatcagc 804 0tcatttttta accaataggc cgaaatcggc aacatccctt ataaatcaaa agaatagacc 8100gçgatagggt tgagtgttgt tccagtttgg aacaagagtc cactattaaa gaacgtggac 8160tccaacgtca aagggcgaaa aaccgtctat cagggcgatg gcccactacg tgaaccatca 8220cccaaatcaa gttttttgcg gtcgaggtgc cgtaaagctc taaatcggaa ccctaaaggg 8280agcccccgat ttagagcttg acggggaaag ccggcgaacg tggcgagaaa ggaagggaag 8340aaagcgaaag gagcgggcgc tagggcgctg gcaagtgtag cggtcacgct gcgcgtaacc 8400accacacccg cgcgcttaat gcgccgctac agggcgcgtc cattcgccat tcaggatcga 8460attaattctt aat * 8473
<210> 15<211> 9073<212> DNA
<213> Seqüência artificial<220>
<223> vetor adenoviral quimérico DS2C-luc codificando agonista Iuc TLR-3 e promotor do cito-megalovírus (CMV), vetor shuttle quimérico, vetor de clonagem rápido<400> 15
taacatcatc aataatatac cttattttgg attgaagcca atatgataat gagggggtgg 60agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagt gtggcggaag 120tgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgttt 180ttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttag gcggatgttg 240tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataaga 300ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgct agagatctgg 360cgaaaggggg atgtgctgca aggcgattaa gttgggtaac gccagggttt tcccagtcac 420gaçgttgtaa aacgacggcc agtgaattgt aatacgactc actatagggc gaattgggta 480ctggccacag agcttggccc attgcatacg ttgtatccat atcataatat gtacatttat 540attggctcat gtccaacatt accgccatgt tgacattgat tattgactag ttattaatag 600taatcaatta cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt 660acggtaaatg gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg 720acgtatgttc ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat 780ttacggtaaa ctgcccactt ggcagtacat caagtgtatc atatgccaag tacgccccct 840attgacgtca atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttatgg 900gactttccta cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg 960ttttggcagt acatcaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc 1020caccccattg acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa 1080tgtcgtaaca actccgcccc attgacgcaa atgggcggta ggcgtgtacg gtgggaggtc 1140tatataagca gagctcgttt agtgaaccgt cagatcgcct ggagacgcca tccaegctgt 1200tttgacctcc atagaagaca ccgggaccga tccagcctga ctctagccta gctctgaagt 1260tggtggtgag gccctgggca ggttggtatc aaggttacaa gacaggttta aggagaccaa 1320tagaaactgg gcatgtggag acagagaaga ctcttgggtt tctgataggc actgactctc 1380tctgcctatt ggtctatttt cccaccctta ggctgctggt ctgagcctag gagatctctc 1440gaggtcgacg gtatcgatgg gtaccggcgg ccgccctatt ctatagtgtc acctaaatgc 1500tagagctcgc tgatcagcct cgactgtgcc ttctagttgc cagccatctg ttgtttgccc 1560ctcccccgtg ccttccttga ccctggaagg tgccactccc actgtccttt cctaataaaa 1620tgaggaaatt gcatcgcatt gtctgagtag gtgtcattct attctggggg gtggggtggg 1680gcaggacagc aagggggagg attgggaaga caatagcagg catgctgggg atgcggtggg 1740ctctatggct tctgaggcgg aaagaaccaa agcttaggct cgagcggccg ccacacaaaa 1800aaccaacaca cagatgtaat gaaaataaag atattttatt tctagagáaa cgatatgggc 1860tgaatacgga tccgtattca gcccatatcg tttcccagat ctctagcgga tctgacggtt 1920cactaaacca gctctgctta tatagacctc ccaccgtaca cgcctaccgc ccatttgcgt 1980caatggggcg gagttgttac gacattttgg aaagtcccgt tgattttggt gccaaaacaa 2040actcccattg acgtcaatgg ggtggagact tggaaatccc cgtgagtcaa accgctatcc 2100acgcccattg atgtactgcc aaaaccgcat caccatggta atagcgatga ctaatacgta 2160gatgtactgc caagtaggaa agtcccataa ggtcatgtac tgggcataat gccaggcggg 2220ccatttaccg tcattgacgt cáataggggg cgtaçttggc atatgataca cttgatgtac 2280tgccaagtgg gcagtttacc gtaaatactc cacccattga cgtcaatgga aagtccctat 2340tggcgttact atgggaacat acgtcattat tgacgtcaat gggcgggggt cgttgggcgg 2400tcagccaggc gggccattta ccgtaagtta tgtaacgcgg aactccatat atgggctatg 24 60aactaatgac cccgtaattg attactatta cagtattacg cgctatgagt aacacaaaat 2520tattcagatt tcacttcctc ttattcagtt ttcccgcgaa aatggccaaa tcttactcgg 2580ttacgcccaa atttactaca acatccgcct aaaaccgcgc gaaaattgtc acttcctgtg 2640tacaccggcg cacaccaaaa acgtcacttt tgccacatcc gtcgcttaca tgtgttccgc 2700caòacttgca acatcacact tccgccacac tactacgtca cccgccccgt tcccacgccc 2760cgcgccacgt cacaaactcc accccctcat tatcatattg gcttcaatcc aaaataaggt 2820atattattga tgatgttaag cttgtcgact cgaagatctg ggcgtggtta agggtgggaa 2880agaatatata aggtgggggt cttatgtagt tttgtatctg ttttgcagca gccgccgccg 2940ccatgagcac caactcgttt gatggaagca ttgtgagctc atatttgaca acgcgcatgc 3000ceccatgggc cggggtgcgt cagaatgtga tgggctccag cattgatggt cgccccgtcc 3060tgcccgcaaa ctctactacc ttgacctacg agaccgtgtc tggaacgccg ttggagactg 3120cagcctccgc cgccgcttca gccgctgcag ccaccgcccg cgggattgtg actgactttg 3180ctttcctgag cccgcttgca agcagtgcag cttcccgttc atccgcccgc gatgacaagt 3240tgacggctct tttggcacaa ttggattctt tgacccggga acttaatgtc gtttctcagc 3300agctgttgga tctgcgccag caggtttctg ccctgaaggc ttcctcccct cccaatgcgg 3360tttaaaacat aaataaaaaa ccagactctg tttggatttg gatcaagcaa gtgtcttgct 3420gtctttattt aggggttttg cgcgcgcggt aggcccggga ccagcggtct cggtcgttga 3480gggtcctgtg tattttttcc aggacgtggt aaaggtgact ctggatgttc agatacatgg 3540gcataagccc gtctctgggg tggaggtagc accactgcag agcttcatgc tgcggggtgg 3600tgttgtagat gatccagtcg tagcaggagc gctgggcgtg gtgcctaaaa atgtctttca 3660gtagcaagct gattgccagg ggcaggccct tggtgtaagt gtttacaaag cggttaagct 3720gggatgggtg catacgtggg gatatgagat gcatcttgga ctgtattttt aggttggcta 3780tgttcccagc catatccctc cggggattca tgttgtgcag aaccaccagc acagtgtatc 3840cggtgcactt gggaaatttg tcatgtagct tagaaggaaa tgcgtggaag aacttggaga 3900cgcccttgtg acctccaaga ttttccatgc attcgtccat aatgatggca atgggcccac 3960gggcggcggc ctgggcgaag atatttctgg gatcactaac gtcatagttg tgttccagga 4020tgagatcgtc ataggccatt tttacaaagc gcgggcggag ggtgccagac tgcggtataa 4080tggttccatc cggcccaggg gcgtagttac cctcacagat ttgcatttcc cacgctttga 4140gttcagatgg ggggatcatg tctacctgcg gggcgatgaa gaaaacggtt tccggggtag 4200gggagatcag ctgggaagaa agcaggttcc tgagcagctg cgacttaccg cagccggtgg 4260gcccgtaaat cacacctatt accgggtgca actggtagtt aagagagctg cagctgccgt 4320catccctgag caggggggcc acttcgttaa gcatgtccct gactcgcatg ttttccctga 4380ccaaatccgc cagaaggcgc tcgccgccca gcgatagcag ttcttgcaag gaagcaaagt 4440ttttcaacgg tttgagaccg tccgccgtag gcatgctttt gagcgtttga ccaagcagtt 4500ccaggcggtc ccacagctcg gtcacctgct ctacggcatc tcgatccagc atatctcctc 4560gtttcgcggg ttggggcggc tttcgctgta cggcagtagt cggtgctcgt ccagacgggc 4620cagggtcatg tctttccacg ggcgcagggt cctcgtcagc gtagtctggg tcacggtgaa 4680ggggtgcgct ccgggctgcg cgctggccag ggtgcgcttg aggctggtcc tgctggtgct 4740gaagcgctgc cggtcttcgc cctgcgcgtc ggccaggtag catttgacca tggtgtcata 4800gtccagcccc tecgcggcgt ggcccttggc gcgcagcttg cccttggagg aggcgccgca 4860cgaggggcag tgcagacttt tgagggcgta gagcttgggc gcgagaaata ccgattccgg 4920ggagtaggca tccgcgocgc aggccccgca gacggtctcg cattccacga gccaggtgag 4980ctctggccgt tcggggtcaa aaaccaggtt tcccccatgc tttttgatgc gtttcttacc 5040tctggtttcc atgagccggt gtccacgctc ggtgacgaaa aggctgtccg tgtccccgta 5100""tacagacttg agagggagtt taaacgaatt caatagcttg ttgcatgggc ggcgatataa 5160aatgcaaggt gctgctcaaa aaatcaggca aagcctcgcg caaaaaagaa agcacatcgt 5220agtcatgctc atgcagataa aggcaggtaa gctccggaac caccacagaa aaagacacca 5280*tttttctctc aaacatgtct gcgggtttct gcataaacac aaaataaaat aacaaaaaaa 5340catttaaaca ttagaagcçt gtcttacaac aggaaaaaca acccttataa gcataagacg 5400gactacggcc atgccggcgt gaccgtaaaa aaactggtca ccgtgattaa aaagcaccac 5460cgacagctcc tcggtcatgt ccggagtcat aatgtaagac tcggtaaaca catcaggttg 5520attcatcggt cagtgctaaa aagcgaccga aatagcccgg gggaatacat acccgcaggc 5580gtagagacaa cattacagcc cccataggag gtataacaaa attaatagga gagaaaaaca 5640cataaacacc tgaaaaaccc tcctgcctag gcaaaatagc accctcccgc tccagaacaa 5700catacagcgc ttcacagcgg cagcctaaca gtcagcctta ccagtaaaaa agaaaacctai 5760ttaaaaaaac accactcgac acggcaccag ctcaatcagt cacagtgtaa aaaagggcca 5820agtgcagagc gagtatatat aggactaaaa aatgacgtaa cggttaaagt ccacaaaaaa 5880cacccagaaa àccgcacgcg aacctacgcc cagaaacgaa agccaaaaaa cccacaactt 5940cctcaaatcg tcacttccgt tttcccacgt tacgtaactt cccattttaa gaaaactaca 6000attcccaaca catacaagtt actccgccct aaaacctacg tcacccgccc cgttcccacg 6060ccccgcgcca cgtcacaaac tccaccccct cattatcata ttggcttcaa tccaaaataa 6120ggtatattat tgatgatgtt aattaacatg catggatcca tatgcggtgt gaaataccgc 6180acagatgcgt aaggagaaaa taccgcatca ggcgctcttc cgcttcctcg ctcactgact 6240cgctgcgctc ggtcgttcgg ctgcggcgag cggtatcagc tcactcaaag gcggtaatac 6300ggttatccac agaatcaggg gataacgcag gaaagaacat gtgagcaaaa ggccagcaaa 6360aggccaggaa ccgtaaaaag gccgcgttgc tggcgttttt ccataggctc cgcccccctg 6420acgagcatca caaaaatcga cgctcaagtc agaggtggcg aaacccgaca ggactataaa 6480gataccaggc gtttccccct ggaagctccc tcgtgcgctc tcctgttccg accctgccgc 6540ttaccggata cctgtccgcc tttctccctt cgggaagcgt ggcgctttct catagctcac 6600gctgtaggta tctcagttcg gtgtaggtcg ttcgctccaã gctgggctgt gtgcacgaac 6660cccccgttca gcccgaccgc tgcgccttat ccggtaacta tcgtcttgag tccaacccgg 6720taagacacga cttatcgcca ctggcagcag ccactggtaa caggattagc agagcgaggt 6780atgtaggcgg tgctacagag ttcttgaagt ggtggcctaa ctacggctac actagaagga 6840cagtatttgg tatctgcgct ctgctgaagc cagttacctt cggaaaaaga gttggtagct 6900cttgatccgg caaacaaacc accgctggta gcggtggttt ttttgtttgc aagcagcaga 6960ttacgcgcag aaaaaaagga tctcaagaag atcctttgat cttttctacg gggtctgacg 7020ctcagtggaa cgaaaactca cgttaaggga ttttggtcat gagattatca aaaaggatct 7080tcacctagat ccttttaaat taaaaatgaa gttttaaatc aatctaaagt atatatgagt 7140aaacttggtc tgacagttac caatgcttaa tcagtgaggc acctatctca gcgatctgtc 7200tatttcgttc atccatagtt gcctgactcc ccgtcgtgta gataactacg atacgggagg 7260gcttaccatc tggccccagt gctgcaatga taccgcgaga cccacgctca ccggctccag 7320atttatcagc aataaaccag ccagccggaa gggccgagcg cagaagtggt cctgcaactt 7380tatccgcctc catccagtct attaattgtt gccgggaagc tagagtaagt agttcgccag 7440ttaatagttt gcgcaacgtt gttgccattg ctgcagccat gagattatca aaaaggatct 7500tcacctagat ccttttcacg tagaaagcca gtccgcagaa acggtgctga ccccggatga 7560atgtcagcta ctgggctatc tggacaaggg aaaacgcaag cgcaaagaga aagcaggtag 7620cttgcagtçg gcttacatgg cgatagctag actgggcggt tttatggaca gcaagcgaac 7 680cggaattgcc agctggggcg ccctctggta aggttgggaa gccctgcaaa gtaaactgga 7740tggctttctc gccgccaagg atctgatggc gcaggggatc aagctctgat caagagacag 7800gatgaggatc gtttcgcatg attgaacaag atggattgca cgcaggttct ccggccgctt 7860gggtggagag gctattcggc tatgactggg cacaacagac aatcggctgc tctgatgccg 7920ccgtgttccg gctgtcagcg caggggcgcc cggttctttt tgtcaagacc gacctgtcçg 7980gtgccctgaa tgaactgcaa gacgaggcag cgcggctatc gtggctggcc acgacgggcg 8040ttccttgcgc agctgtgctc gacgttgtca ctgaagcggg aagggactgg ctgctattgg 8100gcgaagtgçc ggggcaggat ctcctgtcat ctcaccttgc tcctgccgag aaagtatcca 8160tcatggctga tgcaatgcgg cggctgcata cgcttgatcc ggctacctgc ccattcgacc 8220accaagcgãa acatcgcatc gagcgagcac gtactcggat ggaagccggt cttgtcgatc 8280aggatgatct ggacgaagag catcaggggc tcgcgccagc cgaactgttc gccaggctca 8340aggcgagcat gcccgacggc gaggatctcg tcgtgaccca tggcgatgcc tgcttgccga 8400atatcatggt ggaaaatggc cgcttttctg gattcatcga ctgtggccgg ctgggtgtgg 84 60cggaccgcta tcaggacata gcgttggcta cccgtgatat tgctgaagag cttggcggcg 8520aatgggctga ccgcttcctc gtgctttacg gtatcgccgc tcccgattcg cagcgcatcg 8580ccttctatcg ccttcttgac gagttcttct gaattttgtt aaaatttttg ttaaatcagc 8640tcatttttta accaataggc cgaaatcggc aacatccctt ataaatcaaa agaatagacc 8700gcgatagggt tgagtgttgt tccagtttgg aacaagagtc cactattaaa gaacgtggac 8760tccaacgtca aagggcgaaa aaccgtctat cagggcgatg gcccactacg tgaaccatca 8820cccaaatcaa gttttttgcg gtcgaggtgc cgtaaagctc taaatcggaa ccctaaaggg 8880agcccccgat ttagagcttg acggggaaag ccggcgaacg tggcgagaaa ggaagggaag 8940aaagcgaaag gagcgggcgc tagggcgctg gcaagtgtag cggtcacgct gcgcgtaacc 9000accacacccg cgcgcttaat gcgccgctac agggcgcgtc cattcgccat tcaggatcga 9060attaattctt aat 9073
<210> 16<211> 50475<212> DNA
<213> Seqüência artificial<220>
<223> vetor adenoviral quimérico DS2bC-HA codificando agonista Iucl TLR-3, hematoquitininainfluenza (HA) (A/INDO/S/2005; gripe aviária) e promotor do citomegalovírus (CMV), ve-tor shuttle<221> base modificada<222> (1)... (50475)<223> η = g, a, c ou t<400> 16
taacatcatc aataatatac cttattttgg attgaagcca atatgataat gagggggtgg 60^gtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagt gtggcggaag 120tgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgttt 180ttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttag gcggatgttg 240tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataaga 300ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgct agagatctgg 360cgaaaggggg atgtgctgca aggcgattaa gttgggtaac gccagggttt tcccagtcac 420gacgttgtaa aacgacggcc agtgaattgt aatacgactc actatagggc gaattgggta 480ctggccacag agcttggccc attgcatacg ttgtatccat atcataatat gtacatttat 540attggctcat gtccaacatt accgccatgt tgacattgat tattgactag ttattaatag 600taatcaatta cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt 660acggtaaatg gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg 720acgtatgttc ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat 780ttacggtaaa ctgcccactt ggcagtacat caagtgtatc atatgccaag tacgccccct 840attgacgtca atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttatgg 900gactttccta cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg 960ttttggcagt acatcaatgg gogtggatag cggtttgact cacggggatt tccaagtctc 1020caccccattg acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa 1080tgtcgtaaca actccgcccc attgacgcaa atgggcggta ggcgtgtacg gtgggaggtc 1140tatataagca gagctcgttt agtgaaccgt cagatcgcct ggagacgcca tccacgctgt 1200tttgacctcc atagaagaca ccgggaccga tccagcctga ctctagccta gctctgaagt 1260tggtggtgag gccctgggca ggttggtatc aaggttacaa gacaggttta aggagaccaa 1320tagaaactgg gcatgtggag acagagaaga ctcttgggtt tctgataggc actgactctc 1380tctgcctatt ggtctatttt cccaccctta ggctgctggt ctgagcctag gagatctctc 1440gaggtcgacg gtatcgatgc caccatggag aaaatcgtcc tgttgctcgc tattgtgtct 1500ctagtgaaga gcgatcaaat ttgtatcggc taccatgcca ataactcaac agagcaggtc 1560gatactatca tggagaaaaa cgtaacagtt actcatgccc aagacatctt ggaaaagacc 1620cacaacggca aactttgcga cctggatgga gtgaagcccc tgatcctccg ggactgttca 1680gtcgctggtt ggctgctcgg gaaccctatg tgtgatgagt ttatcaacgt gcctgaatgg 1740tcttacattg tggagaaggc taaccctacc aatgacctct gctatcctgg gtcatttaac 1800gattacgagg aactgaaaca cctgttgtct agaattaacc actttgaaaa gatacagatt 1860atacccaagt ctagttggag tgatcacgaa gcctcctcag gcgttãgctc agcgtgtccc 1920tatctgggct ctccatcctt ctttagaaat gtggtctggt taatcaaaaa gaacagtacc 1980tacccaacca tcaaaaagtc ttataacaat accaatcagg aggacctgct cgtgttgtgg 2040ggtatccatc acccgaacga cgccgctgaa cagactaggc tgtatcagaa ccccactaca 2100tacatcagta ttggcacgag tactctgaac cagcgattag tgccaaagat tgcaacacgg 2160agcaaagtaa atgggcaatc tggcaggatg gagtttttct ggacaatctt aaaacccaac 2220gatgcgataa atttcgagtc caatggcaat ttcatcgccc ctgaatacgc ctataagatc 2280gtgaaaaagg gggactctgc aattatgaag tccgaattag agtatggcaa ttgcaacacg 2340aagtgccaga caccaatggg agccattaat agctcaatgc ccttccataa tattcatcca 2400ttgaccattg gggagtgccc aaagtacgtg aagtccaacc gcctggtcct cgcaaccggt 2460ctaagaaata gcccgcagag agaatcgcgg aggaagaaac gtggcctgtt tggcgcgatt 2520gccggattca tcgagggagg ctggcagggt atggtcgatg gttggtacgg ataccaccat 2580agcaacgaac aggggtccgg ctatgcagca gataaggaga gcactcagaa agctattgac 2640ggagttacaa acaaggttaa tagtattata gataaaatga acacgcaatt cgaggccgtt 2700gggagggagt ttaacaatct ggaacgccgg atcgaaaatc tgaatàagaa aatggaagác 2760ggcttccttg acgtgtggac ttataatgca gagctgcttg tactcatgga gaacgagagg 2820accctggatt tccacgatag caàcgtgaag aacctttacg acaaggtgag acttcagctc 2880cgagacaacg ccaaggagct ggggaatgga tgcttcgagt tttaccacaa atgtgacaat 2940gagtgcatgg aaagtatacg caacgggacc tacaattacc ctcagtatag cgaagaggct 3000cggctcaaac gcgaagagat aagcggggtg aaattggaat caatcggaac atatcáaatc 3060ctgtccatct attccaccgt cgcctcttcg ctggccctcg ctatcatgat ggctggtctg 3120tccctatgga tgtgttccaa tggaagectt cagtgccgta tttgtatatg