KR20150021839A - 암특이적 유전자를 표적하는 트랜스-스플라이싱 라이보자임의 조절 유도체를 포함하는 재조합 아데노바이러스 및 이의 용도 - Google Patents

Abstract

본 발명은 암특이적 유전자를 표적하는 트랜스-스플라이싱 라이보자임의 조절 유도체를 포함하는 재조합 아데노바이러스 및 이의 용도에 관한 것으로서, 보다 구체적으로 본 발명은 (i) 조직 특이적 프로모터; 및 (ii) 암특이적 유전자를 표적으로 하는 트랜스-스플라이싱 라이보자임 및 상기 라이보자임의 3' 엑손에 연결된 목적 유전자를 포함하는, 라이보자임-목적 유전자 발현 카세트를 포함하며, 상기 발현카세트는 라이보자임-목적 유전자 발현 카세트의 5' 말단에 스플라이싱 공여/스플라이싱 수여 서열(splicing donor/splicing acceptor sequence, SD/SA sequence)이 연결되고, 3' 말단에 WPRE(Woodchuck hepatitis virus Posttranscriptional Regulatory Element)가 연결된 것을 특징으로 하는, 재조합 아데노바이러스, 상기 재조합 아데노바이러스가 도입된 숙주세포, 상기 재조합 아데노바이러스를 유효성분으로 포함하는 암 예방 또는 치료용 약학 조성물 및 상기 재조합 아데노바이러스 또는 약학 조성물을 치료를 필요로 하는 개체에 투여하는 단계를 포함하는 개체의 암을 치료하는 방법에 관한 것이다. 본 발명의 재조합 아데노바이러스는 조직특이적인 프로모터 하에서도 그 발현증가 효과가 현저함을 확인하였으며, 숙주에 미치는 간독성은 오히려 현저히 감소함에 따라, 항암 효과가 높고, 숙주에 미치는 독성이 현저히 낮아 안전성이 문제가 되는 유전자 치료 분야에서 널리 활용될 수 있을 것이다.

Description

암특이적 유전자를 표적하는 트랜스-스플라이싱 라이보자임의 조절 유도체를 포함하는 재조합 아데노바이러스 및 이의 용도{Recombinant adenovirus comprising regulated derivatives of tumor-targeting trans-splicing ribozyme and uses thereof}

본 발명은 암특이적 유전자를 표적하는 트랜스-스플라이싱 라이보자임의 조절 유도체를 포함하는 재조합 아데노바이러스 및 이의 용도에 관한 것으로서, 보다 구체적으로 본 발명은 (i) 조직 특이적 프로모터; 및 (ii) 암특이적 유전자를 표적으로 하는 트랜스-스플라이싱 라이보자임 및 상기 라이보자임의 3' 엑손에 연결된 목적 유전자를 포함하는, 라이보자임-목적 유전자 발현 카세트를 포함하며, 상기 발현카세트는 라이보자임-목적 유전자 발현 카세트의 5' 말단에 스플라이싱 공여/스플라이싱 수여 서열(splicing donor/splicing acceptor sequence, SD/SA sequence)이 연결되고, 3' 말단에 WPRE(Woodchuck hepatitis virus Posttranscriptional Regulatory Element)가 연결된 것을 특징으로 하는, 재조합 아데노바이러스, 상기 재조합 아데노바이러스가 도입된 숙주세포, 상기 재조합 아데노바이러스를 유효성분으로 포함하는 암 예방 또는 치료용 약학 조성물 및 상기 재조합 아데노바이러스 또는 약학 조성물을 치료를 필요로 하는 개체에 투여하는 단계를 포함하는 개체의 암을 치료하는 방법에 관한 것이다.

암은 국내 사망 원인의 1위를 차지하는 중대 질환으로, 인체의 모든 부위에서 발생할 수 있으며, 환경적 요인, 유전적 요인 등 다양한 요인들에 의해 발생할 수 있다. 암을 정복하기 위한 수많은 연구가 있어 왔지만 아직까지 정복되지 않고 있는 난치병이다. 암에 대한 기존의 치료법으로는 수술, 화학 요법 및 방사선 치료 등이 있으며 의학의 발달로 예후가 좋아지고 있지만, 암세포 뿐 아니라 정상 세포에도 악영향을 끼칠 수 있는 한계가 많다. 최근에는 이러한 치료법들과는 개념이 다른 치료법들이 연구되고 있는데 그 중에서 특히 암세포 만을 효과적으로 치료하기 위한 유전자 치료법이 활발히 연구되고 있다.

유전자 치료(gene therapy)란 통상적인 방법으로는 치료가 곤란한 선천적 또는 후천적 유전자 이상을 유전공학적 방법으로 치료하는 방법을 일컫는다. 구체적으로, 유전자 치료는 선천적 또는 후천적 유전자 결함, 바이러스성 질병, 암 또는 심혈관계 질환 등과 같은 만성 질환의 치료와 예방을 위하여, DNA 및 RNA 등의 유전 물질을 인체 내에 투여하여 치료 단백질을 발현시키거나 특정 단백질의 발현을 억제하도록 하는 치료 방법이다. 이는, 질병의 원인을 유전자 차원에서 해석하여 근본적으로 치료할 수 있기 때문에 난치병의 극복은 물론 기존 의료 방식의 대체 수단으로 기대되고 있는 방법이다.

암에 대한 유전자 치료는 인체 내의 면역반응을 유도하는 면역학적 유전자 치료법과, 사용된 유전자가 직접 암세포를 파괴하거나 사멸을 유도하는 유전자 치료법으로 구분될 수 있다. 후자의 경우에는 유전자를 세포 내로 운반하고 발현시키는 벡터의 역할이 매우 중요한데, 이 중 아데노바이러스 벡터는 유전자 전달의 높은 효율, 미분화세포로 유전자를 전달하는 능력 및 높은 역가의 바이러스 저장물 제조의 용이성으로 인해 가장 유망한 유전자 치료용 벡터 중의 하나로 인정받고 있다.

일반적으로 사용되는 유전자 치료용 아데노바이러스 벡터는 복제에 필수적인 일련의 유전자들을 삭제시키고, 프로모터 활성의 수준이 높은 사이토메갈로바이러스(CMV) 또는 로우스 사르코마 바이러스(RSV) 프로모터를 넣어 치료 목적 단백질을 생체 내에 높은 효율로 발현시킨다.

최근에는, 유전자 치료에 활용될 수 있는 표적 유전자들의 다수가 세포분열을 많이 하는 일반 세포에도 발현함으로 인해서 발생하는 부작용을 줄이기 위한 노력으로 암세포 특이적인 치료(cancer tissue targeted therapy)가 시도되고 있다(Fukuzawa et al., Cancer Res 64: 363-369, 2004). 이를 위해 CMV나 RSV 대신 조직 특이적(tissue-specific) 프로모터를 쓰는 방법이 고려되고 있으나, 특이성이 높아지는 대신 치료 효능이 떨어지는 단점으로 인해 실용화에 이르지 못하고 있는 실정이다.

또한, 최근에는 조직 특이적 프로모터 이외의 인자를 이용하여 조직 특이적인 암치료용 아데노바이러스를 개발하려는 연구가 진행되고 있는데, 대표적인 예로서, 트랜스-스플라이싱 라이보자임 등을 사용하는 방법이 개발되고 있다.

상기 트랜스-스플라이싱 라이보자임을 이용한 조직 특이적인 암치료용 아데노바이러스의 개발에 관한 연구는 테트라하이메나 써모필라(Tetrahymena thermophila)로부터의 그룹 I 인트론 라이보자임이 실험관 내에서뿐만 아니라 박테리아 나아가 인체 세포 내에서 트랜스-스플라이싱 반응을 수행함으로써 별도로 존재하는 두 개의 전사체를 서로 연결시킬 수 있음이 밝혀지면서 주목받게 되었다.

구체적으로, 이러한 그룹 I 인트론을 기초로 한 트랜스-스플라이싱 라이보자임은 질환과 관련된 유전자 전사체 또는 질병 세포에서만 특이적으로 발현되는 특정 RNA를 표적으로 하여, 이들을 정상적인 RNA로 보정하거나 또는 새로운 치료용 유전자 전사체로 치환되도록 재프로그램을 유발할 수 있어, 질환 특이적이며 안전한 유전자 치료 기술이 될 수 있을 것이라 예상되고 있다. 또한, 트랜스-스플라이싱 라이보자임은 질환 특이 RNA를 제거함과 동시에 원하는 치료용 유전자 산물의 발현을 유도할 수 있으므로 치료 효과를 배가시킬 수 있다.