agcggccgcc 3180ctattctata gtgtcaccta aatgctagag ctcgctgátc agcctcgact gtgccttcta 3240gttgccagcc atctgttgtt tgcccctccc ccgtgccttc cttgaccctg gaaggtgcca 3300ctcccactgt cctttcctaa taaaatgagg aaattgcatc gcattgtctg agtaggtgtc 3360attctattct ggggggtggg gtggggcagg acagcaaggg ggaggattgg gaagacaata 3420gcaggcatgc tggggatgcg gtgggctcta tggcttctga ggcggaaaga accaaagctt 3480aacatcatca ataatatacc ttattttgga ttgaagccaa tatgataatg agggggtgga 3540gtttgtgacg tggcgcgggg cgtgggaacg gggcgggtga cgtagtagtg tggcggaagt 3600gtgatgttgc aagtgtggcg gaacacatgt aagcgacgga tgtggcaaaa gtgacgtttt 3660tggtgtgcgc cggtgtacac aggaagtgac aattttcgcg cggttttagg cggatgttgt 3720agtaaatttg ggcgtaaccg agtaagattt ggccattttc gcgggaaaac tgaataagag 3780gaagtgaaat ctgaataatt ttgtgttact catagcgcgt aatactgtaa tagtaatcaa 3840ttacggggtc attagttcat agcccatata tggagttccg cgttacataa cttacggtaa 3900atggcccgcc tggctgaccg cccaacgacc cccgcccatt gacgtcaata atgacgtatg 3960ttcccatagt aacgccaata gggactttcc attgacgtca atgggtggag tatttacggt 4020aaactgccca cttggcagta catcaagtgt atcatatgcc aagtacgccc cctattgacg 4080tcaatgacgg taaatggccc gcctggcatt atgcccagta catgacctta tgggactttc 4140ctacttggca gtacatctac gtattagtca tcgctattac catggtgatg cggttttggc 4200agtacatcaa tgggcgtgga tagcggtttg actcacgggg atttccaagt ctccacccca 4260ttgacgtcaa tgggagtttg ttttggcacc aaaatcaacg ggactttcca aaatgtcgta 4320acaactccgc cccattgacg caaatgggcg gtaggcgtgt acggtgggag gtctatataa 4380gcagagctgg tttagtgaac cgtcagatcc gctagagatc tgggaaacga tatgggctga 4440atacggatcc gtattcagcc catatcgttt ctctagaaat aaaatatctt tattttcatt 4500acatctgtgt gttggttttt tgtgtggcgg ccgctcgagc ctaagcttct agataagata 4560tccgatccac cggatctaga taactgatca taatcagcca taccacattt gtagaggttt 4620tacttgcttt aaaaaacctc ccacacctcc ccctgaacct gaaacataaa atgaatgcaa 4680ttgttgttgt taacttgttt attgcagctt ataatggtta caaataaagc aatagcatca 4740caaatttcac aaataaagca tttttttcac tgcattctag ttgtggtttg tccaaactca 4800tcaatgtatc ttaacgcgga tctgggcgtg gttaagggtg ggaaagaata tataaggtgg 4860gggtcttatg tagttttgta tctgttttgc agcagccgcc gccgccatga gcaccaactc 492gtttgatgga agcattgtga gcttgtcgac tcgaagatct gggcgtggtt aagggtggga 4 98aagaatatat aaggtggggg tcttatgtag ttttgtatct gttttgcagc agccgccgcc 504gccatgagca ccaactcgtt tgatggaagc attgtgagct catatttgac aacgcgcatg 510'cccccatggg ccggggtgcg tcagaatgtg atgggctcca gcattgatgg tcgccccgtc 516'ctgcccgcaa actctactac cttgacctac gagaccgtgt ctggaacgcc gttggagact 522ιgcagcctccg ccgccgcttc agccgctgca gccaccgccc gcgggattgt gactgacttt 528)gctttcctga gcccgcttgç aagcagtgca gcttcccgtt catccgcccg cgatgacaag 534ιttgacggctc ttttggcaca attggattct ttgacccggg aacttaatgt cgtttctcag 540<cagctgttgg atctgcgcca gcaggtttct gccctgaagg cttcctcccc tcccaatgcg 546<gtttaaaaca taaataaaaa accagactct gtttggattt ggatcaagca agtgtcttgc 552<tgtctttatt taggggtttt gcgcgcgcgg taggcccggg accagcggtc tcggtcgttg 558(agggtcctgt gtattttttc caggacgtgg taaaggtgac tctggatgtt cagatacatg 564Cggcataagcc cgtctctggg gtggaggtag caccactgca gagcttcatg ctgcggggtg 570Cgtgttgtaga tgatccagtc gtagcaggag cgctgggcgt ggtgcctaaa aatgtctttc 576Cagtagcaagc tgattgccag gggcaggccc ttggtgtaag tgtttacaaa gcggttaàgc 582Ctgggatgggt gcatacgtgg ggatatgaga tgcatcttgg actgtatttt taggttggct 588Catgttcccag ccatatccct ccggggattc atgttgtgca gaaccaccag cacagtgtat 594Cccggtgcact tgggaaattt gtcatgtagc ttagaaggaa atgcgtggaa gaacttggag 600Cacgcccttgt gacctccaag attttccatg cattcgtcca taatgatggc aatgggccca 606Crí cgggcggcgg cctgggcgaa gatatttctg ggatcactaa cgtcatagtt gtgttccagg 612Catgagatcgt cataggccat ttttacaaag cgcgggcgga gggtgccaga ctgcggtata 618Catggttccat ccggcccagg ggcgtagtta ccctcacaga tttgcatttc ccacgctttg 624Cagttcagatg gggggatcat gtctacctgc ggggcgatga agaaaacggt ttccggggta 6300ggggagatca gctgggaaga aagcaggttc ctgagcagct gcgacttacc gcagccggtg 6360ggcccgtaaa tcacacctat taccgggtgc aactggtagt taagagagct gcagctgccg 6420tcatccctga gcaggggggc cacttcgtta agcatgtccc tgactcgcat gttttccctg 6480accaaatccg ccagaaggcg ctcgccgccc agcgatagca gttcttgcaa ggaagcaaag 6540tttttcaacg gtttgagacc gtccgccgta ggcatgcttt tgagcgtttg accaagcagt 6600tccaggcggt cccacagetc ggtcacctgc tctacggcat ctcgatccag catatctcct 6660cgtttcgcgg gttggggcgg ctttcgctgt acggcagtag tcggtgctcg tccagacggg 6720ccagggtcat gtctttccac gggcgcaggg tcctcgtcag cgtagtctgg gtcacggtga 6780aggggtgcgc tccgggctgc gcgctggcca gggtgcgctt gaggctggtc ctgctggtgc 6840tgaagcgctg ccggtcttcg ccctgcgcgt cggccaggta gcatttgacc atggtgtçat 6900agtccagccc ctccgcggcg tggcccttgg cgcgcagctt gcccttggag gaggcgccgc 6960acgaggggca gtgcagactt ttgagggcgt agagcttggg cgcgagaaat accgattccg 7020gggagtaggc atccgcgccg caggccccgc agacggtctc gcattccacg agccaggtga 7080gctctggccg ttcggggtca aaaaccaggt ttcccccatg ctttttgatg cgtttcttac 7140ctctggtttc catgagccgg tgtccacgct cggtgacgaa aaggctgtcc gtgtccccgt 7200atacagactt gagagggagt ttaaacgaat tcaatagctt gttgcatggg cggcgatata 7260aaatgcaagg tgctgctcaa aaaatcaggc aaagcctcgc gcaaaaaaga aagcacatcg 7320tagtcatgct catgcagata aaggcaggta agctccggaa ccaccacaga aaaagacacc 7380atttttctct caaacatgtc tgcgggtttc tgcataaaca caaaataaaa taacaaaaaa 7440acatttaaac attagaagcc tgtcttacaa caggaaaaac aacccttata agcataagac 7500ggactacggc catgccggcg tgaccgtaaa aaaactggtc accgtgatta aaaagcacca 7560ccgacagctc ctcggtcatg tccggagtca taatgtaaga ctcggtaaac acatcaggtt 7620gattcatcgg tcagtgctaa aaagcgaccg aaatagcccg ggggaataca tacccgcagg 7680cgtagagaca acattacagc ccccatagga ggtataacaa aattaatagg agagaaaaac 7740acataaacac ctgaaaaacc ctcctgccta ggcaaaatag caccctcccg ctccagaaca 7800acatacagcg cttcacagcg gcagcctaac agtcagcctt accagtaaaa aagaaaacct 7860attaaaaaaa caccactcga cacggcacca gctcaatcag tcacagtgta aaaaagggcc 7920aagtgcagag cgagtatata taggactaaa aaatgacgta acggttaaag tccacaaaaa 7980acacccagaa aaccgcacgc gaacctacgc ccagaaacga aagccaaaaa acccacaact 8040tcctcaaatc gtcacttccg ttttcccacg ttacgtaact tcccatttta agaaaactac 8100aattcccaac acatacaagt tactccgccc taaaacctac gtcacccgcc ccgttcccac 8160gccccgcgcc acgtcacaaa ctccaccccc tcattatcat attggcttca atccaaaata 8220aggtatatta ttgatgatgt taattaacat gcatggatcc atatgcggtg tgaaataccg 8280cacagatgcg taaggagaaa ataccgcatc aggcgctctt ccgcttcctc gctcactgac 8340tcgctgcgct cggtcgttcg gctgcggcga gcggtatcag ctcactcaaa ggcggtaata 8400cggttatcca cagaatcagg ggataacgca ggaaagaaca tgtgagcaaa aggccagcaa 84 60aaggccagga accgtaaaaa ggccgcgttg ctggcgtttt tccataggct ccgcccccct 8520gacgagcatc acaaaaatcg acgctcaagt cagaggtggc gaaacccgac aggactataa 8580agataccagg cgtttccccc tggaagctcc ctcgtgcgct ctcctgttcc gaccctgccg 8640cttaçcggat acctgtccgc ctttctccct tcgggaagcg tggcgctttc tcatagctca 8700cgctgtaggt atctcagttc ggtgtaggtc gttcgctcca agctgggctg tgtgcacgaa 8760ccccccgttc agcccgaccg ctgcgcctta tccggtaâct atcgtcttga gtccaacccg 8820gtaagacacg acttatcgcc actggcagca gccactggta acaggattag cagagcgagg 8880tatgtaggcg gtgctacaga gttcttgaag tggtggccta actacggcta cactagaagg 8940acagtatttg gtatctgcgc tctgctgaag ccagttacct tcggaaaaag agttggtagc 9000tcttgatccg gcaaacaaac caccgctggt agcggtggtt tttttgtttg caagcagcag 9060attacgcgca gaaaaaaagg atctcaagaa gatcctttga tcttttctac ggggtctgac 9120gctcagtgga acgaaaactc acgttaaggg attttggtca tgagattatc aaaaaggatc 9180ttcacctaga tccttttaaa ttaaaaatga agttttaaat caatctaaag tatatatgag 9240taaacttggt ctgacagtta ccaatgctta atcagtgagg cacctatctc agcgatctgt 9300ctatttcgtt catccatagt tgcctgactc cccgtcgtgt agataactac gatacgggag 9360ggcttaccat ctggccccag tgctgcaatg ataccgcgag acccacgctc accggctcca 9420gatttatcag caataaacca gccagccgga agggccgagc gcagaagtgg tcctgcaact 94BOttatccgcct ccatccagtc tattaattgt tgccgggaag ctagagtaag tagttcgcca 9540gttaatagtt tgcgcaacgt tgttgccatt gctgcagcca tgagattatc aaaaaggatc 9600- ttcacctaga tccttttcac gtagaaagcc agtccgcaga aacggtgctg accccggatg 9660aatgtcagct actgggctat ctggacaagg gaaaacgcaa gcgcaaagag aaagcaggta 9720gcttgcagtg ggcttacatg gcgatagcta gactgggcgg ttttatggac agcaagcgaa 9780ccggaattgc cagctggggc gccctctggt aaggttggga agccctgcaa agtaaactgg 9840atggctttct cgccgccaag gatctgatgg cgcaggggat caagctctga tcaagagaca 9900ggatgaggat cgtttcgcat gattgaacaa gatggattgc acgcaggttc tccggccgct 9960tgggtggaga ggctattcgg ctatgactgg gcacaacaga caatcggctg ctctgatgcc 10020gccgtgttcc ggctgtcagc gcaggggcgc ccggttcttt ttgtcaagac cgacctgtcc 10080ggtgccctga atgaactgca agacgaggca gcgcggctat cgtggctggc cacgacgggc 10140gttccttgcg cagctgtgct cgacgttgtc actgaagcgg gaagggactg gctgctattg 10200ggcgaagtgc cggggcagga tctcctgtca tctcaccttg ctcctgccga gaaagtatcc 10260atcatggctg atgçaatgcg gcggctgcat acgcttgatc cggctacctg cccattcgac 10320caccaagcga aaçatcgcat cgagcgagca cgtactcgga tggaagccgg tcttgtcgat 10380caggatgatc tggacgaaga gcátcagggg ctcgcgccag ccgaactgtt cgccaggctc 10440aaggcgagca tgcccgacgg cgaggatçtc gtcgtgaccc atggcgatgc ctgcttgccg 10500aatatcatgg tggaaaatgg ccgcttttct ggattcatcg actgtggccg gctgggtgtg 10560gcggaccgct atcaggacat agcgttggct acccgtgata ttgctgaaga gcttggcggc 10620gaatgggctg accgcttcct cgtgctttac ggtatcgccg ctcccgattc gcagcgcatc 10680gccttctatc gccttcttga cgagttcttc tgaattttgt taaaattttt gttaaatcag 10740ctca.tttt.tt aaccaatagg ccgaaatcgg caacatccct tataaatcaa aagaatagac 10800cgcgataggg ttgagtgttg ttccagtttg gaacaagagt ccactattaa agaacgtgga 10860ctccaacgtc aaagggcgaa aaaccgtcta tcagggcgat ggcccactac gtgaaccatc 10920acccaaatca agttttttgc ggtcgaggtg ccgtaaagct ctaaatcgga accctaaagg 10980gagcccccga tttagagctt gacggggaaa gccggcgaac gtggcgagaa aggaagggaa 11040gaaagcgaaa ggagcgggcg ctagggcgct ggcaagtgta gcggtcacgc tgcgcgtaac 11100caccacaccc gcgçgcttaa tgcgccgcta cagggcgcgt ccattcgcca ttcaggatcg 11160aattaattct taattaagga tccnnncctg tcctcgaccg atgcccttga gagccttcaa 11220cccagtcagc tccttccggt gggcgcgggg catgactatc gtcgccgcac ttatgactgt 11280cttctttatc atgcaactcg taggacaggt gccggcagcg ctctgggtca ttttcggcga 11340ggaccgcttt cgctggagcg cgacgatgat cggcctgtcg cttgcggtat tcggaatctt 11400gcacgccçtc gctcaagcct tcgtcactgg tcccgccacc aaacgtttcg gcgagaagca 11460ggccattatc gccggcatgg cggccgacgc gctgggctac gtcttgctgg cgttcgcgac 11520gcgaggctgg atggccttcc ccattatgat tcttctcgct tccggcggca tcgggatgcc 11580cgcgttgcag gccatgctgt ccaggcaggt agatgacgac catcagggac agcttcaagg 11640atcgctcgcg gctcttacca gcctaacttc gatcactgga ccgctgatcg tcacggcgat 11700ttatgccgcc tcggcgagca catggaacgg gttggcatgg attgtaggcg ccgccctata 11760ccttgtctgc ctccccgcgt tgcgtcgcgg tgcatggagc cgggccacct cgacctgaat 11820ggaagccggc ggcacctcgc taacggattc accactccaa gaattggagc caatcaattc 11880ttgcggagaa ctgtgaatgc gcaaaccaac ccttggcaga acatatccat cgcgtccgcc 11940atctccagca gccgcacgcg gcgcatctcg ggcagcgttg ggtcctggcc acgggtgcgc 12000atgatcgtgc tcctgtcgtt gaggacccgg ctaggctggc ggggttgcct tactggttag 12060cagaatgaat caccgatacg cgagcgaacg tgaagcgact gctgctgcaa aacgtctgcg 12120acctgagcaa caacatgaat ggtcttcggt ttccgtgttt cgtaaagtct ggaaacgcgg 12160aagtcagcgc cctgcaccat tatgttccgg atctgcatcg caggatgctg ctggctaccc 12240tgtggaacac ctacatctgt attaacgaag cgctggcatt gaccctgagt gatttttctc 12300tggtcccgcc gcatccatac cgccagttgt ttaccctcac aacgttccag taaccgggca 12360tgttcatcat cagtaacccg tatcgtgagc atcctctctc gtttcatcgg tatcattacc 12420cccatgaaca gaaattcccc cttacacgga ggcatcaagt gaccaaacag gaaaaaaccg 12480cccttaacat ggcccgcttt atcagaagcc agacattaac gcttctggag aaactcaacg 12540agctggâcgc ggatgaacag gcagacatct gtgaatcgct tcacgaccac gctgatgagc 12600tttaccgcag ctgcctcgcg cgtttcggtg atgacggtga aaacctctga cacatgcagc 12660tcccggagac ggtcacagct tgtctgtaag cggatgccgg gagcagacaa gcccgtcagg 12720gcgcgtcagc gggtgttggc gggtgtcggg gcgcagccat gacccagtca cgtagcgata 12780gcggagtgta tactggctta actatgcggc atcagagcag attgtactga gagtgcacca 12840tatgcggtgt gaaataccgc acagatgcgt aaggagaaaa taccgçatca ggcgctcttc 12900cgcttcctcg ctcactgact cgctgcgctc ggtcgttcgg ctgcggcgag cggtatcagc 12960tcactcaaag gcggtaatac ggttatccac agaatcaggg gataacgcag gaaagaacát 13020gtgagcaaaa ggccagcaaa aggccaggaa ccgtaaaaàg gccgcgttgc tggcgttttt 13080ccataggctc cgcccccctg acgagcatca caaaaatcga cgctcaagtc agaggtggcg 13140aaacccgaca ggactataaa gataccaggc gtttccccct ggaagctccc tcgtgcgctc 13200tcctgttccg accctgccgc ttaccggata cctgtccgcc tttctccctt cgggaagcgt 13260
- ggcgctttct caatgctcac gctgtaggta tctcagttcg gtgtaggtcg ttcgctccaa 13320gctgggctgt gtgcacgaac cccccgttca gcccgaccgc tgcgccttat ccggtaacta 13380tcgtcttgag tccaacccgg taagacacga cttatcgcca ctggcagcag ccactggtaa 13440
- caggattagc agagcgaggt atgtaggcgg tgctacagag ttcttgaagt ggtggcctaa 13500ctacggctac actagaagga cagtatttgg tatctgcgct ctgctgaagc cagttacctt 13560cggaaaaaga gttggtagct cttgatccgg caaacaaacc accgctggta gcggtggttt 13620ttttgtttgc aagcagcaga ttacgcgcag aaaaaaagga tctcaagaag atcctttgat 13680cttttctacg gggtctgacg ctcagtggaa cgaaaâctca cgttaaggga ttttggtcat 13740gagattatcá aaaaggatct tcacctagat ccttttaaat taaaaatgaa gttttaaatc 13800aatctaaagt atatatgagt aaacttggtc tgacagttac caatgcttaa tcagtgaggc 13860acctatctca gcgatctgtc tatttcgttc atccatagtt gcctgactcc ccgtcgtgta 13920gataactacg atacgggagg gcttaccatc tggccccagt gctgcaatga taccgcgaga 13980cccacgctca ccggctccag atttatcagc aataaaccag ccagccggaa gggccgagcg 14040cagaagtggt cctgcaactt tatccgcctc catccagtct attaattgtt gccgggaagc 14100tagagtaagt agttcgccag ttaatagttt gcgcaacgtt gttgccattg ctgcagccat 14160gagattatca aaaaggatct tcacctagat ccttttcacg tagaaagcca gtccgcagaa 14220acggtgctga ccccggatga atgtcagcta ctgggctatc tggacaaggg aaaacgcaag 14280cgcaaagaga aagcaggtag cttgcagtgg gcttacatgg cgatagctag actgggcggt 14340tttatggaca gcaagcgaac cggaattgcc agctggggcg ccctctggta aggttgggaa 14 400gccctgcaaa gtaaactgga tggctttctc gccgccaagg atctgatggc gcaggggatc 14460aagctctgat caagagacag gatgaggatc gtttcgcatg attgaacaag atggattgca 14520cgcaggttct ccggccgctt gggtggagag gctattcggc tatgactggg cacaacagac 14580aatcggctgc tctgatgccg ccgtgttccg gctgtcagcg caggggcgcc cggttctttt 14 640tgtcaagacc gacctgtccg gtgccctgaa tgaactgcaa gacgaggcag cgcggctatc 14700gtggctggcc acgacgggcg ttccttgcgc agctgtgctc gacgttgtca ctgaagcggg 14760aagggactgg ctgctattgg gcgaagtgcc ggggcaggat ctcctgtcat ctcaccttgc 14820tcctgccgag aaagtatcca tcatggctga tgcaatgcgg cggctgcata cgcttgatcc 14880ggctacctgc ccattcgacc accaagcgaa acatcgcatc gagcgagcac gtactcggat 14 940ggaagccggt cttgtcgatc aggatgatct ggacgaagag catcaggggc tcgcgccagc 15000cgaactgttc gccaggctca aggcgagcat gcccgacggc gaggatctcgf tcgtgaccca 15060tggcgatgcc tgcttgccga atatcatggt ggaaaatggc cgcttttctg gattcatcga 15120ctgtggccgg ctgggtgtgg cggaccgcta tcaggacata gcgttggcta cccgtgatat 15180tgctgaagag cttggcggcg aatgggctga ccgcttcctc gtgctttacg gtatcgccgc 15240tcccgattcg cagcgcatcg ccttctatcg ccttcttgac gagttcttct gaattttgtt 15300aaaatttttg ttaaatcagc tcatttttta accaataggc cgaaatcggc aacatccctt 15360ataaatcaaa agaãtagacc gcgatagggt tgagtgttgt tccagtttgg aacaagagtc 15420cactattaaa gaacgtggac tccaacgtca aagggcgaaa aaccgtctat cagggcgatg 15480gcccactacg tgaaccatca cccaaatcaa gttttttgcg gtcgaggtgc cgtaaagctc 15540taaatcggaa ccctaaaggg agcccccgat ttagagcttg acggggaaag ccggcgaacg 156Õ0tggcgagaaa ggaagggaag aaagcgaaag gagcgggcgc tagggcgctg gcaagtgtag 15660cggtcacgct gcgcgtaacc accacacccg cgcgcttaat gcgccgctac agggcgcgtc 15720cattcgccat tcaggatcga attaattctt aattaacatc atcaataata taccttattt 15780tggattgaag ccaatatgat aatgaggggg tggagtttgt gacgtggcgc ggggcgtggg 15840aacggggcgg gtgacgtagt agtgtggcgg aagtgtgatg ttgcaagtgt ggcggaacac 15900atgtaagcga cggatgtggc aaaagtgacg tttttggtgt gcgccggtgt acacaggaag 15960tgacaatttt cgcgcggttt taggcggatg ttgtagtaaa tttgggcgta accgagtaag 16020atttggccat tttcgcggga aaactgaata agaggaagtg aaatctgaat aattttgtgt 16080tactcatagc gcgtaatact gctagagatc tggcgaaagg gggatgtgct gcaaggcgat 16140taagttgggt aacgccaggg ttttcccagt cacgacgttg taaaacgacg gccagtgaat 16200tgtaatacga ctcactatag ggcgaattgg gtactggcca cagagcttgg cccattgcat 16260acgttgtatc catatcataa tatgtacatt tatattggct catgtccaac attaccgcca 16320tgttgacatt gattattgac tagttattaa tagtaatcaa ttacggggtc attagttcat 16380agcccatata tggagttccg cgttacataa cttacggtaa atggcccgcc tggctgaccg 16440cccaacgacc cccgcccatt gacgtcaata atgacgtatg ttcccatagt aacgccaata 16500gggactttcc attgacgtca atgggtggag tatttacggt aaactgccca cttggcagta 16560catcaagtgt atcatatgcc aagtacgccc cctattgacg tcaatgacgg taaatggccc 16620gcctggcatt atgcccagta catgacctta tgggactttc ctacttggca gtacatctac 16680gtattagtca tcgctattac catggtgatg cggttttggc agtacatcaa tgggcgtgga 16740tagcggtttg actcacgggg atttccaagt ctccacccca ttgacgtcaa tgggagtttg 16800ttttggcacc aaaatcaacg ggactttcca aaatgtcgta acaactccgc cccattgacg 16860caaatgggcg gtaggcgtgt acggtgggag gtctatataa gcagagctcg tttagtgaac 16920cgtcagatcg cctggagacg ccatccacgc tgttttgacc tccatagaag acaccgggac 16980cgatccagcc tgactctagc ctagctctga agttggtggt gaggccctgg gcaggttggt 17040atcaaggtta caagacaggt ttaaggagac caatagaaac tgggcatgtg gagacagaga 17100~ agactcttgg gtttctgata ggcactgact ctctctgcct attggtctat tttcccaccc 17160ttaggctgct ggtctgagcc taggagatct ctcgaggtcg acggtatcga tgccaccatg 17220gagaaaatcg tcctgttgct cgctattgtg tctctagtga agagcgatca aatttgtatc 17280ggctaccatg ccaataactc aacagagcag gtcgatacta tcatggagaa aaacgtaaca 17340gttactcatg cccaagacat cttggaaaag acccacaacg gcaaactttg cgacctggat 17400ggagtgaagc ccctgatcct ccgggactgt tcagtcgctg gttggctgct cgggaaccct 174 60atgtgtgatg agtttatcaa cgtgcctgaa tggtcttaca ttgtggagaa ggctaaccct 17520accaatgacc tctgctatcc tgggtcattt aacgattacg aggaactgaa acacctgttg 17580tctagaatta accactttga aaagatacag attataccca agtctagttg gagtgatcac 17640gaagcctcct caggcgttag ctcagcgtgt ccctatctgg gctctccatc cttctttaga 17700aatgtggtct ggttaatcaa aaagaacagt acctacccaa ccatcaaaaa gtcttataac 17760aataccaatc aggaggacct gctcgtgttg tggggtatcc atcacccgaa cgacgccgct 17820gaacagacta ggctgtatca gaaccccact acatacatca gtattggcac gagtactctg 17880aaccagcgat tagtgccaaa gattgcaaca cggagcaaag taaatgggca atctggcagg 17940atggagtttt tctggacaat cttaaaaccc aacgatgcga taaatttcga gtccaatggc 18000aatttcatcg cccctgaata cgcctataag atcgtgaaaa agggggactc tgcaattatg 18060aagtccgaat tagagtatgg caattgcaac acgaagtgcc agacaccaat gggagccatt 18120aatagctcaa tgcccttcca taatattcat ccattgacca ttggggagtg cccaaagtac 18180gtgaagtcca accgcctggt cctcgcaacc ggtctaagaa atagcccgca gagagaatcg 18240cggaggaaga aacgtggcct gtttggcgcg attgccggat tcatcgaggg aggctggcag 18300ggtatggtcg atggttggta cggataccac catagcaacg aacaggggtc cggctatgca 18360gcagataagg agagcactca gaaagctatt gacggagtta caaacaaggt taatagtatt 18420atagataaaa tgaacacgca attcgaggcc gttgggaggg agtttaacaa tctggaacgc 18480cggatcgaaa atctgaataa gaaaatggaa gacggcttcc ttgacgtgtg gacttataat 18540gcagagctgc ttgtactcat ggagaacgag aggaccctgg atttccacga tagcaacgtg 18600aagaaccttt acgacaaggt gagacttcag ctccgagaca acgccaagga gctggggaat 18660ggatgcttcg agttttacca caaatgtgac aatgagtgca tggaaagtat acgcaacggg 18720acctacaatt accctcagta tagcgaagag gctcggctca aacgcgaaga gataagcggg 18780gtgaaattgg aatcaatcgg aacatatcaa atcctgtcca tctattccac cgtcgcctct 18840tcgctggccc tcgctatcat gatggctggt ctgtccctat ggatgtgttc caatggaagc 18900cttcagtgcc gtatttgtat atgagcggcc gccctattct atagtgtcac ctaaatgcta 18960gagctcgctg atcagcctcg actgtgcctt ctagttgcca gccatctgtt gtttgcccct 19020cccccgtgcc ttccttgacc ctggaaggtg ccactcccac tgtcctttcc taataaaatg 19080aggaaattgc atcgcattgt ctgagtaggt gtcattctat tctggggggt ggggtggggc 19140aggacagcaa gggggaggat tgggaagaca atagcaggca tgctggggat gcggtgggct 19200ctatggcttc tgaggcggaa agaaccaaag cttaacatca tcaataatat accttatttt 19260ggattgaagc caatatgata atgagggggt ggagtttgtg acgtggcgcg gggcgtggga 19320acggggcggg tgacgtagta gtgtggcgga agtgtgatgt tgcaagtgtg gcggaacaca 19380tgtaagcgac ggatgtggca aaagtgacgt ttttggtgtg cgccggtgta cacaggaagt 19440gacaattttc gcgcggtttt aggcggatgt tgtagtaaat ttgggcgtaa ccgagtaaga 19500tttggccatt ttcgcgggaa aactgaataa gaggaagtga aatctgaata attttgtgtt 19560actcatagcg cgtaatactg taatagtaat caattacggg gtcattagtt catagccS 19620atatggagtt ccgcgttaca taacttacgg taaatggccc gectggctga ccgcccaaca 19680acccccgccc attgacgtca ataatgacgt atgttcccat agtafegcca Sagggact 19740tccattgacg tcaatgggtg gagtatttac ggtaaactgc ccacttggca gtStíaaq 19800tgtatcatat gccaagtacg ccccctattg acgtcaatga cggtaaagg cccgcctggc 19860attagccat gtacatgacc ttatgggact ttcctacttg gcagtacatc tacgtatSg 19920tcatcgctat taccatggtg atgcggtttt ggcagtacat caatgggcgt ggatagcggt 19980ttgactcacg gggatttcca .gtctcc.cc ccattgacgt caatggjagt ttgtttggc 20040accaaaatca acgggacttt ccaaaatgtc gtaacaactc cgccccat?g acgcaaaSg 20100gcggtaggcg tgtacggtgg gaggtctata taagcagagc tggtttagtg aaccgtcaga IJSS tccgctagag atctgggaaa cgatatgggc tgaatacgga tccgtattca gcccatatcg 20220tttctctaga aataaaatat ctttattttc attacatctg tgtgttggtt ttttgtgtgg 20280cggccgctcg agcctaagct tctagataag atatccgatc caccgga?ct agataaXga 20340tcataatcag ccataccaca tttgtagagg ttttacttgc tttaaaaaac ctcccacacc 20400TtIttTal ^ctgaaacat aaaatgaatg caattgttgt tgttaacttg tttattgcíg 2046^cttataatgg ttacaaataa agcaatagca tcacaaattt cacaaataaa gcattttttt 20520cactgcattc tagttgtggt ttgtccaaac tcatcaatgt atcttaacgc Jgatctgggc 2^80gtggttaagg gtgggaaaga atatataagg tgggggtett atgtagtttt gLtctgSt 20640tgcagcagcc gccgccgcca tgagcaccaa ctcgtttgat ggaagcattg tgagctLtc 20700gactcgaaga tctgggcgtg gttaagggtg ggaaagaata tataaggtgg gggtcttJta 20760tagttttgta tctgttttgc agcagccgcc gccgccatga geaccaac?c gKtgatgg! lllllagcattgtga gctcatattt gacaacgcgc atgcccccat gggccggggt gcgtcaqaat 20880gtgatgggct ccagcattga tggtcgcccc gtcctgcccg SactJSc LJcttgacc 20940tacgagaccg tgtctggaac gccgttggàg actgcagcct ccgccgccgc tteagccgct 21000gcagccaccg cccgcgggat tgtgactgac tttgctttcc tgagcccgct tgcaagcagt 2106^gcagettcce gttcatccgc eegegatgae aagttgacgg ctcttttggc aLatJggat 21120tctttgacee gggaacttaa tgtegtttct cagcagctgt tggatctgcg ecagcaggtt 21180tctgccctga aggcttcctc eeetcccaat gcggtttaaa acataaaLI aaaaccajac 21240tctgtttgga tttggatcaa gcaagtgtct tgetgtcttt atttaggggt tttgcgcjcg 213oScggtaggccc gggaceagcg gtctcggtcg ttgagggtcc tgtgta???t ttceaggfcg 2136^tggtaaaggt gaetctggat gttcagatac atgggeataa gcccgtctct ggggtggagj 21420tagcaccact gcagagcttc atgctgcggg gtggtgttgt agatgatcca gíegtaJcS 2^480gagcgctggg cgtggtgcct aaaaatgtct tteagtagea agctgattgc caggggcagg 21540eccttggtgt aagtgtttac aaageggtta agetgggatg ggtgcatacg tggggatajg 216Magatgcatct tggactgtat ttttaggttg gctatgttcc cagccatatc cctSggggí 2166^ttcatgttgt geagaaccac cagcacagtg tatccggtge acttgggaaa tttgtSS? Z1720agcttagaag gaaatgcgtg gaagaacttg gagacgccct tgtgacctcc aagattttcc 21780atgcattcgt ccataatgat ggcaatgggc ccacgggcgg c|gcctgggc gaagataítt Ill40ctgggateac taacgtcata gttgtgttcc aggatgagat egtcataggc catítttaca 21900aagcgcgggc ggagggtgcc agactgcggt ataatggttc catccggccc aggggcgtag 21960ttaccctcac agatttgcat ttcccacgct ttgagttcag atggggggat catgtctacc 22020tgcggggcga tgaagaaaac ggttteeggg gtaggggagl tcagSJgga agaaagcagg I20S0ttcctgagca gctgcgactt accgcagccg gtgggcccgt aaatcacacc tlttaccggg 22140tgcaactggt agttaagaga gctgcagctg ccgtcatccc tgagcagggg ggccacttcq 22200ttaagcatgt eeetgacteg eatgttttce etgaccaaat ccgcca|Xg gcgc^egecg 22260cccagcgata gcagttcttg caaggaagca aagtttttca acggtttgag accgtccqcc 22320gtaggcatgc ttttgagcgt ttgaccaagc agttccaggc gg^cccacag ctcggtcacc 22380
tS™ SSicgTt'= "9^tatct cctc^tttcg cgggttgggg cggc?ttcgc 22440tgtacggcag tagtcggtgc tcgtccagac gggccagggt eatgtetttc cacgggcgca 22500gggtcctcgt cagcgtagtc tgggtcacgg tgaaggggtg cgctccgggc tgegcgctgg 22560ecagggtgcg ettgaggctg gtcctgctgg tgctgaagcg ctgccggtct tcgícltgcg 22620cgtcggccag gtagcatttg accatggtgt eatagtecag eecctccgcg gcgtggccct 22680tggcgcgcag cttgcccttg gaggaggcgc cgcacgaggg gcagtgcaga cttttgaggg 22740cgtagagctt gggcgcgaga aataccgatt ccggggagta ggcatccgcg ccgcaggccc 22800cgcagacggt ctcgcattcc acgagccagg tgagctetgg cegttcgggg teaaaaacca 22860ggtttccccc atgctttttg atgcgtttct tacctctggt ttccatgagc cggtgtccac 22920gctcggtgac gaaaaggctg tccgtgtccc cgtatacaga cttgagaggc ctgtcctcga 22980gcggtgttce gcggtectcc tcgtatagaa actcggacca ctctgagaca aaggctcgeg 23040tccaggccag cacgaaggag gctaagtggg aggggtagcg gtcgttgtcc actagggggt 23100ccactcgctc cagggtgtga agacacatgt egccctcttc ggcatcaagg aaggtgattg 23160gtttgtaggt gtaggccacg tgaccgggtg ttcctgaagg ggggctataa aagggggtgg 23221gggcgcgttc gtcctcactc tcttccgcat cgctgtctgc gagggccagc tg?£gggg?í 2328.agtactccct ctgaaaagcg ggcatgactt ctgcgctaag attgtcagtt tccaaaaacg 2334(aggaggattt gatattcacc tggcccgcgg tgatgccttt gagggtggcc gcatccatct 2340(ggtcagaaaa gacaatcttt ttgttgtcaa gcttggtggc aaacgacccg tagagggcgt 2346Ítggacagcaa cttggcgatg gagcgcaggg tttggttttt gtcgcgatcg gcgcgctcct 2352(tggccgcgat gtttagctgc acgtattcgc gcgcaacgca ccgccattcg ggaaagacgg 2358Ctggtgcgctc gtcgggcacc aggtgcacgc gccaaccgcg gttgtgcagg gtgacaaggt 2364Ccaacgctggt ggctacctct ccgcgtaggc gctcgttggt ccagcagagg cggccgccct 2370Ctgcgcgagca gaatggcggt agggggtcta gctgcgtctc gtccgggggg tctgcgtcca 2376Ccggtaaagac cccgggcagc aggcgcgcgt cgaagtagtc tatcttgcat ccttgcaagt 2382Cctagcgcctg ctgccatgcg cgggcggcaa gcgcgcgctc gtatgggttg agtgggggac 23880cccatggcat ggggtgggtg agcgcggagg cgtacatgcc gcaaatgtcg taaacgtaga 2394 0ggggctctct gagtattcca agatatgtag ggtagcatct tccaccgcgg atgctggcgc 24000gcacgtaatc gtatagttcg tgcgagggag cgaggaggtc gggaccgagg ttgctacggg 24060cgggctgctc tgctcggaag actatctgcc tgaagatggc atgtgagttg gatgatatgg 24120ttggacgctg gaagacgttg aagctggcgt ctgtgagacc taccgcgtca cgcacgaagg 24180aggcgtagga gtcgcgcagc ttgttgacca gctcggcggt gacctgcacg tctagggcgc 24240
- agtagtccag ggtttccttg atgatgtcat acttatcctg tccctttttt ttccacagct 24300cgcggttgag gacaaactct tcgcggtctt tccagtactc ttggatcgga aacccgtcgg 24360cctccgaacg gtaagagcct agcatgtaga actggttgac ggcctggtàg gcgcagcatc 24420
- ccttttctac gggtagcgcg tatgcctgcg cggccttccg gagcgaggtg tgggtgagcg 24480caaaggtgtc cctgaccatg actttgaggt actggtattt gaagtcagtg tcgtcgcatc 24540cgccctgctc ccagagcaaa aagtccgtgc gctttttgga acgcggattt ggcagggcga 24 600aggtgacatc gttgaagagt atctttcccg cgcgaggcat aaagttgcgt gtgatgcgga 24 660agggtcccgg cacctcggaa cggttgttaa ttacctgggc ggcgagcacg atctcgtcaa 24720agccgttgat gttgtggccc acaatgtaaa gttccaagaa gcgcgggatg cccttgatgg 24780aaggcaattt tttaagttcc tcgtaggtga gctcttcagg ggagctgagc ccgtgctctg 24840aaagggccca gtctgcaaga tgagggttgg aagcgacgaa tgagctccac aggtcacggg 24 900ccattagcat ttgcaggtgg tcgcgaaagg tcctaaactg gcgacctatg gccatttttt 24 960ctggggtgat gcagtagaag gtaagcgggt cttgttccca gcggtcccat ccaaggttcg 25020cggctaggtc tcgcgcggca gtcactagag gctcatctcc gccgaacttc atgaccagca 25080tgaagggcac gagctgcttc ccaaaggccc ccatccaagt ataggtctct acatcgtagg 25140tgacaaagag acgctcggtg cgaggatgcg agccgatcgg gaagaactgg atctcccgcc 25200accaattgga ggagtggcta ttgatgtggt gaaagtagaa gtccctgcga cgggccgaac 25260actogtgctg gcttttgtaa aaacgtgcgc agtactggca gcggtgcacg ggctgtacat 25320cctgcacgag gttgacctga cgaccgcgca caaggaagca gagtgggaat ttgagcccct 25380cgcctggcgg gtttggctgg tggtcttcta cttcggctgc ttgtccttga ccgtctggct 25440gctcgagggg agttacggtg gatcggacca ccacgccgcg cgagcccàaa gtccagatgt 25500ccgcgcgcgg cggtcggagc ttgatgacaa catcgcgcag atgggagctg tccatggtct 25560ggagctcccg cggcgtcagg tcaggcggga gctcctgcag gtttacctcg catagacggg 25620tcagggcgcg ggctagatcc aggtgatacc taatttccag gggctggttg gtggcggcgt 25680cgatggcttg caagaggccg catccccgcg gcgcgactac ggtaccgcgc ggcgggcggt 25740gggccgcggg ggtgtccttg gatgatgcat ctaaaagcgg tgacgcgggc gagcccccgg 25800aggtaggggg ggctccggac ccgccgggag agggggcagg ggcacgtcgg cgccgcgcgc 25860gggcaggagc tggtgctgcg cgcgtaggtt gctggcgaac gcgacgacgc ggcggttgat 25920ctcctgaatc tggcgcctct gcgtgaagac gacgggcccg gtgagcttga gcctgaaaga 25980gagttcgaca gaatcaattt cggtgtcgtt gacggcggcc tggcgcaaaa tctcctgcac 26040gtctcctgag ttgtcttgat aggcgatctc ggccatgaac tgctcgatct cttcctcctg 26100gagatctccg cgtccggctc gctccacggt ggcggcgagg tcgttggaaa tgcgggccat 26160gagctgcgag aaggcgttga ggcctccctc gttccagacg cggctgtaga ccacgccccc 26220ttcggcatcg cgggcgogca tgaccacctg cgcgagattg agctccacgt gccgggcgaa 26280gacggcgtag tttcgcaggc gctgaaagag gtagttgagg gtggtggcgg tgtgttctgc 26340cacgaagaag tacataaccc agcgtcgcaa cgtggattcg ttgatatccc ccaaggcctc 26400aaggcgctcc atggcctcgt agaagtccac ggcgaagttg aaaaactggg agttgcgcgc 264 60cgacacggtt aactcctcct ccagaagacg gatgagctcg gcgacagtgt cgcgcacctc 26520gcgctcaaag gctacagggg cctcttcttc ttcttcaatc tcctcttcca taagggcctc 26580cccttcttct tcttctggcg gcggtggggg aggggggaca cggcggcgac gacggcgcac 26640cgggaggcgg tcgacaaagc gctcgatcat ctccccgcgg cgacggcgca tggtctcggt 26700gacggcgcgg ccgttctcgc gggggcgcag ttggaagacg ccgcccgtca tgtcccggtt 26760atgggttggc ggggggctgc catgcggcag ggatacggcg ctaacgatgc atctcaacaa 26820ttgttgtgta ggtactccgc cgccgaggga cctgagcgag tccgcatcga ccggatcgga 26880aaacctctcg agaaaggcgt ctaaccagtc acagtcgcaa ggtaggctga gcaccgtggc 26940gggcggcagc gggcggcggt cggggttgtt tctggcggag gtgctgctga tgatgtaatt 27000aaagtaggcg gtcttgagac ggcggatggt cgacagaagc accatgtcct tgggtccggc 27060ctgctgaatg cgcaggcggt cggccatgcc ccaggcttcg ttttgacatc ggcgcaggtc 27120tttgtagtag tcttgcatga gcctttctac cggcacttct tcttctcctt cctcttgtcc 27180tgcatctctt gcatctatcg ctgcggcggc ggcggagttt ggccgtaggt ggcgccctct 27240tcctcccatg cgtgtgaccc cgaagcccct catcggctga agcagggcta ggtcggcgac 27300aacgcgctcg gctaatatgg cctgctgcac ctgcgtgagg gtagactgga agtcatccat 27360gtccacaaag cggtggtatg cgcccgtgtt gatggtgtaa gtgcagttgg ccataacgga 27420ccagttaacg gtctggtgac ccggctgcga gagctçggtg tacctgagac gcgagtaagc 27480cctcgagtca aatacgtagt cgttgcaagt ccgcaccagg tactggtatc ccaccaaaaa 27540gtgcggcggc ggctggcggt agaggggcca gcgtagggtg gccggggctc cgggggcgag 27600atcttccaac ataaggcgat gatatccgta gatgtacctg gacatccagg tgatgccggc 27660ggcggtggtg gaggcgcgcg gaaagtcgcg gacgcggttc cagatgttgc gcagcggcaa 27720aaagtgctcc atggtcggga cgctctggcc ggtcaggcgc gcgcaatcgt tgacgctcta 27780ccgtgcaaaa ggagagcctg taagcgggca ctcttccgtg gtctggtgga taaattcgca 27840agggtatcat ggcggacgac cggggttcga gccccgtatc cggccgtccg ccgtgatcca 27900
- tgcggttacc gcccgcgtgt cgaacccagg tgtgcgacgt cagacaacgg gggagtgctc 27960cttttggctt ccttccaggc gcggcggctg ctgcgctagc ttttttggcc actggccgcg 28020cgcagcgtaa gcggttaggc tggaaagcga aagcattaag tggctcgctc cctgtagccg 28080