특히, 최근 연구에 있어 암 조직에서 특이적으로 작용할 수 있는 hTERT(human Telomerase reverse transcriptase)를 타겟하는 트랜스-스플라이싱 라이보자임이 알려지면서, 이를 이용한 암치료제를 개발하려는 시도가 활발히 진행되고 있다. 그러나, 이들이 조직 특이적인 프로모터와의 조합에 의하여 높은 조직특이성을 보이는 반면 발현 효율이 매우 낮아, 치료 효율 측면의 단점을 아직까지 극복하지 못하고 있다.

한편, 유전자 치료 방법에 있어 사용되어지는 치료용 유전자로는 단순 포진 바이러스의 티미딘 키나제(이하, HSVtk로 약칭함), 대장균의 사이토신 탈아미노효소(CD) 및 대장균의 퓨린 뉴클레오사이드 포스포릴라제(이하, PNP로 약칭함) 유전자 등이 알려져 있다. 이들을 이용한 유전자 치료는 유전자 지향성 효소 프로드럭 치료(gene-directed enzyme prodrug therapy, GDEPT)라 불리우며, 모두 프로드럭을 사용하는 공통점이 있다. GDEPT에 사용되는 프로드럭으로는 간사이클로비르(GCV), 5-플루오로우라실(5-FU) 및 6-메틸퓨린-2-데옥시리보사이드(6-MeP-dR)가 각각 HSV-TK, CD 및 PNP와 같이 사용되고 있다. 세포 독성이 없는 프로드럭은 도입된 유전자들에 의해 세포에 독성이 있는 약물로 변환되는데 주로 인산화에 의해 활성이 생긴다. 자살 유전자를 이용한 유전자 요법의 장점은 이들 유전자가 도입된 세포에서 활성화된 약물에 의해 인접한 세포도 사멸시키는 소위 방관자 효과가 크다는데 있는데, 이는 유전자의 도입 효율이 낮은 상태에서 취할 수 있는 최선의 전략으로 일컬어지는 기술이다.

이러한, 유전자 치료 전략에 있어 HSVtk를 이용하는 것은 상당히 보편화되어 있다. 구체적으로, HSVtk/GCV 시스템은 자살 유전자 요법 중에서 가장 널리 사용되는 방법 중 하나로 WO 90/07936, US 5,837,510, US 5,861,290, WO 98/04290, WO 97/37542 및 US 5,631,236 등에 개시되어 있다. HSVtk 유전자를 발현하는 세포는 간사이클로비르(GCV)를 인산화할 수 있고, 그 결과 DNA를 복제하는 작용을 방해하여 세포 사멸을 유도할 수 있다. 이 방법은 현재 다양한 인간 암의 유전자 치료시 30가지 이상의 임상 시험에 사용되고 있다. 그러나, 이 또한 증식되는 세포만이 사멸할 수 있고 방관자 효과가 탁월한 편이 아니며, 다량 사용시 세포 독성 문제도 야기할 수 있다는 문제점을 갖고 있으므로, 현재는 세포 사멸 효과와 방관자 효과를 향상시키기 위해 두 가지 이상의 프로드럭을 사용하여 암을 정복하고자 하는 연구가 활발히 진행되고 있다.

이러한 상황 하에서, 본 발명자들은 조직 특이성과 치료 효능이 동시에 향상된 암 치료 유전자 치료 방안을 개발하기 위하여 예의 연구노력한 결과, 조직 특이적인 프로모터에 의해 발현 조절되는 암 조직 특이적 트랜스-스플라이싱 라이보자임과 이에 의해 HSVtk 유전자가 조절되어 발현되도록 디자인한 재조합 아데노바이러스에 조절 유도체를 구성으로 추가하여, 높은 조직 특이성을 유지할 뿐만 아니라 암 조직에 특이적인 우수한 치료효과를 나타내고, 뿐만 아니라 유전자 치료에 따른 부작용을 현저히 줄일 수 있음을 확인하고, 본 발명을 완성하였다.