- gagggttatt ttccaagggt tgagtcgcgg gacccccggt tcgagtctcg gaccggccgg 28140actgcggcga acgggggttt gcctccccgt catgcaagac cccgcttgca aattcctccg 28200gaaacaggga cgagcccctt ttttgctttt cccagatgca tccggtgctg cggcagatgc 28260gcccccctcc tcagcagcgg caagagcaag agcagcggca gacatgcagg gcaccctccc 28320ctcctcctac cgcgtcagga ggggcgacat ccgcggttga cgcggcagca gatggtgatt 28380acgaaccccc gcggcgccgg gcccggcact acctggactt ggaggagggc gagggcctgg 28440cgcggctagg agcgccctct cctgagcggt acccaagggt gcagctgaag cgtgatacgc 28500gtgaggcgta cgtgccgcgg cagaacctgt ttcgcgaccg cgagggagag gagcccgagg 28560agatgcggga tcgaaagttc cacgcagggc gcgagctgcg gcatggcctg aatcgcgagc 28620ggttgçtgcg cgaggaggac tttgagcccg acgcgcgaaccgggattagt cccgcgcgcg 28680cacacgtggc ggccgccgac ctggtaaccg catacgagca gacggtgaac caggagatta 28740actttcaaaa aagctttaac aaccacgtgc gtacgcttgt ggcgcgcgag gaggtggcta 28800taggactgat gcatctgtgg gactttgtaa gcgcgctgga gcaaaaccca aatagcaagc 28860cgctcatggc gcagctgttc cttatagtgc agcacagcag ggacaacgag gcattcaggg 28920atgcgctgct aaacatagta gagcccgagg gccgctggct gctcgatttg ataaacatcc 28980tgcagagcat agtggtgcag gagcgcagct tgagcctggc tgacaaggtg gccgccatca 29040actattccat gçttagcctg ggcaagtttt acgcccgcaa gatataccat accccttacg 29100ttcccataga caaggaggta aagatcgagg ggttctacat gcgcatggcg ctgaaggtgc 29160ttàccttgag cgacgacctg ggcgtttatc gcaacgagcg catccacaag gccgtgagcg 29220tgagccggcg gcgcgagctc agcgaccgcg agctgatgca cagcctgcaa agggccctgg 29280ctggcacggg cagcggcgat agagaggccg agtcctactt tgacgcgggc gctgacctgc 29340gctgggcccc aagccgacgc gccctggagg cagctggggc cggacctggg ctggcggtgg 29400cacccgcgcg cgctggcaac gtcggcggcg tggaggaata tgacgaggac gatgagtacg 29460agccagagga cggcgagtac taagcggtga tgtttctgat cagatgatgc aagacgcaac 29520ggacccggcg gtgcgggcgg cgctgcagag ccagccgtcc ggccttaact ccacggacga 29580ctggcgccag gtcatggacc gcatcatgtc gctgactgcg cgcaatcctg acgcgttccg 29640gcagcagccg caggccaacc ggctctccgc aattctggaa gcggtggtcc cggcgcgcgc 29700aaaccccacg cacgagaagg tgctggcgat cgtaaaçgcg ctggccgaaa acagggccat 29760ccggcccgac gaggccggcc tggtctacga cgcgctgctt cagcgcgtgg ctcgttacaa 29820cagcggcaac gtgcagacca acctggaccg gctggtgggg gatgtgcgcg aggccgtggc 29880gcagcgtgag cgcgcgcagc agcagggcaa cctgggctcc atggttgcac taaacgcctt 29940cctgagtaca cagcccgcca acgtgccgcg gggacaggag gactacacca actttgtgag 30000cgcactgcgg ctaatggtga ctgagacacc gcaaagtgag gtgtaccagt ctgggccaga 30060ctattttttc cagaccagta gacaaggcct gcagaccgta aacctgagcc aggctttcaa 30120aaacttgcag gggctgtggg gggtgcgggc tcccacaggc gaccgcgcga ccgtgtctag 30180cttgctgacg cccaactcgc gcctgttgct gctgctaata gcgcccttca cggacagtgg 30240cagcgtgtcc cgggacacat acctaggtca cttgctgaca ctgtaccgcg aggccatagg 30300tcaggcgcat gtggacgagc atactttcca ggagattaca agtgtcagcc gcgcgctggg 30360gcaggaggac acgggcagcc tggaggcaac cctaaactac ctgctgacca accggcggca 30420gaagatcccc tcgttgcaca gtttaaacag cgaggaggag cgcattttgc gctacgtgca 30480gcagagcgtg agccttaacc tgatgcgcga cggggtaacg cccagcgtgg cgctggacat 30540gaccgcgcgc aacatggaac cgggcatgta tgcctcaaac cggccgttta tcaaccgcct 30600aatggactac ttgcatcgcg cggccgccgt gaaccccgag tatttcacca atgccatctt 30660gaacccgcac tggctaccgc cccctggttt ctacaccggg ggattcgagg tgcccgaggg 30720taacgatgga ttcctctggg acgacataga cgacagcgtg ttttccccgc aaccgcagac 30780cctgctagag ttgcaacagc gcgagcaggc agaggcggcg ctgcgaaagg aaagcttccg 30840caggccaagc agcttgtccg atçtaggcge tgcggccccg cggtcagatg ctagtagccc 30900àtttccaagc ttgatagggt ctcttaccag cactcgcacc acccgcccgc gcctgctggg 30960cgaggaggag tacctaaaca actcgctgct gcagccgcag cgcgaaaaaa acctgcctcc 31020ggcatttccc aacaacggga tagagagcct agtggacaag atgagtagat ggaagacgta 31080cgcgcaggag cacagggacg tgccaggccc gcgcccgccc acccgtcgtc aaaggcacga 31140ccgtcagcgg ggtctggtgt gggaggacga tgactcggca gacgacagca gcgtcctgga 31200tttgggaggg agtggcaacc cgtttgcgca ccttcgcccc aggctgggga gaatgtttta 31260aaaaaaaaaa àgcatgatgc aaaataaaaa actcaccaag gccatggcac cgagcgttgg 31320ttttcttgta ttccccttag tatgcggcgc gcggcgatgt atgaggaagg tcctcctccc 31380tcctacgaga gtgtggtgag cgcggcgcca gtggcggcgg cgctgggttc tcccttcgat 31440gctcccctgg acccgccgtt tgtgcctccg cggtacctgc ggcctaccgg ggggagaaac 31500agcatccgtt actctgagtt ggcaccccta ttcgacacca cccgtgtgta cctggtggac 31560aacaagtcaa cggatgtggc atccctgaac taccagaacg accacagcaa ctttctgacc 31620acggtcattc àaaacaatga ctacagcccg ggggaggcaa gcacacagac catcaatctt 31680gacgaccggt cgcactgggg cggcgacctg aaaaccatcc tgcataccaa catgccaaat 31740gtgaacgagt tcatgtttac caataagttt aaggcgcggg tgatggtgtc gcgcttgcct 31800actaaggàca atcaggtgga gctgaaatac gagtgggtgg agttcacgct gcccgagggc 31860aactactccg agaccatgac catagacctt atgaacaacg cgatcgtgga gcactacttg 31920aaagtgggca gacagaacgg ggttctggaa agcgacatcg gggtaaagtt tgacacccgc 31980aacttcâgac tggggtttga ccccgtcact ggtcttgtca tgcctggggt atatacaaac 32040gaagccttcc atccagacat cattttgctg ccaggatgcg gggtggactt cacccaeagc 32100cgcctgagca acttgttggg catcegcaag cggcaaccct tccaggaggg ctttaggatc 32160acctacgatg atctggaggg tggtaacatt cccgcactgt tggatgtgga cgcctaccag 32220gcgagcttga aagatgacac cgaácagggc gggggtggcg caggcggcag caacagcagt 32280ggcagcggcg cggaagagaa ctccaacgcg gcagccgcgg caatgcagcc ggtggaggac 32340atgaacgatc atgccattcg cggcgacacc tttgccacac gggctgagga gaagcgcgct 32400gaggccgaag cagcggccga agctgccgcc cccgctgcgc aacccgaggt cgagaagcct 32460cagaagaaac cggtgatcaa acçcctgaca gaggacagca agaaacgcag ttacaaccta 32520ataagcaatg acagcacctt cacccagtac cgcagctggt accttgcata caactacggc 32580gaccctcaga ccggaatccg ctcatggacc ctgctttgca ctcctgacgt aacctgcggc 32640tcggagcagg tctactggtc gttgccagac atgatgcaag accccgtgac cttccgctcc 32700acgcgccaga tcagcaactt tccggtggtg ggcgccgagc tgttgcccgt gcactccaag 32760agcttctaca acgaccaggc cgtctactcc caactcatcc gccagtttac ctctctgacc 32820cacgtgttca atcgctttcc cgagaaccag attttggcgc gcccgccagc ccccaccatc 32880accaccgtca gtgaaaacgt tectgctctc acagatcacg ggacgctacc gctgcgcaac 32940agcatçggag gagtccagcg agtgaccatt actgacgcca gacgccgcac ctgcccctac 33000gtttacaagg ccctgggcat agtctcgccg cgcgtcctat cgagccgcac tttttgagca 33060agcatgtcca tccttatatc gcccagcaat aacacaggct ggggcctgcg cttcccaagc 33120aagatgtttg gcggggccaa gaagcgctcc gaccaacacc cagtgcgcgt gcgcgggcac 33180taccgcgcgc cctggggcgc gcacaaacgc ggccgcactg ggcgcaccac cgtcgatgac 33240gccatcgacg cggtggtgga ggaggcgcgc aactacacgc ccacgccgcc accagtgtcc 33300acagtggacg cggccattca gaccgtggtg cgcggagccc ggcgctatgc taaaatgaag 33360agacggcgga ggcgcgtagc acgtcgccac cgccgccgac ccggcactgc cgcccaacgc 33420gcggcggcgg ccctgcttaa ccgcgcacgt cgcaccggcc gacgggcggc catgcgggcc 33480gctcgaaggc tggccgcggg tattgtcact gtgcccccca ggtccaggcg acgagcggcc 33540gccgcagcag ccgcggccat tagtgctatg actcagggtc gcaggggcaa cgtgtattgg 33600gtgcgcgact cggttagcgg cctgcgcgtg cccgtgcgca cccgcccccc gcgcaactag 33660attgcaagaa aaaactactt agactcgtac tgttgtatgt atccagcggc ggcggcgcgc 33720aacgaagcta tgtccaagcg caaaatcaaa gaagagatgc tccaggtcat cgcgccggag 33780atctatggcc ccccgaagaa ggaagagcag gattacaagc cccgaaagctaaagcgggtc 33840aaaaagaaaa agaaagatga tgatgatgaa cttgacgacg aggtggaact gctgcacgct 33900accgcgccca ggcgacgggt acagtggaaa ggtcgacgcg taaaacgtgt tttgcgaccc 33960ggcaccaccg tagtctttac gcccggtgag cgctccaccc gcacctacaa gqgcgtgtat 34020gatgaggtgt acggcgacga ggacctgctt gagcaggcca acgagcgcct cggggagttt 34080gcctacggaa agcggcataa ggacatgctg gcgttgccgc tggacgaggg caacccaaca 34140cctagcctaa agcccgtaac actgcagcag gtactgcccg cgcttgcacc gtccgaagaa 34200aagcgcggcc taaagcgcga gtctggtgac ttggcaccca ccgtgcagct gatggtaccc 34260aagcgccagc gactggaaga tgtcttggaa aaaatgaccg tggaacctgg gctggagccc 34320gaggtccgcg tgcggccaat caagcaggtg gcgccgggac tgggcgtgca gaccgtggac 34380gttcagatac ccactaccag tagcaccagt attgccaccg ccacagaggg catggagaca 34440caaacgtccc cggttgcctc agcggtggcg gatgccgcgg tgcaggcggt cgctgcggcc 34500gcgtccaaga cctctacgga ggtgcaaacg gacccgtgga tgtttcgcgt ttcagccccc 34560cggcgcccgc gcggttcgag gaagtacggc gccgccagcg cgctactgcc cgaatatgcc 34 620ctacatcctt ccattgcgcc tacccccggc tatcgtggct acacctaccg ccccagaaga 34680cgagcaacta cccgacgccg aaccaccact ggaacccgcc gccgccgtcg ccgtcgccag 34740cccgtgctgg ccccgatttc cgtgcgcagg gtggctcgcg aaggaggcag gaccctggtg 34800ctgccaacag cgcgctacca ccccagcatc gtttaaaagc cggtctttgt ggttcttgca 34860gatatggccc tcacctgccg cctccgtttc ccggtgccgg gattccgagg aagaatgcac 34 920cgtaggaggg gcatggccgg ccacggcctg acgggcggca tgcgtcgtgc gcaccaccgg 34 980cggcggcgcg cgtcgcaccg tcgcatgcgc ggcggtatcc tgcccctcct tattccactg 35040atcgccgcgg cgattggcgc cgtgcccgga attgcatccg tggccttgca ggcgcagaga 35100càctgattaa aaacaagttg catgtggaaa aatcaaaata aaaagtctgg actctcacgc 35160tcgcttggtc ctgtaactat tttgtagaat ggaagacatc aactttgcgt ctctggcccc 35220gcgacacggc tcgcgcccgt tcatgggaaa ctggcaagat atcggcacca gcaatatgag 35280cggtggcgcc ttcagctggg gctcgctgtg gagcggcatt aaaaatttcg gttccaccgt 35340taagaactat ggcagcaagg cctggaacag cagcacaggc cagatgctga gggataagtt 35400gaaagagcaa aatttccaac aaaaggtggt agatggcctg gcctctggca ttagcggggt 35460ggtggacctg gccaaccagg cagtgcaaaa taagattaac agtaagcttg atccccgccc 35520tcccgtagag gagcctccac cggccgtgga gacagtgtct ccagaggggc gtggcgaaaa 35580gcgtccgcgc cccgacaggg aagaaactct ggtgacgcaa atagacgagc ctccctcgta 35640cgaggaggca ctaaagcaag gcctgcccac cacccgtccc atcgcgccca tggctaccgg 35700agtgctgggc cagcacacac ccgtaacgct ggacctgcct ccccccgccg acacccagca 35760gaaacctgtg ctgccaggcc cgaccgccgt tgttgtaacc cgtcctagcc gcgcgtccct 35820gcgccgcgcc gccagcggtc cgcgatcgtt gcggcccgta gccagtggca actggcaaag 35880cacactgaac agcatcgtgg gtctgggggt gcaatccctg aagcgccgac gatgcttctg 35940aatagctáac gtgtcgtatg tgtgtcatgt atgcgtccat gtcgccgcca gaggagctgc 36000tgagccgccg cgcgcccgct ttccaagatg gctacccctt cgatgatgcc gcagtggtct 36060tacatgcaca tctcgggcca ggacgcctcg gagtacctga gccccgggct ggtgcagttt 36120gcccgcgcca ccgagacgta cttcagcctg aataacaagt ttagaaaccccacggtggcg 36180cctacgcacg acgtgaccac agaccggtcc cagcgtttga cgctgcggtt catccctgtg 36240gaccgtgagg atactgcgta ctcgtacaag gcgcggttca ccctagctgt gggtgataac 36300cgtgtgctgg acatggcttc cacgtacttt gacatccgcg gcgtgctgga caggggccct 36360acttttaagç cctactctgg cactgcctac aacgccctgg ctcccaaggg tgccccaaat 36420ccttgcgaat gggatgaagc tgctactgct cttgaaataa acctagaaga agaggacgat 36480gacaacgaag acgaagtaga cgagcaagct gagcagcaaa aaactcacgt atttgggcag 36540gcgccttatt ctggtataaa tattacaaag gagggtattc aaataggtgt cgaaggtcaa 36600acacctaaat atgccgataa aacatttcaa cctgaacctc aaataggaga atctcagtgg 36660tacgaaactg aaattaatca tgcagctggg agagtcctta aaaagactac cccaatgaaa 36720ccatgttacg gttcatatgc aaaacccaca aatgaaaatg gagggcaagg cattcttgta 36780aagcaacaaa atggaaagct agaaagtcaa gtggaaatgc aatttttctc aactactgag 36840gcgaccgcag gcaatggtga taacttgact cctaaagtgg tattgtacag tgaagatgta 36900gatatagaaa ccccagacac tcatatttct tacatgccca ctattaagga aggtaactca 36960cgagaactaa tgggccaaca atctatgccc aacaggccta attacattgc ttttagggac 37020aattttattg gtctaatgta ttacaacagc acgggtaata tgggtgttct ggcgggccaa 37080gcatcgcagt tgaatgctgt tgtagatttg caagacagaa acacagagct ttcataccag 37140cttttgcttg attccattgg tgatagaacc aggtactttt ctatgtggaa tcaggctgtt 37200gacagctatg atccagatgt tagaattatt gaaaatcatg gaactgaaga tgaacttcca 37260aattactgct ttccactggg aggtgtgatt aatacagaga ctcttaccaa ggtaaaacct 37320aaaacaggtc aggaaaatgg atgggaaaaa gatgctacag aattttcaga taaaaatgaa 37380ataagagttg gaaataattt tgccatggaa atcaatctaa atgccaacçt gtggagaaat 37440ttcctgtact ccaacatagc gctgtatttg cccgacaagc taaagtacag tccttccaac 37500gtaaaaattt ctgataaccc aaacacctac gactacatga acaagcgagt ggtggctccc 37560gggttagtgg actgctacat taaccttgga gcacgctggt cccttgacta tatggacaac 37620gtcaacccat ttaaccacca ccgcaatgct ggcctgcgct accgctcaat gttgctgggc 37680aatggtcgct atgtgccctt ccacatccag gtgcctcaga agttctttgc cattaaaaac 37740ctccttctcc tgccgggctc atacacctac gagtggaact tcaggaagga tgttaacatg 37800gttctgcaga gctccctagg aaatgaccta agggttgacg gagccagcat taagtttgat 37860agcatttgcc tttacgccac cttcttcccc atggcccaca acaccgcctc cacgcttgag 37920gccatgctta gaaacgacac caacgaccag tcctttaacg actatctctc cgccgccaac 37980atgctctacc ctatacccgc caacgctacc aacgtgccca tatccatccc ctcccgcaac 38040tgggcggctt tccgcggctg ggccttcacg cgccttaaga ctaaggaaac cccatcactg 38100ggctcgggct acgaccctta ttacacctac tctggctcta taccctacct agatggaacc 38160ttttacctca accacacctt taagaaggtg gccattacct ttgactcttc tgtcagctgg 38220cctggcaatg accgcctgct tacccccaac gagtttgaaa ttaagcgctc agttgacggg 38280gagggttaca acgttgccca gtgtaacatg accaaagact ggttcctggt acaaatgcta 38340gctaactaca acattggcta ccagggcttc tatatcccag agagctacaa ggaccgcatg 38400tactccttct ttagaaactt ccagcccatg agccgtcagg tggtggatga tactaaatac 38460aaggactacc aacaggtggg catcctacac caacacaaca actctggatt tgttggctac 38520cttgccccca ccatgcgcga aggacaggcc taccctgcta acttccccta tccgcttata 38580ggcaagaccg cagttgacag cattacccag aaaaagtttc tttgcgatcg.caccctttgg 38640cgcatcccat tctccagtaa ctttatgtcc atgggcgcac tcacagacct gggccaaaac 38700cttctctacg ccaactccgc ccacgcgcta gacatgactt ttgaggtgga tcccatggac 38760gagcccaccc ttctttatgt tttgtttgaa gtctttgacg tggtccgtgt gcaccggccg 38820caccgcggcg tcatcgaaac cgtgtacctg cgcacgccct tctcggccgg caacgccaca 38880< acataaagaa gcaagcaaca tcaacaacag ctgccgccat gggctccagt gagcaggaac 38940tgaaagccat tgtcaaagat cttggttgtg ggccatattt tttgggcacc tatgácaagc 39000gctttccâgg ctttgtttct ccacacaagc tcgcctgcgc catagtcaat acggccggtc 39060gcgagactgg gggcgtacac tggatggcct ttgcctggaa cccgcactca aaaacatgct 39120acctctttga gccctttggc ttttctgacc agcgactcaa gcaggtttac cagtttgagt 39180acgagtcact cctgcgccgt agcgccattg cttcttcccc cgaccgctgt ataacgctgg 39240aaaàgtccac ccaaagcgta caggggccca actcggccgc ctgtggacta ttctgctgca 39300tgtttctcca cgcctttgcc aactggcccc aaactcccat ggatcacaac cccaccatga 39360accttattac cggggtaccc aactccatgc tcaacagtcc ccaggtacag cccaccctgc 39420gtcgcaacca ggaacagctc tacagcttcc tggagcgcca ctcgccctac ttccgcagcc 39480acagtgcgca gattaggagc gccacttctt tttgtcactt gaaaaacatg taaaaatáat 39540gtactagaga cactttcaat aaaggcaaat gcttttattt gtacactctc gggtgattat 39600ttacccccac ccttgccgtc tgcgccgttt aaaaatcaaa ggggttctgc cgcgcatcgc 39660tatgcgccac tggcagggac acgttgcgat actggtgttt agtgctccac ttaaactcag 39720gcacaaccat ccgcggcagc tcggtgaagt tttcactcca caggctgcgc accatcacca 39780acgcgtttag caggtcgggc gccgatatct tgaagtcgca gttggggcct ccgccctgcg 39840cgcgcgagtt gcgatacaca gggttgcagc actggaacac tatcagcgcc gggtggtgca 39900cgctggccag cacgctcttg tcggagatca gatccgcgtc caggtcctcc gcgttgctca 39960gggcgaacgg agtcaacttt ggtagctgcc ttcccaaaaa gggcgcgtgc ccaggctttg 40020agttgcactc gcaccgtagt ggcatcaaaa ggtgaccgtg cccggtctgg gcgttaggat 40080acagcgcctg cataaaagcc ttgatctgct taaaagccac ctgagccttt gcgccttcag 40140agaagaacat gccgcaagac ttgccggaaa actgattggc cggacaggcc gcgtcgtgca 40200cgcagcacct tgcgtcggtg ttggagatct gcaccacatt tcggccccac cggttcttca 40260cgatcttggc cttgctagac tgctccttca gcgcgcgctg cccgttttcg ctcgtcacat 40320ccatttcaat cacgtgctcc ttatttatca taatgcttcc gtgtagacac ttaagctcgc 40380cttcgatctc agcgcagcgg tgcagccaca acgcgcagcc cgtgggctcg tgatgcttgt 40440aggtcacctc tgcaaacgac tgcaggtacg cctgcaggaa tcgccccatc atcgtcacaa 40500aggtcttgtt gctggtgaag gtcagctgca acccgcggtg ctcctcgttc agccaggtct 40560tgcatacggc cgccagagct tccacttggt caggcagtag tttgaagttc gcctttagat 40620cgttatccac gtggtacttg tccatcagcg cgcgcgcagc ctccatgccc ttctcccacg 40680cagacacgat cggcacactc agcgggttca tcaccgtaat ttcactttcc gcttcgctgg 4 0740gctcttcctc ttcctcttgc gtccgcatac cacgcgccac tgggtcgtct tcattcagcc 40800gccgcactgt gcgcttacct cctttgccat gcttgattag caccggtggg ttgctgaaac 40860ccaccatttg tagcgccaca tcttctcttt cttcctcgct gtccacgatt acctctggtg 40920atggcgggcg ctcgggcttg ggagaagggc gcttcttttt cttcttgggc gcaatggcca 40980aatccgccgc cgaggtcgat ggccgcgggc tgggtgtgcg cggcaccagc gcgtcttgtg 41040atgagtcttc ctcgtcctcg gactcgatac gccgcctcat ccgctttttt gggggcgccc 41100ggggaggcgg cggcgacggg gacggggacg acacgtcctc catggttggg ggacgtcgcg 41160ccgcaccgcg tccgcgctcg ggggtggttt cgcgctgctc ctcttcccga ctggccattt 41220ccttctccta taggcagaaa aagatcatgg agtcagtcga gaagaaggac agcctaaccg 41280ccccctctga gttcgccacc accgcctcca ccgatgccgc caacgcgcct accaccttcc 41340ccgtcgaggc acccccgctt gaggaggagg aagtgattat cgagcaggac ccaggttttg 41400taagcgaaga cgacgaggac cgctcagtac caacagagga taaaaagcaa gaccaggaca 414 60acgcagaggc aaacgaggaa caagtcgggc ggggggacga aaggcatggc gactacctag 41520atgtgggaga cgacgtgctg ttgaagcatc tgcagcgcca gtgcgccatt atctgcgacg 41580cgttgcaaga gcgcagcgat gtgcccctcg ccatagcgga tgtcagcctt gcctacgaac 41640gccacctatt ctcaccgcgc gtacccccca aacgccaaga aaacggcaca tgcgagccca 41700acccgcgcct caacttctac cccgtatttg ccgtgccaga ggtgcttgcc acctatcaca 41760tctttttcca aaactgcaag atacccctat cctgccgtgc caaccgcagc cgagcggaca 41820agcagctggc cttgcggcag ggcgctgtca tacctgatat cgcctcgctc aacgaagtgc 41880caaaaatctt tgagggtctt ggacgcgacg agaagcgcgc ggcaaacgct ctgcaacagg 41940aaaacagcga aaatgaaagt cactctggag tgttggtgga actcgagggt gacaacgcgc 42000gcctagccgt actaaaacgc agcatcgagg tcacccactt tgcctacccg gcacttaacc 42060taccccccaa ggtcatgagc acagtcatga gtgagctgat cgtgcgccgt gcgcagcccc 42120tggagaggga tgcaaatttg caagaacaaa cagaggaggg cctacccgca gttggcgacg 42180agcagctagc gcgctggctt caaacgcgcg agcctgccga cttggaggag cgacgcaaac 42240taatgatggc cgcagtgctc gttaccgtgg agcttgagtg catgcagcgg ttctttgctg 42300acccggagat gcagcgcaag ctagaggaaa cattgcacta cacctttcga cagggctacg 42360tacgccaggc ctgcaagatc tccaacgtgg agctctgcaa cctggtctcc taccttggaa 42420ttttgcacga aaaccgcctt gggcaaaacg tgcttcattc cacgctcaag ggcgaggcgc 42480gccgcgacta cgtccgcgac tgcgtttact tatttctatg ctacacctgg cagacggcca 42540, tgggcgtttg gcagcagtgc ttggaggagt gcaacctcaa ggagctgcag aaactgctaa 42600agcaaaactt gaaggaccta tggacggcct tcaacgagcg ctccgtggcc gcgcacctgg 42660cggacatcat tttccccgaa cgcctgctta aaaccctgca acagggtctg ccagacttca 42720ccagtcaaag catgttgcag aactttagga actttatcct agagcgctca ggaatcttgc 42780ccgccacctg ctgtgcactt cctagcgact ttgtgcccat taagtaccgc gaatgccctc 42840cgccgctttg gggccactgc taccttctgc agctagccaa ctaccttgcc taccactctg 42900acataatgga agacgtgagc ggtgacggtc tactggagtg tcactgtcgc tgcaacctat 42960gcaccccgca ccgctccctg gtttgcaatt cgcagctgct taacgaaagt caaattatçg 43020gtacctttga gctgcagggt ccctcgcctg acgaaaagtc cgcggctccg gggttgaaac 43080tcactccggg gctgtggacg tcggcttacc ttcgcaaatt tgtacctgag gactaccacg 4 3140cccacgagat taggttctac gaagaccaat cccgcccgcc aaatgcggag cttaccgcct 43200gcgtcattac ccagggccac attcttggcc aattgcaagc catcaacaaa gcccgccaag 4 3260agtttctgct acgaaaggga cggggggttt acttggaccc ccagtccggc gaggagctca 43320acccaatccc cccgccgccg cagccctatc agcagcagcc gcgggccctt gcttcccagg 43380atggcaccca aaaagaagct gcagctgccg ccgccaccca cggacgagga ggaatactgg 4 3440gacagtcagg cagaggaggt tttggacgag gaggaggagg acatgatgga agactgggag 43500agcctagacg aggaagcttc cgaggtcgaa gaggtgtcag acgaaacacc gtcaccctcg 43560gtcgcattcc cctcgccggc gccccagaáa tcggcaaccg gttccagcat ggctacaacc 4 3620tccgctcctc aggcgccgcc ggcactgccc gttcgccgac ccaaccgtag atgggacacc 4 3680actggaacca gggccggtaa gtccaagcag ccgccgccgt tagcccaaga gcaacaacag 43740cgccaaggct accgctcatg gcgcgggcac aagaacgcca tagttgcttg cttgcaagac 4 3800tgtgggggca acatctcctt cgcccgccgc tttcttctct accatcacgg cgtggccttc 43860ccccgtaaca tcctgcatta ctaccgtcat ctctacagcc catactgcac cggcggcagc 43920ggcagcggca gcaacagcag cggccacaca gaagcaaagg cgaccggata gcaagactct 43980gacaaagccc aagaaatcca cagcggcggc agcagcagga ggaggagcgc tgcgtctggc 4 4040gcccaacgaa cccgtatcga cccgcgagct tagaaacagg atttttccca ctctgtatgc 44100tatatttcaa cagagcaggg gccaagaaca agagctgaaa ataaaaaaca ggtctctgcg 44160atccctcacc cgcagctgcc tgtatcacaa aagcgaagat cagcttcggc gcacgctgga 4 4220agacgcggag gctctcttca gtaaatactg cgcgctgact cttaaggact agtttcgcgc 4 4280cctttctcaa atttaagcgc gaaaactacg tcatctccag cggccacacc cggcgccagc 44340acctgtcgtc agcgccatta tgagcaagga aattcccacg ccctacatgt ggagttacca 44400gccacaaatg ggacttgcgg ctggagctgc ccaagactac tcaacccgaa taaactacat 44460gagcgcggga ccccacatga tatcccgggt caacggaatc cgcgcccacc gaaaccgaat 44520tctcttggaa caggcggcta ttaccaccac acctcgtaat aaccttaatc cccgtagttg 44580gcccgctgcc ctggtgtacc aggaaagtcc cgctcccacc actgtggtac ttcccagaga 4 4640cgcccaggcc gaagttcaga tgactaactc aggggcgcag cttgcgggcg gctttcgtca 4 4700cagggtgcgg tcgcccgggc agggtataac tcacctgaca atcagagggc gaggtattca 44760gctcaacgac gagtcggtga gctcctcgct tggtctccgt ccggacggga catttcagat 4 4820cggcggcgcc ggccgtcctt cattcacgcc tcgtcaggca atcctaactc tgcagacctc 4 4880gtcctctgag ccgcgctctg gaggcattgg aactctgcaa tttattgagg agtttgtgcc 4 4940atcggtctac tttaacccct tctcgggacc tcccggccac tatccggatc aatttattcc 4 5000taactttgac gcggtaaagg actcggcgga cggctacgac tgaatgttaa gtggagaggc 45060agagcaactg cgcctgaaac acctggtcca ctgtcgccgc cacaagtgct ttgcccgcga 45120ctccggtgag ttttgctact ttgaattgcc cgaggatcat atcgagggcc cggcgcacgg 45180cgtccggctt accgcccagg gagagcttgc ccgtagcctg attcgggagt ttacccagcg 45240ccccctgcta gttgagcggg acaggggacc ctgtgttctc actgtgattt gcaactgtcc 45300taaccttgga ttacatcaag atcctctagt tataactaga gtacccgggg atcttattcc 45360ctttaactaa taaaaaaaaa taataaagca tcacttactt aaaatcagtt agcaaatttc 45420tgtccagttt attcagcagc acctccttgc cctcctccca gctctggtat tgcagcttcc 45480tcctggctgc aaactttctc cacaatctaa atggaatgtc agtttcctcc tgttcctgtc 45540catccgcacc cactatcttc atgttgttgc agatgaagcg cgcaagaccg tctgaagata 45600ccttcaaccc cgtgtatcca tatgacacgg aaaccggtcc tccaactgtg ccttttctta 45660ctcctccctt tgtatccccc aatgggtttc aagagagtcc ccctggggta ctctctttgc 45720gcctatccga acctctagtt acctccaatg gcatgcttgc gctcaaaatg ggcaacggcc 45780tctctctgga cgaggccggc aaccttacct cccaaaatgt aaccactgtg agcccacctc 45840tcaaaaaaac caagtcaaac ataaacctgg aaatatctgc acccctcaca gttacctcag 4 5900aagccctaac tgtggctgcc gccgcacctc taatggtcgc gggcaacaca ctcaccatgc 45960aatcacaggc cccgctaacc gtgcacgact ccaaacttag cattgccacc caaggacccc 46020tcacagtgtc agaaggaaag ctagccctgc aaacatcagg ccccctcacc accaccgata 46080gcagtaccct tactatcact gcctcacccc ctctaactac tgccactggt agcttgggca 46140ttgaçttgaa agagcccatt tatacacaaa atggaaaact aggactaaag tacggggctc 46200ctttgcatgt aacagacgac ctaaacactt tgaccgtagc aactggtcca ggtgtgacta 46260ttaataátac ttccttgcaa actaaagtta ctggagcctt gggttttgat tcácaaggca 46320atatgcaact taatgtagca ggaggactaa ggattgattc tcaaaacaga cgccttatac 46380ttgatgttag ttatccgttt gatgctcaaa accaactaaa tctaagacta ggacagggcc 46440ctctttttat aaactcagcc cacaacttgg atattaacta caacaaaggc ctttácttgt 46500ttacagcttc aaacaattcc aaaaagcttg aggttaacct aagcactgcc aaggggttga 46560tgtttgacgc tacagccata gccattaatg caggagatgg gcttgaattt ggttcaccta 46620atgcaccaaa cacaaatccc ctcaaaacaa aaattggcca tggcctagaa tttgattcaa 46680acaaggctat ggttcctaaa ctaggaactg gccttagttt tgacagcaca ggtgccatta 46740cagtaggaaa caaaaataat gataagctaa ctttgtggac cacaccagct ccatctccta 46800actgtagact aaatgcagag aaagatgcta aactcacttt ggtcttaaca aaatgtggca 46860gtcaaatact tgctacagtt tcagttttgg ctgttaaagg cagtttggct ccaatatctg 46920gaacagttca aagtgctcat cttattataa gatttgacga aaatggagtg ctactaaaca 46980attccttcct ggacccagaa tattggaact ttagaaatgg agatcttact gaaggcacag 47040cctatacaaa cgctgttgga tttatgccta acctatcagc ttatccaaaa tctcacggta 47100aaactgccaa aagtaacatt gtcagtcaag tttacttaaa cggagacaaa actaaacctg 47160taacactaac cattacacta aacggtacac aggaaacágg agacacaact ccaagtgcat 47220actctatgtc attttcatgg gactggtctg gccacaacta cattaatgaa atatttgcca 47280catcctctta cactttttca tacattgccc aagaataaag aatcgtttgt gttatgtttc 47340aacgtgttta tttttcaatt gcagaaaatt tcaagtcatt tttcattcag tagtatagcc 47400ccaccaccac atagcttata cagatcaccg taccttaatc aaactcacag aaccctagta 47460ttcaacctgc cacctccctc ccaacacaca gagtacacag tcctttctcc ccggctggcc 47520ttaaaaagca tcatatcatg ggtaacagac atattcttag gtgttatatt ccacacggtt 47580tcctgtcgag ccaaacgctc atcagtgata ttaataaact ccccgggcag ctcacttaag 47640ttcatgtcgc tgtccagctg ctgagccaca ggctgctgtc caacttgcgg ttgcttaacg 47700ggcggcgaag gagaagtcca cgcctacatg ggggtagagt cataatcgtg catcaggata 47760gggcggtggt gctgcagcag cgcgcgaata aactgctgcc gccgccgctc cgtcctgcag 47820gaatacaaca tggcagtggt ctcctcagcg atgattcgca ccgcccgcag cataaggcgc 47880cttgtcctcc gggcacagca gcgcaccctg atctcactta aatcagcaca gtaactgcag 47940cacagcacca caatattgtt caaaatccca cagtgcaagg cgctgtatcc aaagctcatg 48000gcggggacca cagaacccac gtggccatca taccacaagc gcaggtagat taagtggcga 48060cccctcataa acacgctgga cataaacatt acctcttttg gcatgttgta attcaccacc 48120tcccggtacc atataaacct ctgattaaac atggcgccat ccaccaccat cctaaaccag 48180ctggccaaaa cctgcccgcc ggctatacac tgcagggaac cgggactgga acaatgacag 48240tggagagccc aggactcgta accatggatc atcatgctcg tcatgatatc aatgttggca 48300caacacaggc acacgtgcat acacttcctc aggattacaa gctcctcccg cgttagaacc 48360atatcccagg gaacaaccca ttcctgaatc agcgtaaatc ccacactgca gggaagacct 48420cgcacgtaac tcacgttgtg cattgtcaaa gtgttacatt cgggcagcag cggatgatcc 48480tccagtatgg tagcgcgggt ttctgtctca aaaggaggta gacgatccct actgtacgga 48540gtgcgccgag acaaccgaga tcgtgttggt cgtagtgtca tgccaaatgg aacgccggac 48600gtagtcatat ttcctgaagc aaaaccaggt gcgggcgtga caaacagatc tgcgtctccg 48660gtctcgccgc ttagatcgct ctgtgtagta gttgtagtat atccactctc tcaaagcatc 48720caggcgcccc ctggcttcgg gttctatgta aactccttca tgcgccgctg ccctgataac 48780atccaccacc gcagaataag ccacacccag ccaacctaca cattcgttct gcgagtcaca 48840cacgggagga gcgggaagag ctggaagaac catgtttttt tttttattcc aaaagattat 48900ccaaaacctc àaaatgaaga tctattaagt gaacgcgctc ccctccggtg gcgtggtcaa 48960actctacagc caaagaacag ataatggcat ttgtaagatg ttgcacaatg gcttccaaaa 4 9020ggcaaacggc cctcacgtcc aagtggacgt aaaggctaaa cccttcaggg tgaatctcct 4 9080ctataaacat tccagcacct tcaaccatgc ccaaataatt ctcatctcgc caccttctca 49140atatatctct aagcaaatcc cgaatattaa gtccggccat tgtaaaaatc tgctccagag 4 9200cgccctccac cttcagcctc aagcagcgaa tcatgattgc aaaaattcag gttcctcaca 49260gacctgtata agattcaaaa gcggaacatt aacaaaaata ccgcgatccc gtaggtccct 49320tcgcagggcc agctgaacat aatcgtgcag gtctgcacgg accagcgcgg ccacttcccc 4 9380gccaggáacc ttgacaaaag aacccacact gattatgaca cgcatactcg gagctatgct 4 9440aaccagcgta gccccgatgt aagctttgtt gcatgggcgg cgatataaaa tgcaaggtgc 49500tgctcaaaaa atcaggcaaa gcctcgcgca aaaaagaaag cacatcgtag tcatgctcat 49560gcagataaag gcaggtaagc tccggaacca ccacagaaaa agacaccatt tttctctcaa 4 9620acatgtctgc gggtttctgc ataaacacaa aataaaataa caaaaaaaca tttaaacatt 49680agaagcctgt cttacaacag gaaaaacaac ccttataagc ataagacgga ctacggccat 49740gccggcgtga ccgtaaaaaa actggtcacc gtgattaaaa agcaccaccg acagctcctc 49800ggtcatgtcc ggagtcataa tgtaagactc ggtaaacaca tcaggttgat tcatcggtca 4 9860gtgctaaaaa gcgaccgaaa tagcccgggg gaatacatac ccgcaggcgt agagacaaca 4 9920ttacagcccc cataggaggt ataacaaaat taataggaga gaaaaacaca taaacacctg 4998Óaaaaaccctc ctgcctaggc aaaatagcac cctcccgctc cagaacaaca tacagcgctt 50040cacagcggca gcctaacagt cagccttacc agtaaaaaag aaaacctatt aaaaaaacac 50100cactcgacac ggcaccagct caatcagtca cagtgtaaaa aagggccaag tgcagagcga 50160gtatatatag gactaaaaaa tgacgtaacg gttaaagtcc acaaaaaaca cccagaaaac 50220cgcacgcgaa cctacgccca gaaacgaaag ccaaaaaacc cacaacttcc tcaaatcgtc 50280acttccgttt tcccàcgtta cgtaacttcc çattttaaga aaactacaat tcccaacaca 50340tacaagttac tccgccctaa aacctacgtç acccgccccg ttcccacgcc ccgcgccacg 50400tcacaaactc caccccctca ttatcatatt ggcttcaatc caaaataagg tatattattg 504 60atgatnnnnn ttaat 50475
<210> 17<211> 39301<212> DNA
<213> Seqüência artificial<220>
<223> vetor adenoviral quimérico NDl. 1 214, vetor pAd contendo DS2C-luc<221> base modificada<222>(1)... (39301)<223> η = g, a, c ou t<400> 17
taaggatccn nrvcctgtcct cgaccgatgc ccttgagagc cttcaaccca gtcagctcct 60tccggtgggc gcggggcatg actatcgtcg ccgcacttat gactgtcttc tttatcatgc 120aactcgtagg acaggtgccg gcagcgctct gggtcatttt cggcgaggac cgctttcgct 180ggagcgcgac gatgatcggc ctgtcgcttg cggtattcgg aatcttgcac gccctcgctc 240aagccttcgt cactggtccc gccaccaaac gtttcggçga gaagcaggcc attatcgccg 300gcatggcggc cgacgcgctg ggctacgtct tgctggcgtt cgcgacgcga ggctggatgg 360ccttccccat tatgattctt ctcgcttccg gcggcatcgg gatgcccgcg ttgcaggcca 420tgctgtccag gcaggtagat gacgaccatc agggacagct tcaaggatcg ctcgcggctc 480ttaccagcct aacttcgatc actggaccgc tgatcgtcac ggcgatttat gccgcctcgg 540cgagcacatg gaacgggttg gcatggattg taggcgccgc cctatacctt gtctgcctcc 600ccgcgttgcg tcgcggtgca tggagccggg ccacctcgac ctgaatggaa gccggcggca 660cctcgctaac ggattcacca ctccaagaat tggagccaat caattcttgc ggagaactgt 720gaatgcgcaa accaaccctt ggcagaacat atccatcgcg tccgccatct ccagcagccg 780cacgcggcgc atctcgggca gcgttgggtc ctggccacgg gtgcgcatga tcgtgctcct 840gtcgttgagg acccggctag gctggcgggg ttgccttact ggttagcaga atgaatcacc 900gatacgcgag cgaacgtgaa gcgactgctg ctgcaaaacg tctgcgacct gagcaacaac 960atgaatggtc ttcggtttcc gtgtttcgta aagtctggaa acgcggaagt cagcgccctg 1020caccattatg ttccggatct gcatcgcagg atgctgctgg ctaccctgtg gaacacctac 1080atctgtattá acgaagcgct ggcattgacc ctgagtgatt tttctctggt cccgccgcat 1140ccataccgcc agttgtttac cctcacaacg ttccagtaac cgggcatgtt catcatcagt 1200aacccgtatc gtgagcatcc tctctcgttt catcggtatc attaccccca tgaacagaaa 1260ttccccctta cacggaggca tcaagtgacc aaacaggaaa aaaccgccct taacatggcc 1320cgctttatca gaagccagac attaacgctt ctggagaaac tcaacgagct ggacgcggat 1380gaacaggcag acatctgtga atcgcttcac gaccacgctg atgagcttta ccgcagctgc 1440ctcgcgcgtt tcggtgatga cggtgaaaac ctctgacaca tgcagctccc ggagacggtc 1500acagcttgtc tgtaagcgga tgccgggagc agacaagccc gtcagggcgc gtcagcgggt 1560gttggcgggt gtcggggcgc agccatgacc cagtcacgta gcgatagcgg agtgtatact 1620ggcttaacta tgcggcatca gagcagattg tactgagagt gcaccatatg cggtgtgaaa 1680taccgcacag atgcgtaagg agaaaatacc gcatcaggcg ctcttccgct tcctcgctca 1740ctgactcgct gcgctcggtc gttcggctgc ggcgagcggt atcagctcac tcaaaggcgg 1800taatacggtt atccacagaa tcaggggata acgcaggaaa gaacatgtga gcaaaaggcc 1860agcaaaaggc caggaaccgt aaaaaggccg cgttgctggc gtttttccat aggctccgcc 1920cccctgacga gcatcacaaa aatcgacgct caagtcagag gtggcgaaac ccgacaggãc 1980tataaagata ccaggcgttt ccccctggaa gctccctcgt gcgctctcct gttccgaccc 2040tgccgcttac cggatacctg tccgcctttc tcccttcggg aagcgtggcg ctttctcaat 2100gctcacgctg taggtatctc agttcggtgt aggtcgttcg ctccaagctg ggctgtgtgc 2160acgaaccccc cgttcagccc gaccgctgcg ccttatccgg taactatcgt cttgagtcca 2220acccggtaag acacgactta tcgccactgg cagcagccac tggtaacagg attagcagag 2280cgaggtatgt aggcggtgct acagagttct tgaagtggtg gcctaactac ggctacacta 2340gaaggacagt atttggtatc tgcgctctgc tgaagccagt taccttcgga aaaagagttg 2400gtagctcttg atccggcaaa caaaccaccg ctggtagcgg tggttttttt gtttgcaagc 2460agcagattac gcgcagaaaa aaaggatctc aagaagatcc tttgatcttt tctacggggt 2520ctgacgctca gtggaacgaa aactcacgtt aagggatttt ggtcatgaga ttatcaaaaa 2580ggatcttcac ctagatcctt ttaaattaaa aatgaagttt taaatcaatc taaagtatat 2640atgagtaaac ttggtctgac agttaccaat gcttaatcag tgaggcacct atctcagcga 2700tctgtctatt tcgttcatcc atagttgcct gactccccgt cgtgtagata actacgatac 2760gggagggctt accatctggc cccagtgctg caatgatacc gcgagaccca cgctcaccgg 2820ctccagattt atcagcaata aaccagccag ccggaagggc cgagcgcaga agtggtcctg 2880caactttatc cgcctccatc cagtctatta attgttgccg ggaagctaga gtaagtagtt 2940cgccagttaa tagtttgcgc aacgttgttg ccattgctgc agccatgaga ttatcaaaaa 3000ggatcttcac ctagatcctt ttcacgtaga aagccagtcc gcagaaacgg tgctgacccc 3060ggatgaatgt cagctactgg gctatctgga caagggaaaa cgcaagcgca aagagaaagc 3120aggtagcttg cagtgggctt acatggcgat agctagactg ggcggtttta tggacagcaa 3180gcgaaccgga attgccagct ggggcgccct ctggtaaggt tgggaagccc tgcaaagtaa 3240actggatggc tttctcgccg ccaaggatct gatggcgcag gggatcaagc tctgatcaag 3300agacaggatg aggatcgttt cgcatgattg aacaagatgg attgcacgca ggttctccgg 3360ccgcttgggt ggagaggcta ttcggctatg actgggcaca acagacaatc ggctgctctg 3420atgccgccgt gttccggctg tcagcgcagg ggcgcccggt tctttttgtc aagaccgacc 3480tgtccggtgc cctgaatgaa ctgcaagacg aggcagcgcg gctatcgtgg ctggccacga 3540cgggcgttcc ttgcgcagct gtgctcgacg ttgtcactga agcgggaagg gactggctgc 3600tattgggcga agtgccgggg caggatctcc tgtcatctca ccttgctcct gccgagaaag 3660tatccatcat ggctgatgca atgcggcggc tgcatacgct tgatccggct acctgcccat 3720tcgaccacca agcgaaacat cgcatcgagc gagcacgtac tcggatggaa gccggtcttg 3780tcgatcagga tgatctggac gaagagcatc aggggctcgc gccagccgaa ctgttcgcca 3840ggctcaaggc gagcatgccc gacggcgagg atctcgtcgt gacccatggc gatgcctgct 3900tgccgaatat catggtggaa aatggccgct tttctggatt catcgactgt ggccggctgg 3960gtgtggcgga ccgctatcag gacatagcgt tggctacccg tgatattgct gaagagcttg 4020gcggcgaatg ggctgaccgc ttcctcgtgc tttacggtat cgccgctccc gattcgcagc 4080gcatcgcctt ctatcgcctt cttgacgagt tcttctgaat tttgttaaaa tttttgttaa 4140atcagctcat tttttaacca ataggccgaa atcggcaaca tcccttataa atcaaaagaa 4200tagaccgcga tagggttgag tgttgttcca gtttggaaca agagtccact attaaagaac 4260gtggactcca acgtcaaagg gcgaaaaacc gtctatcagg gcgatggccc actacgtgaa 4320ccatcaccca aatcaagttt tttgcggtcg aggtgccgta aagctctaaa tcggaaccct 4380aaagggagcc cccgatttag agcttgacgg ggaaagccgg cgaacgtggc gagaaaggaa 4440gggaagaaag cgaaaggagc gggcgctagg gcgctggcaa gtgtagcggt cacgctgcgc 4500gtaaccacca cacccgcgcg cttaatgcgc cgctacaggg cgcgtccatt cgccattcag 4560gatcgaatta attcttaatt aacatcatca ataatatacc ttattttgga ttgaagccaa 4620tatgataatg agggggtgga gtttgtgacg tggcgcgggg cgtgggaacg gggcgggtga 4680cgtagtagtg tggcggaagt gtgatgttgc aagtgtggcg gaacacatgt aagcgacgga 4740tgtggcaaaa gtgacgtttt tggtgtgcgc cggtgtacac aggaagtgac aattttcgcg 4800cggttttagg cggatgttgt agtaaatttg ggcgtaaccg agtaagattt ggccattttc 4860gcgggaaaac tgaataagag gaagtgaaat ctgaataatt ttgtgttact catagcgcgt 4920aatactgcta gagatctggc gaaaggggga tgtgctgcaa ggcgattaag ttgggtaaçg 4980ccagggtttt cccagtcacg acgttgtaaa acgacggcca gtgaattgta atacgactca 5040ctatagggcg aattgggtac tggccacaga gcttggccca ttgcatacgt tgtatccata 5100tcataatatg tacatttata ttggctcatg tccaacatta ccgccatgtt gacattgatt 5160attgactagt tattaatagt aatcaattac ggggtcatta gttcatagcc catatatgga 5220gttccgcgtt acataactta cggtaaatgg cccgcctggc tgaccgccca acgacccccg 5280cccattgacg tcaataatga cgtatgttcc catagtaacg ccaataggga ctttccattg 5340acgtcaatgg gtggagtatt tacggtaaac tgcccacttg gcagtacatc aagtgtatca 5400tatgccaagt acgcccccta ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc 5460ccagtacatg accttatggg actttcctac ttggcagtac atctacgtat tagtcatcgc 5520tattaccatg gtgatgcggt tttggcagta catcaatggg cgtggatagc ggtttgactc 5580acggggattt ccaagtctcc accccattga cgtcaatggg agtttgtttt ggcaccaaaa 5640tcaacgggac tttccaaaat gtcgtaacaa ctccgcccca ttgacgcaaa tgggcggtag 5700gcgtgtacgg tgggaggtct atataagcag agctcgttta gtgaaccgtc agatcgcctg 5760gagacgccat ccacgctgtt ttgacctcca tagaagacac cgggaccgat ccagcctgac 5820tctagcctag ctctgaagtt ggtggtgagg ccctgggcag gttggtatca aggttacaag 5880acaggtttaa ggagaccaat agaaactggg catgtggaga cagagaagac tcttgggttt 5940ctgataggca ctgactctct ctgcctattg gtctattttc ccacccttag gctgctggtc 6000tgagcctagg agatctctcg aggtcgacgg tatcgatgcc accatggaga aaatcgtcct 6060gttgctcgct attgtgtctc tagtgaagag cgatcaaatt tgtatcggct accatgccaa 6120taactcaaca gagcaggtcg atactatcat ggagaaaaac gtaacagtta ctcatgccca 6180agacatcttg gaaaagaccc acaacggcaa actttgcgac ctggatggag tgaagcccct 6240gàtcctccgg gactgttcag tcgctggttg gctgctcggg aaccctatgt gtgatgagtt 6300tatcaacgtg cctgaatggt cttacafctgt ggagaaggct aaccctacca atgacctctg 6360ctatcctggg tcatttaacg attacgagga actgaaacac ctgttgtcta gaattaacca 6420ctttgaaaag atacagatta tacccaagtc tagttggagt gatcacgaag cctcctcagg 6480cgttagctca gcgtgtccct atctgggctc tccatccttc tttagaaatg tggtctggtt 654 0aatcaaaaag aacagtacct acccaaccat caaaaagtct tataacaata ccaatcagga 6600ggacctgctc gtgttgtggg gtatccatca cccgaacgac gccgctgaac agactaggct 6660gtatcagaac cccactacat acatcagtat tggcacgagt actctgaacc agcgattagt 6720gccaaagatt gcaacacgga gcaaagtaaa tgggcaatct ggcaggatgg agtttttctg 6780gacaatctta aaacccaacg atgcgataaa tttcgagtcc aatggcaatt tcatcgcccc 6840tgaatacgcc tataagatcg tgaaaaaggg ggactctgca attatgaagt ccgaattaga 6900gtatggcaat tgcaacacga agtgccagac accaatggga gccattaata gctcaatgcc 6960cttccataat attcatccat tgaccattgg ggagtgccca aagtacgtga agtccaaccg 7020cctggtcctc gcaaccggtc taagaaatag cccgcagaga gaatcgcgga ggaagaaacg 7080tggcctgttt ggcgcgattg ccggattcat cgagggaggc tggcagggta tggtcgatgg 7140ttggtacgga taccaccata gcaacgaaca ggggtccggc tatgcagcag ataaggagag 7200cactcagaaa gctattgacg gagttacaaa caaggttaat agtattatag ataaaatgaa 7260cacgcaattc gaggccgttg ggagggagtt taacaatctg gaacgccgga tcgaaaatct 7320gaataagaaa atggaagacg gcttccttga cgtgtggact tataatgcag agctgcttgt 7380actcatggag aacgagagga ccctggattt ccacgatagc aacgtgaaga acctttacga 7440caaggtgaga cttcagctcc gagacaacgc caaggagctg gggaatggat gcttcgagtt 7500ttaccacaaa tgtgacaatg agtgcatgga aagtatacgc aacgggacct acaattaccc 7560tcagtatagc gaagaggctc ggctçaaacg cgaagagata agcggggtga aattggaatc 7620aatcggaaca tatcaaatcc tgtccatcta ttccaccgtc gcctcttcgc tggccctcgc 7680tatcatgatg gctggtctgt ccctatggat gtgttccaat ggaagccttc agtgccgtat 7740ttgtatatga gcggccgccc tattctatag tgtcacctaa atgctagagc tcgctgatca 7800gcctcgactg tgccttctag ttgccagcca tctgttgttt gcccctcccc cgtgccttcc 7860ttgaccctgg aaggtgccac tcccactgtc ctttcctaat aaaatgagga aattgcatcg 7920cattgtctga gtaggtgtca ttctattctg gggggtgggg tggggcagga cagcaagggg 7980gaggattggg aagacaatag caggcatgct ggggatgcgg tgggctctat ggcttctgag 8040gcggaaagaa ccaaagctta acatcatcaa taatatacct tattttggat tgaagccaat 8100atgataatga gggggtggag tttgtgacgt ggcgcggggc gtgggaacgg ggcgggtgac 8160gtagtagtgt ggcggaagtg tgatgttgca agtgtggcgg aacacatgta agcgacggat 8220gtggcaaaag tgacgttttt ggtgtgcgcc ggtgtacaca ggaagtgaca attttcgcgc 8280ggttttaggc ggatgttgta gtaaatttgg gcgtaaccga gtaagatttg gccattttcg 834 0cgggaaaact gaataagagg aagtgaaatc tgaataattt tgtgttactc atagcgcgta 8400atactgtaat agtaatcaat tacggggtca ttagttcata gcccatatat ggagttccgc 8460gttacataac ttacggtaaa tggcccgcct ggctgaccgc ccaacgaccc ccgcccattg 8520acgtcaataa tgacgtatgt tcccatagta acgccaatag ggactttcca ttgacgtcaa 8580tgggtggagt atttacggta aactgcccac ttggcagtac atcaagtgta tcatatgcça 8640agtacgcccc ctattgacgt caatgacggt aaatggcccg cctggcatta tgcccagtac 8700atgaccttat gggactttcc tacttggcag tacatctacg tattagtcat cgctattacc 8760atggtgatgc ggttttggca gtacatcaat gggcgtggat agcggtttga ctcacgggga 8820tttccaagtc tccaccccat tgacgtcaat gggagtttgt tttggcacca aaatcaacgg 8880gactttccaa aatgtcgtaa caactccgcc ccattgacgc aaatgggcgg taggcgtgta 8940cggtgggagg tctatataag cagagctggt ttagtgaacc gtcagatccg ctagagatct 9000gggaaacgat atgggctgaa tacggatccg tattcagccc atatcgtttc tctagaaata 9060aaatatcttt attttcatta catctgtgtg ttggtttttt gtgtggcggc cgctcgagcc 9120taagcttcta gataagatat ccgatccacc ggatctagat aactgatcat aatcagccat 9180accacatttg tagaggtttt acttgcttta aaaaacctcc cacacctccc cctgaacctg 9240aaacataaaa tgaatgcaat tgttgttgtt aacttgttta ttgcagctta taatggttac 9300aaataaagca atagcatcac aaatttcacà aataaagcat ttttttcact gcattctagt 9360tgtggtttgt ccaaactcat caatgtatct taacgcggat ctgggcgtgg ttaagggtgg 9420gaaagaatát ataaggtggg ggtcttatgt agttttgtat ctgttttgca gcagccgccg 9480cçgccatgag caccaactcg tttgatggaa gcattgtgag cttgtcgact cgaagatctg 9540ggcgtggtta agggtgggaa agaatatata aggtgggggt cttatgtagt tttgtatctg 9600ttttgcagca gccgccgccg ccatgagcac caactcgttt gatggaagca ttgtgagctc 9660atatttgaca acgcgcatgc ccccatgggc cggggtgcgt cagaatgtga tgggctccag 9720cattgatggt cgccccgtcc tgcccgcaaa ctctactacc ttgacctacg agaccgtgtc 9780tggaacgccg ttggagactg cagcctccgc cgccgcttca gccgctgcag ccaccgcccg 9840cgggattgtg actgactttg ctttcctgag cccgcttgca agcagtgcag cttcccgttc 9900atccgcccgc gatgacaagt tgacggctct tttggcacaa ttggattctt tgacccggga 9960acttaatgtc gtttctcagc agctgttgga tctgcgccag caggtttctg ccctgaaggc 10020ttcctcccct cccaatgcgg tttaaaacat aaataaaaaa ccagactctg tttggatttg 10080gatcaagcaa gtgtcttgct gtctttattt aggggttttg cgcgcgcggt aggcccggga 10140ccagcggtct cggtcgttga gggtcctgtg tattttttcc aggacgtggt aaaggtgact 10200ctggatgttc agatacatgg gcataagccc gtctctgggg tggaggtagc accactgcag 10260agcttcatgc tgcggggtgg tgttgtagat gatccagtcg tagcaggagc gctgggcgtg 10320gtgcctaaaa atgtctttca gtagcaagct gattgccagg ggcaggccct tggtgtaagt 10380gtttacaaag cggttaagct gggatgggtg catacgtggg gatatgagat gcatcttgga 10440ctgtattttt aggttggcta tgttcccagc catatccctc cggggattca tgttgtgcag 10500aaccaccagc acagtgtatc cggtgcactt gggaaatttg tcatgtagct tagaaggaaa 10560tgcgtggaag aacttggaga cgcccttgtg acctccaaga ttttccatgc attcgtccat 10620aatgatggca atgggcccac gggcggcggc ctgggcgaag atatttctgg gatcactaac 10680gtcatagttg tgttccagga tgagatcgtc ataggccatt tttacaaagc gcgggcggag 10740ggtgccagac tgcggtataa tggttccatc cggcccaggg gcgtagttac cctcacagat 10800ttgcatttcc cacgctttga gttcagatgg ggggatcatg tctacctgcg gggcgatgaa 10860gaaaacggtt tccggggtag gggagatcag ctgggaagaa agcaggttcc tgagcagctg 10920cgacttaccg cagccggtgg gcccgtaaat cacacctatt accgggtgca actggtagtt 10980aagagagctg cagctgccgt catccctgag caggggggcc acttcgttaa gcatgtccct 11040gactcgcatg ttttccctga ccaaatccgc cagaaggcgc tcgccgccca gcgatagcag 11100ttcttgcaag gaagcaaagt ttttcaacgg tttgagaccg tccgccgtag gcatgctttt 11160gagcgtttga ccaagcagtt ccaggcggtc ccacagctcg gtcacctgct ctacggcatc 11220tcgatccagc atatctcctc gtttcgcggg ttggggcggc tttcgctgta cggcagtagt 11280cggtgctcgt ccagacgggc cagggtcatg tctttccacg ggcgcagggt cctcgtcagc 11340gtagtctggg tcacggtgaa ggggtgcgct ccgggctgcg cgctggccag ggtgcgcttg 11400aggctggtcc tgctggtgct gaagcgctgc cggtcttcgc cctgcgcgtc ggccaggtag 114 60catttgacca tggtgtcata gtccagcccc tccgcggcgt ggcccttggc gcgcagcttg 11520cccttggagg aggcgccgca cgaggggcag tgcagacttt tgagggcgta gagcttgggc 11580gcgagaaata ccgattccgg ggagtaggca tccgcgccgc aggccccgca gacggtctcg 11640cattccacga gccaggtgag ctctggccgt tcggggtcaa aaaccaggtt tcccccatgc 11700tttttgatgc gtttcttacc tctggtttcc atgagccggt gtccacgctc ggtgacgaaa 11760aggctgtccg tgtccccgta tacagacttg agaggcctgt cctcgagcgg tgttccgcgg 11820tcctcctcgt atagaaactc ggaccactct gagacaaagg ctcgcgtcca ggccagcacg 11880aaggaggcta agtgggaggg gtagcggtcg ttgtccacta gggggtccac tcgctccagg 11940gtgtgaagac acatgtcgcc ctcttcggca tcaaggaagg tgattggttt gtaggtgtag 12000gccacgtgac cgggtgttcc tgaagggggg ctataaaagg gggtgggggc gcgttcgtcc 12060tcactctctt ccgcatcgct gtctgcgagg gccagctgtt ggggtgagta ctccctctga 12120aaagcgggca tgacttctgc gctaagattg tcagtttcca aaaacgagga ggatttgata 12180ttcacctggc ccgcggtgat gcctttgagg gtggccgcat ccatctggtc agaaaagaca 12240atctttttgt tgtcaagctt ggtggcaaac gacccgtaga gggcgttgga cagcaacttg 12300gcgatggagc gcagggtttg gtttttgtcg cgatcggcgc gctccttggc cgcgatgttt 12360agctgcacgt attcgcgcgc aacgcaccgc cattcgggaa agacggtggt gcgctcgtcg 12420ggcaccaggt gcacgcgcca accgcggttg tgcagggtga caaggtcaac gctggtggct 12480acctctccgc gtaggcgctc gttggtccag cagaggcggc cgcccttgcg cgagcagaat 12540ggcggtaggg ggtctagctg cgtctcgtcc ggggggtctg cgtccacggt aaagaccccg 12600ggcagcaggc gcgcgtcgaa gtagtctatc ttgcatcctt gcaagtctag cgcctgctgc 12660catgcgcggg cggcaagcgc gcgctcgtat gggttgagtg ggggaccccá tggcatgggg 12720tgggtgagcg cggaggcgta catgccgcaa atgtcgtaaa cgtagagggg ctctctgagt 12780attccaagat atgtagggta gcatcttcca ccgcggatgc tggcgcgcac gtaatcgtat 12840agttcgtgcg agggagcgag gaggtcggga ccgaggttgc tacgggcggg ctgctctgct 12900cggaagacta tctgcctgaa gatggcatgt gagttggatg atatggttgg acgctggaag 12960acgttgaagc tggcgtctgt gagacctacc gcgtcacgca cgaaggaggc gtaggagtcg 13020cgcagcttgt tgaccagctc ggcggtgacc tgcacgtcta gggcgcagta gtccagggtt 13080tccttgatga tgtcatactt atcctgtccc ttttttttcc acagctcgcg gttgaggaca 13140aactcttcgc ggtctttcca gtactcttgg atcggaaacc cgtcggcctc cgaacggtaa 13200gagcctagca tgtagaactg gttgacggcc tggtaggcgc agcatccctt ttctacgggt 13260agcgcgtatg cctgcgcggc cttccggagc gaggtgtggg tgagcgcaaa ggtgtccctg 13320accatgactt tgaggtactg gtatttgaag tcagtgtcgt cgcatccgcc ctgctcccag 13380agcaaaaagt ccgtgcgctt tttggaacgc ggatttggca gggcgaaggt gacatcgttg 13440aagagtatct ttcccgcgcg aggcataaag ttgcgtgtga tgcggaaggg tcccggcacc 13500tcggaacggt tgttaattac ctgggcggcg agcacgatct cgtcaaagcc gttgatgttg 13560tggcccacaa tgtaaagttc caagaagcgc gggatgccct tgatggaagg caatttttta 13620agttcctcgt aggtgagctc ttcaggggag ctgagcccgt gctctgaaag ggcccagtct 13680gcaagatgag ggttggaagc gacgaatgag ctccacaggt cacgggccat tagcatttgc 13740aggtggtcgc gaaaggtcct aaactggcga cctatggcca ttttttctgg ggtgatgcag 13800tagaaggtaa gcgggtcttg ttcccagcgg tcccatccaa ggttcgcggc taggtctcgc 13860gcggcagtca ctagaggctc atctccgccg aacttcatga ccagcatgaa gggcacgagc 13920tgcttcccaa aggcccccat ecaagtatag gtctctacat cgtaggtgac aaagagacgc 13980tcggtgcgag gatgcgagcc gatcgggaag aactggatct cccgccacca attggaggag 14040tggctattga tgtggtgaaa gtagaagtcc ctgcgacggg ccgaacactc gtgctggctt 14100ttgtaaaaac gtgcgcagta ctggcagcgg tgcacgggct gtacatcctg cacgaggttg 14160acctgacgac cgcgeacaag gaagcagagt gggaatttga gccçctcgcc tggcgggttt 14220ggctggtggt cttctacttc ggctgcttgt ccttgaccgt ctggctgctc gaggggagtt 14280acggtggatc ggaccaccac gccgcgcgag cccaaagtcc agatgtccgc gcgcggcggt 14340cggàgcttga tgacaacatc gcgcagatgg gagctgtcca tggtctggag ctcccgcggc 14400gtcaggtcag gcgggagctc ctgcaggttt acctcgcata gacgggtcag ggcgcgggct 14460agatccaggt gatacctaat ttccaggggc tggttggtgg cggcgtcgat ggcttgcaag 14520aggccgcatc cccgcggcgc gactacggta ccgcgcggcg ggcggtgggc cgcgggggtg 14580tccttggatg atgcatctaa aagcggtgac gcgggcgagc ccccggaggt agggggggct 14640ccggacccgc cgggagaggg ggcaggggca cgtcggcgcc gcgcgcgggc aggagctggt 14700gctgcgcgcg taggttgctg gcgaacgcga cgacgcggcg gttgatctcc tgaatctggc 14760gcctctgcgt gaagacgacg ggcccggtga gcttgagcct gaaagagagt tcgacagaat 14820caatttcggt gtcgttgacg gcggcctggc gcaaaatctc ctgcacgtct cctgagttgt 14880cttgataggc gatctcggcc atgaactgct cgatctcttc ctcctggaga tctccgcgtc 14940cggctcgctc cacggtggcg gcgaggtcgt tggaaatgcg ggccatgagc tgcgagaagg 15000cgttgaggcc tccctcgttc cagacgcggc tgtagaccac gcccccttcg gcatcgcggg 15060cgcgcatgac cacctgcgcg agattgagct ccacgtgccg ggcgaagacg gcgtagtttc 15120gcaggcgctg aaagaggtag ttgagggtgg tggcggtgtg ttctgccacg aagaagtaca 15180taacccagcg tcgcaacgtg gattcgttga tatcccccaa ggcctcaagg cgctccatgg 15240cctcgtagaa gtccacggcg aagttgaaaa actgggagtt gcgcgccgac acggttaact 15300cctcctccag aagacggatg agctcggcga cagtgtcgcg cacctcgcgc tcaaaggcta 15360caggggcctc ttcttcttct tcaatctcct cttccataag ggcctcccct tcttcttctt 15420ctggcggcgg tgggggaggg gggacacggc ggcgacgacg gcgcaccggg aggcggtcga 15480caaagcgctc gatcatctcc ccgcggcgac ggcgcatggt ctcggtgacg gcgcggccgt 15540tctcgcgggg gcgcagttgg aagacgccgc ccgtcatgtc ccggttatgg gttggcgggg 15600ggctgccatg cggcagggat acggcgctaa cgatgcatct caacaattgt tgtgtaggta 15660ctccgccgcc gagggacctg agcgagtccg catcgaccgg atcggaaaac ctctcgagaa 1572Caggcgtctaa ccagtcacag tcgcaaggta ggctgagcac cgtggcgggc ggcagcgggc 1578Cggcggtcggg gttgtttctg gcggaggtgc tgctgatgat gtaattaaag taggcggtct 1584Ctgagacggcg gatggtcgac agaagcacca tgtccttggg tccggcctgc tgaatgcgca 15900ggcggtcggc catgccccag gcttcgtttt gacatcggcg caggtctttg tagtagtçtt 15960gcatgagcct ttctaccggc acttcttctt ctccttcctc ttgtcctgca tctcttgcat 16020ctatcgctgc ggcggcggcg gagtttggcc gtaggtggcg ccctcttcct cccatgcgtg 16080tgaccccgaa gcccctcatc ggctgaagca gggctaggtc ggcgacaacg cgctcggcta 16140atatggcctg ctgcacctgc gtgagggtag actggaagtc atccatgtcc acaaagcggt 16200ggtatgcgcc cgtgttgatg gtgtaagtgc agttggccat aacggaccag ttaacggtct 16260ggtgacccgg ctgcgagagc tcggtgtacc tgagacgcga gtaagccctcgagtcaaata 16320cgtagtcgtt gcaagtccgc accaggtact ggtatcccac caaàaagtgc ggcggcggct 16380ggcggtagag gggccagcgt agggtggccg gggctccggg ggcgagatct tccaacataa 16440ggcgatgata tccgtagatg tacctggaca tccaggtgat gccggcggcg gtggtggagg 16500cgcgcggaaa gtcgcggacg cggttccaga tgttgcgcag cggcaaaaag tgctccatgg 16560tcgggacgct ctggccggtc aggcgcgcgc aatcgttgac gctctaccgt gcaaaaggag 16620agcctgtaag cgggcactct tccgtggtct ggtggataaa ttcgcaaggg tatcatggcg 16680gacgaccggg gttcgagccc cgtatccggc cgtccgccgt gatccatgcg gttaccgccc 16740gcgtgtcgaa cccaggtgtg cgacgtcaga caacggggga gtgctccttt tggcttcctt 16800ccaggcgcgg cggctgctgc gctagctttt ttggccactg gccgcgcgca gcgtaagcgg 16860ttaggctgga aagcgaaagc attaagtggc tcgctccctg tagccggagg gttattttcc 16920aagggttgag tcgcgggacc cccggttcga gtctcggacc ggccggactg cggcgaacgg 16980gggtttgcct ccccgtcatg caagaccccg cttgcaaatt cctccggaaa cagggacgag 17040cccctttttt gcttttccca gatgcatccg gtgctgcggc agatgcgccc ccctcctcag 17100cagcggcaag agcaagagca gcggcagaca tgcagggcac cctcccctcc tcctaccgcg 17160tcaggagggg cgacatccgc ggttgacgcg gcagcagatg gtgattacga acccccgcgg 17220cgccgggccc ggcactacct ggacttggag gagggcgagg gcctggcgcg gctaggagcg 17280ccctctcctg agcggtaccc aagggtgcag ctgaagcgtg atacgcgtga ggcgtacgtg 17340ccgcggcaga acctgtttcg cgaccgcgag ggagaggagc ccgaggagat gcgggatcga 17400aagttccacg cagggcgcga gctgcggcat ggcctgaatc gcgagcggtt gctgcgcgag 17460gaggactttg agcccgacgc gcgaaccggg: attagtcccg cgcgcgcaca cgtggcggcc 17520gccgacctgg taaccgcata cgagcagacg gtgaaccagg agattaactt tcaaaaaagc 17580tttaacaacc acgtgcgtac gcttgtggcg cgcgaggagg tggctatagg actgatgcat 17640ctgtgggact ttgtaagcgç gctggagcaa aacccaaata gcaagccgct catggcgcag 17700ctgttcctta tagtgcagca cagcagggac aacgaggcat tcagggatgc gctgctaaac 17760atagtagagc ccgagggccg ctggctgctc gatttgataa acatcctgca gagcatagtg 17820gtgcaggagc gcagcttgag cctggctgac aaggtggccg ccatcaacta ttccatgctt 17880agcctgggca agttttacgc ccgcaagata taccataccc cttacgttcc catagacaag 17940gaggtaaaga tcgaggggtt ctacatgcgc atggcgctga aggtgcttac cttgagcgac 18000gacctgggcg tttatcgcaa cgagcgcatc cacaaggccg tgagcgtgag ccggcggcgc 18060gagctcagcg accgcgagct gatgcacagc ctgcaaaggg ccctggctgg cacgggcagc 18120ggcgatagag aggccgagtc ctactttgac gcgggcgctg acctgcgctg ggccccaagc 18180cgacgcgccc tggaggcagc tggggccgga cctgggctgg cggtggcacc cgcgcgcgct 18240ggcaacgtcg gcggcgtgga ggaatatgac gaggacgatg agtacgagcc agaggacggc 18300gagtactaag cggtgatgtt tctgatcaga tgatgcaaga cgcaacggac ccggcggtgc 18360gggcggcgct gcagagccag ccgtceggcc ttaactccac ggacgactgg cgccaggtca 18420tggaccgcat catgtcgctg actgcgcgca atcctgacgc gttccggcag cagccgcagg 18480ccaaccggct ctccgcaatt ctggaagcgg tggtcccggc gcgcgcaaac cccacgcacg 18540agaaggtgct ggcgatcgta aacgcgctgg ccgaaaacag ggccatccgg cccgacgagg 18600ccggcctggt ctacgacgcg ctgcttcagc gcgtggctcg ttacaacagc ggcaacgtgc 18660agaccaacct ggaccggctg gtgggggatg tgcgcgaggc cgtggcgcag cgtgagcgcg 18720cgcagcagca gggcaacctg ggctccatgg ttgcactaaa cgccttcctg agtacacagc 18780ccgccaacgt gccgcgggga caggaggact acaccaactt tgtgagcgca ctgcggctaa 1884 0tggtgactga gácaccgcaa agtgaggtgt accagtctgg gccagactat tttttccaga 18900ccagtagaca aggcctgcag accgtaaacc tgagccaggc tttcaaaaac ttgcaggggc 18960tgtggggggt gcgggctccc acaggcgacc gcgcgaccgt gtctagcttg ctgacgccca 19020actcgcgcct gttgctgctg ctaatagcgc ccttcacgga cagtggcagc gtgtcccggg 19080acacatacct aggtcacttg ctgacactgt accgcgaggc cataggtcág gcgcatgtgg 19140acgagcatac tttccaggag attacaagtg tcagccgcgc gctggggcág gaggacacgg 19200gcagcctgga ggcaacccta aactacctgc tgaccaaccg gcggcagaag atcccctcgt 19260-tgcacagttt aaacagcgag gaggagcgca ttttgcgcta cgtgcagcag agcgtgagcc 19320ttaacctgat gcgcgacggg gtaacgccca gcgtggcgct ggacatgacc gcgcgcaaca 19380tggaaccggg catgtatgcc tcaaaccggc cgtttatcaa ccgcctaatg gactacttgc 19440atcgcgcggc cgccgtgãac cccgagtatt tcaccaatgc catcttgaac ccgcactggc 19500taccgccccc tggtttctac accgggggat tcgaggtgcc cgagggtaac gatggattcc 19560tctgggacga catagacgac agcgtgtttt ccccgcaacc gcagaccctg ctagagttgc 19620aacagçgcga gcaggcagag gcggcgctgc gaaaggaaag cttccgcagg ccaagcagct 19680tgtccgatct aggcgctgcg gccccgcggt cagatgctag tagcccattt ccaagçttga 19740tagggtctct taccagcact cgcaccaccc gcccgcgcct gctgggcgag gaggagtacc 19800taaacaactc gctgctgcag ccgcagcgcg aaaaaaacct gcctccggca tttcccaaca 19860acgggataga gagcctagtg gacaagatga gtagatggaa gacgtacgcg caggagcaca 19920gggacgtgcc aggcccgcgc ccgcccaccc gtcgtcaaag gcacgaccgt cagcggggtc 19980tggtgtggga ggacgatgac tcggcagacg acagcagcgt cctggatttg ggagggagtg 20040gcaacccgtt tgcgcacctt cgccccaggc tggggagaat gttttaaaaa aaaaaaagca 20100tgatgcaaaa taaaaaactc accaaggcca tggcaccgag cgttggtttt cttgtattcc 20160ccttagtatg cggcgcgcgg cgatgtatga ggaaggtcct cctccctcct acgagagtgt 20220ggtgagcgcg gcgccagtgg cggcggcgct gggttctccc ttcgatgctc ccctggaccc 20280gccgtttgtg cctccgcggt acctgcggcc taccgggggg agaaacagca tccgttactc 20340tgagttggca cccctattcg acaccacccg tgtgtacctg gtggacaaca agtcaaçgga 204 00.tgtggcatcc ctgaactacc agaacgacca cagcaacttt ctgacoacgg tcattcaàaa 20460caatgactac agcccggggg aggcaagcac acagaccatc aatcttgacg accggtcgca 20520ctggggcggc gacctgaaaa ccatcctgca taccaacatg ccaaatgtga acgagttcat 20580gtttaccaat aagtttaagg cgcgggtgat ggtgtcgcgc ttgcctacta aggacaatca 2064 0ggtggagctg aaatacgagt gggtggagtt cacgctgccc gagggcaact actccgagac 20700catgaccata gaccttatga acaacgcgat cgtggagcac tacttgaaag tgggcagaca 20760gaacggggtt ctggaaagcg acatcggggt aaagtttgac acccgcaact tcagactggg 20820gtttgacccc gtcactggtc ttgtcatgcc tggggtatat acaaacgaag ccttccatcc 20880agacatcatt ttgctgccag gatgcggggt ggacttcacc cacagccgcc tgagcaactt 20940gttgggcatc cgcaagcggc aacccttcca ggagggcttt aggatcacctacgatgatct 21000ggagggtggt aacattcccg cactgttgga tgtggacgcc taccaggcga gcttgaaaga 21060tgacaccgaa cagggcgggg gtggcgcagg cggcagcaac agcagtggca gcggcgcgga 21120agagaactcc aacgcggcag ccgcggcaat gcagccggtg gaggacatga acgatcatgc 21180cattcgcggc gacacctttg ccacacgggc tgaggagaag cgcgctgagg ccgaagcagc 21240ggccgaagct gccgcccccg ctgcgcaacc cgaggtcgag aagcctcaga agaaaccggt 21300gatcaaaccc ctgacagagg acagcaagaa acgcagttac aacctaataa gcaatgacag 21360caccttcacc cagtaccgca gctggtacct tgcatacaac tacggcgacc ctcagaccgg 21420aatccgctca tggaccctgc tttgcactcc tgacgtaacc tgcggctcgg agcaggtçta 21480ctggtcgttg ccagacatga tgcaagaccc cgtgaccttc cgctccacgc gccagatcag 21540caactttccg gtggtgggcg ccgagctgtt gcccgtgcac tccaagagct tctacaacga 21600ccaggccgtc tactcccaac tcatccgcca gtttacctct ctgacccacg tgttcaatcg 21660. ctttcccgag aaccagattt tggcgcgccc gccagcccec accatcacca ccgtcagtga 21720aaacgttcct gctctcacag atcacgggac gctaccgctg cgcaacagca tcggaggagt 21780ccagcgagtg accattactg acgccagacg ccgcacctgc ccctacgttt acaaggccct 21840gggcatagtc tcgccgcgcg tcctatcgag ccgcactttt tgagcaagca tgtccatcct 21900tatatcgccc agcaataaca caggctgggg cctgcgcttc ccaagcaaga tgtttggcgg 21960ggccaagaag cgctccgacc aacacccagt gcgcgtgcgc gggcactacc gcgcgccctg 22020gggcgcgcac aaacgcggcc gcactgggcg caccaccgtc gatgacgcca tcgacgcggt 22080ggtggaggag gcgcgcaact acacgcccac gccgccacca gtgtccacag tggacgcggc 22140cattcagacc gtggtgcgcg gagcccggcg ctatgctaaa atgaagagac ggcggaggcg 22200cgtagcacgt cgccaccgcc gccgacccgg cactgccgcc caacgcgcgg cggcggccct 22260gcttaaccgc gcacgtcgca ccggccgacg ggcggccatg cgggccgctc gaaggctggc 22320cgcgggtatt gtcactgtgc cccccaggtc caggcgacga gcggccgccg cagcagccgc 22380ggccattagt gctatgactc agggtcgcag gggcaacgtg tattgggtgc gcgactcggt 22440tagcggcctg cgcgtgcccg tgcgcacccg ccccccgcgc aactagattg caagaaaaaa 22500ctacttagac tcgtactgtt gtatgtatcc agcggcggcg gcgcgcaacg aagctatgtc 22560caagcgcaaa atcaaagaag agatgctcca ggtcatcgcg ccggagatct atggcccccc 22620gaagaaggaa gagcaggatt acaagccccg aaagctaaag cgggtcaaaa agaaaaagaa 22680agatgatgat gatgaacttg acgacgaggt ggaactgctg cacgctaccg cgcccaggcg 22740acgggtacag tggaaaggtc gacgcgtaaa acgtgttttg cgacccggca ccaccgtagt 22800ctttacgccc ggtgagcgct ccacccgcac ctacaagcgc gtgtatgatg aggtgtacgg 22860cgacgaggac ctgcttgagc aggccaacga gcgcctcggg gagtttgcct acggaaagcg 22920gcataaggac atgctggcgt tgccgctgga cgagggcaac ccaacaccta gcctaaagcc 22 980cgtaacactg cagcaggtgc tgcccgcgct tgcaccgtcc gaagaaaagc gcggcctaaa 23040gcgcgagtct ggtgacttgg cacccaccgt gcagctgatg gtacccaagc gccagcgact 23100ggaagatgtc ttggaaaaaa tgaccgtgga acctgggctg gagcccgagg tccgcgtgcg 23160gccaatcaag caggtggcgc cgggactggg cgtgcagacc gtggacgttc agatacccac 23220taccagtagc accagtattg ccaccgccac agagggcatg gagacacaaa cgtccccggt 23280tgcctcagcg gtggcggatg ccgcggtgca ggcggtcgct gcggccgcgt ccaagacctc 23340tacggaggtg caaacggacc cgtggatgtt tcgcgtttca gccccccggc gcccgcgcgg 23400ttcgaggaag tacggcgccg ccagcgcgct actgcccgaa tatgccctac atccttccat 23460tgcgcctacc cccggctatc gtggctacac ctaccgcccc agaagacgag caactacccg 23520acgccgaacc accactggaa cccgccgccg ccgtcgccgt cgccagcccg tgctggcccc 23580gatttccgtg cgcagggtgg ctcgcgaagg aggcaggacc ctggtgctgc caacagcgcg 23640ctaccacccc agcatcgttt aaaagccggt ctttgtggtt cttgcagatá tggccctcac 23700ctgccgcctc cgtttcccgg tgccgggatt ccgaggaaga atgcaccgta ggaggggcat 23760ggccggccac ggcctgacgg gcggcatgcg tcgtgcgcac caccggcggc ggcgcgcgtc 23820gcaccgtcgc atgcgcggcg gtatcctgcc cctccttatt ccactgatcg ccgcggcgat 23880tggcgccgtg cccggaattg catccgtggc cttgcaggcg cagagacact gattaaaaac 23940aagttgcatg tggaaaaatc aaaataaaaa gtctggactc tcacgctcgc ttggtcctgt 24000aactattttg tagaatggaa gacatcaact ttgcgtctct ggccccgcga cacggctcgc 24060gcccgttcat gggaaactgg caagatatcg gcaccagcaa tatgagcggt ggcgccttca 24120gctggggctc gctgtggagc ggcattaaaa atttcggttc caccgttaag aactatggca 24180gcaaggcctg gaacagcagc acaggccaga tgctgaggga taagttgaaa gagcaaaatt 24240tccaacaaaa ggtggtagat ggcctggcct ctggcattag cggggtggtg gacctggcca 24300accaggcagt gcaaaataag attaacagta agcttgatcc ccgccctccc gtagaggagc 24360ctccaccggc cgtggagaca gtgtctccag aggggcgtgg cgaaaagcgt ccgcgccccg 24420acagggaaga aactctggtg acgcaaatag acgagcctcc ctcgtacgag gaggcactaa 24 480agcaaggcct gcccaccacc cgtcccatcg cgcccatggc taccggagtg ctgggccagc 24540acacacccgt aacgctggac ctgcctcccc ccgccgacac ccagcagaaa cçtgtgctgç 24600caggcccgac cgccgttgtt gtaacccgtc ctagccgcgc gtccctgcgc cgcgccgcca 24 660gcggtccgcg atcgttgcgg cccgtagcca gtggcaactg gcaaagcaca ctgaacagca 24720tcgtgggtct gggggtgcaa tccctgaagc gccgacgatg cttctgaata gctaacgtgt 24780cgtatgtgtg tcatgtatgc gtccatgtcg ccgccagagg agctgctgag ccgccgcgcg 24840cccgctttcc aagatggcta ccccttcgat gatgccgcag tggtcttacâ tgcacatctc 24900gggccaggac gcctcggagt acctgagccc cgggctggtg cagtttgccc gcgccaccga 24960gacgtacttc agcctgaata acaagtttag aaaccccacg gtggcgccta cgcacgacgt 25020gaccacagac cggtcccagc gtttgacgct gcggttcatc cctgtggacc gtgaggatac 25080tgcgtactcg tacaaggcgc ggttcaccct agctgtgggt gataaccgtg tgctggacat 25140ggcttccacg tactttgaca tccgcggcgt gctggacagg ggccctactt ttaaigcccta 25200ctctggcact gcctacaacg ccctggctcc caagggtgcc ccaaatcctt gcgaatggga 25260tgaagctgct actgctcttg aaataaacct agaagaagag gacgatgaca acgaagacga 2S320agtagacgag caagctgagc agcaaaaaac tcacgtattt gggcaggcgc cttattctgg 25380tataaatatt acaaaggagg gtattcaaat aggtgtcgaã ggtcaaacac ctaaatatgc 25440cgataaaaca tttcaacctg aacctcaaat aggagaatct cagtggtacg aaactgaaat 25500taatcatgca gctgggagag tccttaaaaa gactacccca atgaaaccat gttacggttc 25560atatgcaaaa cccacaaatg aaaatggagg gcaaggcatt cttgtaaagc aacaaaatgg 25620aaagctagaa agtcaagtgg aaatgcaatt tttctcaact actgaggcga ccgcaggcaa 25680tggtgataac ttgactccta aagtggtatt gtacagtgaa gatgtagata tagaaacccc 25740agacactcat atttcttaca tgcccactat taaggaaggt aactcacgag aactaatggg 25800ccaacaatct atgcccaaca ggcctaatta cattgctttt agggacaatt ttattggtct 25860aatgtattac aacagcacgg gtaatatggg tgttctggcg ggccaagcat cgcagttgaa 25920tgctgttgta gatttgcaag acagaaacac agagctttca taccagcttt tgcttgattc 25980cattggtgat agaaccaggt acttttctat gtggaatcag gctgttgaca gctatgatcc 26040agatgttaga attattgaaa atcatggaac tgaagatgaa cttccaaatt actgctttcc 26100actgggaggt gtgattaata cagagactct taccaaggta aaacctaaaa caggtcagga 26160aaatggatgg gaaaaagatg ctacagaatt ttcagataaa aatgaaataa gagttggaaa 26220taattttgcc atggaaatca atctaaatgc caacctgtgg agaaatttcc tgtactccaa 2 6280catagcgctg tatttgcccg acaagctaaa gtacagtcct tccaacgtaa aaatttctga 26340taacccaaac acctacgact acatgaacaa gcgagtggtg gctcccgggt tagtggactg 2 6400ctacattaac cttggagcac gctggtccct tgactatatg gacaacgtca acccatttaa 26460ccaccaccgc aatgctggcc tgcgctaccg ctcaatgttg ctgggcaatg gtcgctatgt 2 6520gcccttccac atccaggtgc ctcagaagtt ctttgccatt aaaaacctcc ttctcctgcc 26580gggctcatac acctacgagt ggaacttcag gaaggatgtt aacatggttc tgcagagctc 26640cctaggaaat gacctaaggç ttgacggagc cagcattaag tttgatagca tttgccttta 26700cgccaccttc ttccccatgg cccacaacac cgcctccacg cttgaggcca tgcttagaaa 26760cgacaccaac gaccagtcct ttaacgacta tctctccgcc gccaacatgc tctaccctat 26820acccgccaac gctaccaacg tgcccatatc catcccctcc cgcaactggg cggctttccg 26880cggctgggcc ttcacgcgcc ttaagactaa ggaaacccca tçactgggct cgggctacga 26940cccttattac acctactctg gctctatacc ctacctagát ggaacctttt acctcaacca 27000cacctttaag aaggtggcca ttacctttga ctcttctgtc agctggcctg gcaatgaccg 27060cctgcttacc cccaacgagt ttgaaattaa gcgctcagtt gacggggagg gttacaacgt 27120tgcccagtgt aacatgacca aagactggtt cctggtacaa atgctagcta actacaacat 27180tggctaccag ggcttctata tcccagagag ctacaaggac cgcatgtact ccttctttag 27240aaacttccag cccatgagcc gtcaggtggt ggatgatact aaatacaagg actaccaaca 27300ggtgggcatc ctacaccaac acaacaactc tggatttgtt ggctaccttg cccccaccat 27360gcgcgaagga caggcctacc ctgctaactt cccctatccg cttataggca agaccgcagt 27420tgacagcatt acccagaaaa agtttctttg cgatcgcacc ctttggcgca tcccattctc 27480cagtaacttt atgtccatgg gcgcactcac agacctgggc caaaaccttc tctacgccaa 27540ctccgcccac gcgctagaca tgacttttga ggtggatccc atggacgagc ccacccttct 27600ttatgttttg tttgaagtct ttgacgtggt ccgtgtgcac cggccgcacc gcggcgtcat 27660cgàaaccgtg tacctgcgca cgcccttctc ggccggcaac gccacaacat aaagaagcaa 27720gcaacatcaa caacagctgc cgccatgggc tccagtgagc aggaactgaa agccattgtc 27780aaagatcttg gttgtgggcc atattttttg ggcacctatg acaagcgctt tccaggcttt 27840gtttctccac acaagctcgc ctgcgccata gtcaatacgg ccggtcgcga gactgggggc 27900gtacactgga tggcctttgc ctggaacccg cactcaaaaa catgctacct ctttgagccc 27960tttggctttt ctgaccagcg actcaagcag gtttaccagt ttgagtacga gtcactcctg 28020cgccgtagcg ccattgcttc ttcccccgac cgctgtataa cgctggaaaa gtccacccaa 28080agcgtacagg ggcccaactc ggccgcctgt ggactattct gctgcatgtt tctccacgcc 28140tttgccaact ggccccaaac tcccatggat cacaacccca ccatgaacct tattaccggg 28200gtacccaact ccatgctcaa cagtccccag gtacagccca ccctgcgtcgcaaccaggaa 28260cagctctaca gcttcctgga gcgccactcg ccctacttcc gcagccacag tgcgcagatt 28320aggagcgcca cttctttttg tcacttgaaa aacatgtaaa aataatgtac tagagacact 28380ttcaataaag gcaaatgctt ttatttgtac actctcgggt gattatttac ccccaccctt 28440gocgtctgcg ccgtttâaaa atcaaagggg ttctgccgcg catcgctatg cgccactggc 28500agggacacgt tgcgatactg gtgtttagtg ctccacttaa actcaggcac aaccatccgc 28560ggcagctcgg tgaagttttc actccacagg ctgcgcacca tcaccaacgc gtttagcagg 28620tcgggcgccg atatcttgaa gtcgcagttg gggcctccgc cctgcgcgcg cgagttgcga 28680tacacagggt tgcagcactg gaacactatc agcgccgggt ggtgcacgct ggccagcacg 28740ctcttgtcgg agatcagatc cgcgtccagg tcctccgcgt tgctcagggc gaacggagtc 28800aactttggta gctgccttcc caaaaagggc gcgtgcccag gctttgagtt gcactcgcac 28860cgtagtggca tcaaaaggtg accgtgcccg gtctgggcgt taggatacag cgcctgcata 28920aaagccttga tctgcttaaa agccacctga gcctttgcgc cttcagagaa gaacatgccg 28980çaagacttgc cggaaaactg attggccgga caggccgcgt cgtgcacgca gcaccttgcg 29040tcggtgttgg agatctgcac cacatttcgg ccccaccggt tcttcacgat cttggccttg 29100ctagactgct ccttcagcgc gcgctgcccg ttttcgctcg tcacatccat ttcaatcacg 29160tgctccttat ttatcataat gcttccgtgt agacacttaa gctcgccttc gatctcagcg 29220cagcggtgca gccacaacgc gcagcccgtg ggctcgtgat gcttgtaggt cacctctgca 29280aacgactgca ggtacgcctg caggaatcgc cccatcatcg tcacaaaggt cttgttgctg 29340gtgaaggtca gctgcaaccc gcggtgctcc tcgttcagcc aggtcttgca tacggccgcc 29400agagcttcca cttggtcagg cagtagtttg aagttcgcct ttagatcgtt atccacgtgg 29460tacttgtcca tcagcgcgcg cgcagcctcc atgcccttct cccacgcaga cacgatcggc 29520acactcagcg ggttcatcac cgtaatttca ctttccgctt cgctgggctc ttcctcttcc 29580tcttgcgtcc gcataccacg cgccactggg tcgtcttcat tcagccgccg cactgtgcgc 2964 0ttacctcctt tgccatgctt gattagcacc ggtgggttgc tgaaacccac catttgtagc 29700gccacatctt ctctttcttc ctcgctgtcc acgattacct ctggtgatgg cgggcgctcg 29760ggcttgggag aagggcgctt ctttttcttc ttgggcgcaa tggccaaatc cgccgccgag 29820gtcgatggcc gcgggctggg tgtgcgcggc accagcgcgt cttgtgatga gtcttcctcg 29880tcctcggact cgatacgccg cctcatccgc ttttttgggg gcgcccgggg aggcggcggc 29940gacggggacg gggacgacac gtcctccatg gttgggggac gtcgcgccgc accgcgtccg 30000cgctcggggg tggtttcgcg ctgctcctct tcccgactgg ccatttcctt ctcctatagg 30060cagaaaaaga tcatggagtc agtcgagaag aaggacagcc taaccgcccc ctctgagttc 30120gccaccaccg cctccaccga tgccgccaac gcgcctacca ccttccccgt cgaggcaccc 30180ccgcttgagg aggaggaagt gattatcgag caggacccag gttttgtaag cgaagacgac 30240gaggaccgct cagtaccaac agaggataaa aagcaagacc aggacaacgc agaggcaaac 30300gaggaacaag tcgggcgggg ggacgaaagg catggcgact acctagatgt gggagacgac 30360gtgctgttga agcatctgca gcgccagtgc gccattatct gcgacgcgtt gcaagagcgc 30420agcgatgtgc ccctcgccat agcggatgtc agccttgcct acgaacgcca cctattctca 30480ccgcgcgtac cccccaaacg ccaagaaaac ggcacatgcg agcccaaccc gcgcctcaac 30540ttctaccccg tatttgccgt gccagaggtg cttgccacct atcacatctt tttccaaaac 30600tgcaagatac ccctatcctg ccgtgccaac cgcagccgag cggacaagca gctggccttg 30660cggcagggcg ctgtcatacc tgatatcgcc tcgctcaacg aagtgccaaa aatctttgag 30720ggtcttggac gcgacgagaa gcgcgcggca aacgctctgc aacaggaaaa cagcgaaaat 30780gaaagtcact ctggagtgtt ggtggaactc gagggtgaca acgcgcgcct agccgtacta 30840aaacgcagca tcgaggtcac ccactttgcc tacccggcac ttaacctacc ccccaaggtc 30900atgagcacag tcatgagtga gctgatcgtg cgccgtgcgc agcccctgga gagggatgca 30960aatttgcaag aacaaacaga ggagggccta cccgcagttg gcgacgagca gctagcgcgc 31020tggcttcaaa cgcgcgagcc tgccgacttg gaggagcgac gcaaactaat gatggccgca 31080gtgctcgtta ccgtggagct tgagtgcatg cagcggttct ttgctgaccc ggagatgcag 31140cgcaagctag aggaaacatt gcactacacc tttcgacagg gctacgtacg ccaggcctgc 31200aagatctcca acgtggagct ctgcaacctg gtctcctacc ttggaatttt gcacgaaaac 31260cgccttgggc aaaacgtgct tcattccacg ctcaagggcg aggcgcgccg cgactacgtc 31320cgcgactgcg tttacttatt tctatgctac acctggcaga cggccatggg cgtttggcag 31380cagtgcttgg aggagtgcaa cctcaaggag ctgcagaaac tgctaaagca aaacttgaag 31440gacctatgga cggccttcaa cgagcgctcc gtggccgcgc acctggcgga catcattttc 31500cccgaacgcc tgcttaaaac cctgcaacag ggtctgccag acttcaccag tcaaagcatg 31560ttgcagaact ttaggaactt tatcctagag cgctcaggaa tcttgcccgc cacctgctgt 31620gcacttccta gcgactttgt gcccattaag taccgcgaat gccctccgcc gctttggggc 31680cactgctacc ttctgcagct agccaactac cttgcctacc actctgacat aatggaagac 31740gtgagcggtg acggtctact ggagtgtcac tgtcgctgca acctatgcac cccgcaccgc 31800tccctggttt gcaattcgca gctgcttaac gaaagtcaaa ttatcggtac ctttgagctg 31860cagggtccct cgcctgacga aaagtccgcg gctccggggt tgaaactcac tccggggctg 31920tggacgtcgg cttaccttcg caaatttgta cctgaggact accacgccca cgagattagg 31980ttctacgaag accaatcccg cccgccaaat gcggagctta ccgcctgcgt cattacccag 32040ggccacattc ttggccaatt gcaagccatc aacaaagccc gccaagagtt tctgctacga 32100aagggacggg gggtttactt ggacccccag tccggcgagg agctcaaccc aatccccccg 32160ccgccgcagc cctatcagca gcagccgcgg gcccttgctt cccaggatgg cacccaaaaa 32220gaagctgcag ctgccgccgc cacccacgga cgaggaggaa tactgggaca gtcaggcaga 32280ggaggttttg gacgaggagg aggaggacat gatggaagac tgggagagcc tagacgagga 32340agcttccgag gtcgaagagg tgtcagacga aacaccgtca ccctcggtcg cattcccctc 32400gccggcgccc cagaaatcgg caaccggttc cagcatggct acaacctccg ctcctcaggc 32460gccgccggca ctgcccgttc gccgacccaa ccgtagatgg gacaccactg gaaccagggc 32520cggtaagtcc aagcagccgc cgccgttagc ccaagagcaa caacagcgcc aaggctaccg 32580ctcatggcgc gggcacaaga acgccatagt tgcttgcttg caagactgtg ggggcaacat 32640ctccttcgcc cgccgctttc ttctctacca tcacggcgtg gccttccccc gtaacatcct 32700gcattactac cgtcatctct acagcccata ctgcaccggc ggcagcggca gcggcagcaa 32760çagcagcggc cacacagaag caaaggcgac cggatagcaa gactctgaca aagcccaaga 32820aatccacagc ggcggcagca gcaggaggag gagcgctgcg tctggcgccc aacgaacccg 32880tatcgacccg cgagcttaga aacaggattt ttcccactct gtatgctata tttcaacaga 32940gcaggggcca agaacaagag ctgaaaataa aaaacaggtc tctgcgatcc ctcacccgca 33000gctgcctgta tcacaaaagc gaagatcagc ttcggcgcac gctggaagac gcggaggctc 33060tcttcagtaa atactgcgcg ctgactctta aggactagtt tcgcgccctt tctcaaattt 33120aagcgcgaaa actacgtcat ctccagcggc cacacccggc gccagcacct gtcgtcagcg 33180ccattatgag caaggaaatt cccacgccct acatgtggag ttaccagcca caaatgggac 33240ttgcggctgg agctgcccaa gactactcaa cccgaataaa ctacatgagc gcgggacccc 33300acatgatatc ccgggtcaac ggaatccgcg cccaccgaaa ccgaattctc ttggaacagg 33360cggctattac caccacacct cgtaataacc ttaatccccg tagttggccc gctgccctgg 33420tgtaccagga aagtcccgct cccaccactg tggtacttcc cagagacgcc caggccgaag 33480ttcagatgac taactcaggg gcgcagcttg cgggcggctt tcgtcacagg gtgcggtcgc 33540ccgggcaggg tataactcac ctgacaatca gagggcgagg tattcagctc aacgacgagt 33600cggtgagctc ctcgcttggt ctccgtccgg acgggacatt tcagatcggc ggcgccggcc 33660gtccttcatt cacgcctcgt caggcaatcc taactctgca gacctcgtcc tctgagccgc 33720gctctggagg cattggaact ctgcaattta ttgaggagtt tgtgccatcg gtctacttta 33780accccttctc gggacctccc ggccactatc cggatcaatt tattcctaac tttgacgcgg 33840taaaggactc ggcggacggc tacgactgaa tgttaagtgg agaggcagag caactgcgcc 33900tgaaacacct ggtccactgt cgccgccaca agtgctttgc ccgcgactcc ggtgagtttt 33960gctactttga attgcccgag gatcatatcg agggcccggc gcacggcgtc cggcttaccg 34020cccagggaga gcttgcccgt agcctgattc gggagtttac ccagcgcccc ctgctagttg 34080agcgggacag gggaccctgt gttctcactg tgatttgcaa ctgtcctaac cttggattac 34140atcaagatcc tctagttata actagagtac ccggggatct tattcccttt aactaataaa 34200aaaaaataat aaagcatcac ttacttaaaa tcagttagca aatttctgtc cagtttattc 34260agcagcacct ccttgccctc ctcccagctc tggtattgca gcttcctcct ggctgcaaac 34320tttctccaca atctaaatgg aatgtcagtt tcctcctgtt cctgtccatc cgcacccact 34380atcttcatgt tgttgcagat gaagcgcgca agaccgtctg aagatacctt caaccccgtg 34440tatccatatg acacggaaac cggtcctcca actgtgcctt ttcttactcc tccctttgta 34500tcccccaatg ggtttcaaga gagtccccct ggggtactct ctttgcgcct atccgaacct 34560Gtagttacct ccaatggcat gcttgcgctc aaaatgggca acggcctctc tctggacgag 34620gccggcaacc ttacctecca aaatgtaacc actgtgagcc cacctctcaa aaaaaccaag 34680tcaaacataa acctggaaat atctgcaccc cteacagtta cctcagaagc cctaactgtg 34740gctgccgccg cacctctaat ggtcgcgggc aacacactca ccatgcaatc acaggccccg 34800ctaaccgtgc acgactccaa acttagcatt gccacccaag gacccctcac agtgtcagaa 34860ggaaagctag ccctgcaaac atcaggcccc ctcaccacca ccgatagcag tacccttact 34 920atcactgcct caccccctct aactactgcc actggtagct tgggcattga cttgaaágag 34980cccatttata cacaaaatgg aaaactagga ctaaagtacg gggctccttt gcatgtaaca 35040gacgacctaa acactttgac cgtagcaact ggtccaggtg tgactattaa taatacttcc 35100ttgcaaacta aagttactgg agccttgggt tttgattcac aaggcaatat gcaacttaat 35160gtagcaggag gactaaggat tgattctcaa aacagacgcc ttatacttgâ tgttagttat 35220ccgtttgatg ctcaaaacca actaaatcta agactaggac agggccctct ttttataaac 35280tcagcccaca acttggatat taactacaac aaaggccttt acttgtttac agcttcaaac 35340aattccaaaa agcttgaggt taacctaagc actgccaagg ggttgatgtt tgacgctaca 35400gccatagcca ttaatgcagg agatgggctt gaatttggtt cacctaatgc accaaacaca 354 60aatcccctca aaacaaaaat tggccatggc ctagaatttg attcaaacaa ggctatggtt 35520cctaaactag gaactggcct tagttttgac agcacaggtg ccattacagt aggaaacaaa 35580aataatgata agctaacttt gtggaccaca ccagctccat ctcctaactg tagactaaat 35640gcagagaaag atgctaaact cactttggtc ttaacaaaat gtggcagtca aatacttgct 35700acagtttcag ttttggctgt taaaggcagt ttggctccaa tatctggaac agttcaaagt 35760gctcatctta ttataagatt tgacgaaaat ggagtgctac taaacaattc cttcctggac 35820ccagaatatt ggaactttag aaatggagat cttactgaag gcacagccta tacaaacgct 35880gttggattta tgcctaacct atcagcttat ccaaaatctc acggtaaaac tgccaaaagt 35940aacattgtca gtcaagttta cttaaacgga gacaaaacta aacctgtaac actaaccatt 36000acactaaacg gtacacagga aacaggagac acaactccaa gtgcatactc tatgtcattt 36060tcatgggact ggtctggcca caactacatt aatgaaatat ttgccacatc ctcttacact 36120ttttcataca ttgcccaaga ataaagaatc gtttgtgtta tgtttcaacg tgtttatttt 36180tcaattgcag aaaatttcaa gtcatttttc attcagtagt atagccccac caccacatag 36240cttatacaga tcaccgtacc ttaatcaaac tcacagaacc ctagtattca acctgccacc 36300tccctcccaa cacacagagt acacagtcct ttctccccgg ctggccttaa aaagcatcat 36360atcatgggta acagacatat tcttaggtgt tatattccac acggtttcct gtcgagccaa 36420acgctcatca gtgatattaa taaactcccc gggcagctca cttaagttca tgtcgctgtc 36480cagctgctga gccacaggct gctgtccaac ttgcggttgc ttaacgggcg gcgaaggaga 36540agtccacgcc tacatggggg tagagtcata atcgtgcatc aggatagggc ggtggtgctg 36600cagcagcgcg cgaataaact gctgccgccg ccgctccgtc ctgcaggaat acaacatggc 36660agtggtctcc tcagcgatga ttcgcaccgc ccgcagcata aggcgccttg tcctccgggc 36720acagcagcgc accctgatct cacttaaatc agcacagtaa ctgcagcaca gcaccacaat 36780attgttcaaa atcccacagt gcaaggcgct gtatccaaag ctcatggcgg ggaccacaga 36840acccacgtgg ccatcatacc acaagcgcag gtagattaag tggcgacccc tcataaacac 36900gctggacata aacattacct cttttggcat gttgtaattc accacctccc ggtaccatat 36960aaacctctga ttaaacatgg cgccatccac caccatccta aaccagctgg ccaaaacctg 37020cccgccggct atacactgca gggaaccggg actggaacaa tgacagtgga gagcccagga 37080ctcgtaacca tggatcatca tgctcgtcat gatatcaatg ttggcacaac acaggcacac 37140gtgcatacac ttcctcagga ttacaagctc ctcccgcgtt agaaccatat cccagggaac 37200aacccattcc tgaatcagcg taaatcccac actgcaggga agacctcgca cgtaactcac 37260gttgtgcatt gtcaaagtgt tacattcggg cagcagcgga tgatcctcca gtatggtagc 37320gcgggtttct gtctcaaaag gaggtagacg atccctactg tacggagtgc gccgagacaa 37380ccgagatcgt gttggtcgta gtgtcatgcc aaatggaacg ccggacgtag tcatatttcc 37440tgaagcaaaa ccaggtgcgg gcgtgacaaa cagatctgcg tctccggtct cgccgcttag 37500atcgctctgt gtagtagttg tagtatatcc actctctcaa agcatccagg cgccccctgg 37560cttcgggttc tatgtaaact ccttcatgcg ccgctgccct gataacatcc accaccgcag 37620aataagccac acccagccaa cctacacatt cgttctgcga gtcacacacg ggaggagcgg 37680gaagagctgg aagaaccatg tttttttttt tattccaaaa gattatccaa aacctcaaaa 37740tgaagatcta ttaagtgaac gcgctcccct ccggtggcgt ggtcaaactc tacagccaaa 37800gaacagataa tggcatttgt aagatgttgc acaatggctt ccaaaaggca aacggccctc 37860acgtccaagt ggacgtaaag gctaaaccct tcagggtgaa tçtcctctat aaacattcca 37920gcaccttcaa ccatgcccaa ataattctoa tctcgccacc ttctcaatat atctctaagc 37980aaatcccgaa tattaagtcc ggccattgta aaaatctgct ccagagcgcc ctccaccttc 38040agcctcaagc agcgaatcat gattgcaaaa attcaggttc ctcacagacc tgtataagat 38100tcaaaagcgg aacattaaca aaaataccgc gatcccgtag gtcccttcgc agggccagct 38160gaacataatc gtgcaggtct gcacggacca gcgcggccac ttccccgcca ggaaccttga 38220caaaagaacc cacactgatt atgacacgca tactcggagc tatgctaacc agcgtagccc 38280cgatgtaagc tttgttgcat gggcggcgat ataaaatgca aggtgctgct caaaaaatca 38340ggcaaágcct cgcgcaaaaa agaaagcaca tcgtagtcat gctcatgcag ataaaggcag 38400gtaagctccg gaaccaccac agaaaaagac accatttttc tctcaaacat gtctgcgggt 38460ttctgcataa acacaaaata aaataacaaa aaaacattta aacattagaa gcctgtctta 38520caacaggaaa aacaaccctt ataagcataa gacggactac ggccatgccg gcgtgaccgt 38580aaaaaaactg gtcaccgtga ttaaaaagca ccaccgacag ctcctcggtc atgtccggag 38640tcataatgta agactcggta aacacatcag gttgattcat cggtcagtgc taaaaagcga 38700ccgaaatagc ccgggggaat acatacccgc aggcgtagag acaacattac agcccccata 38760ggaggtataa caaaattaat aggagagaaa aacacataaa cacctgaaaa accctcctgc 38820ctaggcaaaa tagcaccctc ccgctccaga acaacataca gcgcttcaca gcggcagcct 38880aacagtcagc cttaccagta aaaaagaaaa cctattaaaa aaacaccact cgacacggca 38940ccagctcaat cagtcacagt gtaaaaaagg gccaagtgca gagcgagtat atataggaçt 39000aaaaaatgac gtaacggtta aagtccacaa aaaacaccca gaaaaccgca cgcgaaccta 39060cgcccagaaa cgaaagccaa aaaacccaca acttcctcaa atcgtcactt ccgttttccc 39120acgttacgta acttcccatt ttaagaaaac tacaattccc aacacataca agttactccg 39180ccctaaaacc tacgtcaccc gccccgttcc cacgccccgc gccacgtcac aaactccacc 39240ccctcattat catattggct tcaatccaaa ataaggtata ttattgatga tannnnttaa 39300

Claims (28)

1. Vetor de expressão adenoviral quimérico, referido vetor com-preendendo um cassete de expressão compreendendo os seguintes ele-mentos:(a) um primeiro promotor operavelmente ligado a um ácido nu-cléico que codifica um agonístico de receptor-3 (TLR-3) similar a toll; e(b) um segundo promotor operavelmente ligado a um ácido nu-cléico que codifica um polipeptídeo heterólogo.
2. Vetor de expressão adenoviral quimérico, de acordo com areivindicação 1, no qual o ácido nucléico que codifica o agonístico TLR-3compreende um ácido nucléico que codifica um dsBNA.
3. Vetor de expressão adenoviral quimérico, de acordo com areivindicação 1, no qual o ácido nucléico que codifica o agonístico TLR-3compreende uma seqüência selecionada a partir do grupo consistindo em:SEQ ID Nes: 3, 4, 5, 8, 9, 10, 11 e 12.
4. Vetor de expressão adenoviral quimérico, de acordo com areivindicação 1, no qual o polipeptídeo heterólogo é um polipeptídeo de HIVenv.
5. Vetor de expressão adenoviral quimérico, de acordo com areivindicação 4, no qual o polipeptídeo de HIV env é selecionado a partir dogrupo consistindo em: gp41, gp120 e gp160.
6. Vetor de expressão adenoviral quimérico, de acordo com a rei-vindicação 1, no qual o polipeptídeo heterólogo é um polipeptídeo de gripe HA.
7. Vetor de expressão adenoviral quimérico, de acordo com areivindicação 1, no qual o primeiro promotor e o segundo promotor são osmesmos.
8. Vetor de expressão adenoviral quimérico, de acordo com areivindicação 7, no qual o primeiro promotor e o segundo promotor são cadaum promotor de CMV.
9. Composição imunogênica compreendendo o vetor de expres-são como definido na reivindicação 1, e um veículo farmaceuticamente acei-tável.
10. Método para induzir uma resposta imune, referido métodocompreendendo administrar uma quantidade imunologicamente eficaz dovetor como definido na reivindicação 1, a um indivíduo mamífero, no qual aresposta imune é dirigida contra os polipeptídeos heterólogos, e no qual avia de administração é selecionada a partir do grupo consistindo em: oral,intranasal e mucosal.
11. Método, de acordo com a reivindicação 10, no qual o poli-peptídeo heterólogo é expresso em uma célula selecionada a partir do grupoconsistindo em: uma célula dendrítica, uma célula de microdobra, e uma cé-lula epitelial intestinal.
12. Método, de acordo com a reivindicação 10, no qual referidomamífero é um ser humano.
13. Composição imunogênica, referida composição compreen-dendo:(a) um vetor de expressão adenoviral quimérico compreendendoum promotor operavelmente ligado a um ácido nucléico que codifica um po-lipeptídeo heterólogo;(b) um agonístico TLR-3; e(c) um veículo farmaceuticamente aceitável.
14. Composição, de acordo com a reivindicação 13, no qual opromotor é um CMV.
15. Composição, de acordo com a reivindicação 13, no qual oagonístico TLR-3 é selecionado a partir do grupo consistindo em: dsRNA epoli l:C.
16. Composição, de acordo com a reivindicação 13, no qual opolipeptídeo heterólogo é um polipeptídeo de HIV env.
17. Composição, de acordo com a reivindicação 16, no qual opolipeptídeo de HIV env é selecionado a partir do grupo consistindo em:gp41, gp120 e gp160.
18. Composição, de acordo com a reivindicação 13, no qual opolipeptídeo heterólogo é um polipeptídeo de gripe HA.
19. Composição, de acordo com a reivindicação 13, no qual oagonístico TLR-3 é administrado dentro de 48 horas da administração dopolipeptídeo heterólogo.
20. Composição, de acordo com a reivindicação 13, no qual oagonístico TLR-3 é um ácido nucléico compreendendo uma seqüência sele-cionada a partir do grupo consistindo em: SEQ ID Ngs: 3, 4, 5, 8, 9, 10, 11 e-12.
21. Método para induzir uma resposta imune, referido métodocompreendendo administrar a um indivíduo mamífero(a) um vetor de expressão adenoviral quimérico compreendendoum promotor operavelmente ligado a um ácido nucléico que codifica um po-lipeptídeo heterólogo;(b) um agonístico TLR-3;no qual a resposta imune é dirigida contra o polipeptídeo heteró-logo.
22. Método, de acordo com a reivindicação 21, no qual o promo-tor é selecionado a partir do grupo consistindo no: promotor de CMV e opromotor beta actina humana.
23. Método, de acordo com a reivindicação 21, no qual o poli-peptídeo heterólogo é um polipeptídeo de HIV env.
24. Método, de acordo com a reivindicação 23, no qual o poli-peptídeo de HIV env é selecionado a partir do grupo consistindo em: gp41,gp120 e gp160.
25. Método, de acordo com a reivindicação 21, no qual o poli-peptídeo heterólogo é um polipeptídeo de gripe HA.
26. Método, de acordo com a reivindicação 21, no qual o agonís-tico TLR-3 é um dsRNA.
27. Método, de acordo com a reivindicação 21, no qual o agonís-tico TLR-3 é administrado dentro de 48 horas da administração do vetor deexpressão adenoviral quimérico.
28. Ácido nucléico isolado compreendendo a seqüência coloca-da em SEQ ID Nes: 1,2,3,7, 14, 15, 16 ou 17.
BRPI0708344A 2006-02-28 2007-02-28 vetores adenovirais quiméricos e composição imunogênica BRPI0708344B8 (pt)

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