본 발명의 목적은 (i) 조직 특이적 프로모터; 및 (ii) 암특이적 유전자를 표적으로 하는 트랜스-스플라이싱 라이보자임 및 상기 라이보자임의 3' 엑손에 연결된 목적 유전자를 포함하는, 라이보자임-목적 유전자 발현 카세트를 포함하며, 상기 발현카세트는 라이보자임-목적 유전자 발현 카세트의 5' 말단에 스플라이싱 공여/스플라이싱 수여 서열(splicing donor/splicing acceptor sequence, SD/SA sequence)이 연결되고, 3' 말단에 WPRE(Woodchuck hepatitis virus Posttranscriptional Regulatory Element)가 연결된 것을 특징으로 하는, 재조합 아데노바이러스를 제공하는 것이다.

본 발명의 다른 목적은 상기 재조합 아데노바이러스가 도입된 숙주세포를 제공하는 것이다.

본 발명의 또 다른 목적은 상기 재조합 아데노바이러스를 유효성분으로 포함하는 암 예방 또는 치료용 약학 조성물을 제공하는 것이다.

본 발명의 또 다른 목적은 상기 재조합 아데노바이러스 또는 약학 조성물을 치료를 필요로 하는 개체에 투여하는 단계를 포함하는, 개체의 암을 치료하는 방법을 제공하는 것이다.

상기 목적을 달성하기 위한 본 발명의 일 실시양태에 의하면, 본 발명은 암특이적 유전자를 표적하는 트랜스-스플라이싱 라이보자임의 조절 유도체를 포함하는 재조합 아데노바이러스를 제공한다. 구체적으로는, (i) 조직 특이적 프로모터; 및 (ii) 암특이적 유전자를 표적으로 하는 트랜스-스플라이싱 라이보자임 및 상기 라이보자임의 3' 엑손에 연결된 목적 유전자를 포함하는, 라이보자임-목적 유전자 발현 카세트를 포함하며, 상기 발현카세트는 라이보자임-목적 유전자 발현 카세트의 5' 말단에 스플라이싱 공여/스플라이싱 수여 서열(splicing donor/splicing acceptor sequence, SD/SA sequence)이 연결되고, 3' 말단에 WPRE(Woodchuck hepatitis virus Posttranscriptional Regulatory Element)가 연결된 것을 특징으로 하는, 재조합 아데노바이러스를 제공한다.

본 발명의 상기 재조합 아데노바이러스는 라이보자임 및 목적 유전자의 양 말단에 SD/SA 서열 및 WPRE를 구성요소로 포함시킬 때, 생체 내에서 암치료 효과가 탁월한 것을 확인한 것을 기초로, 기존에는 보고된 바 없는 본 발명자들이 최초로 고안한 재조합 아데노바이러스에서의 SD/SA 서열 및 WPRE 동시 사용에 기초한다.

본 발명의 용어 "아데노바이러스"는 아데노바이러스 벡터와 동일한 의미로 사용될 수 있으며, 아데노비리다에(Adenoviridae) 속에 속하는 바이러스를 의미한다. 상기 아데노바이러스는 외피(envelop)가 없이 이중가닥 DNA 게놈이 20면체 캡시드(icosahedral capsid) 안에 들어있고 헥손(hexon) 단백질이 캡시드의 전면을 둘러싸고 있는 DNA 바이러스로서, 게놈 DNA 크기는 약 36 kbp이며 바이러스가 증식하는데 필수적인 E1a 유전자 부위와 바이러스가 패키징되는데 필수적인 유전자 등을 포함한다. 각 면이 접하는 12개의 접선에 존재하는 5량체 펜톤 염기(pentameric penton base)와 바이러스 표면 밖으로 돌출된 3량체 섬유 단백질(trimeric fiber protein)으로 구성된 펜톤 복합체가 아데노바이러스의 세포 내로의 도입을 용이하게 한다. 본 발명의 목적상, 상기 아데노바이러스를 기반으로 재조합 아데노바이러스를 제조함으로써, 바이러스의 증식은 차단하여 감염 위험을 줄이면서 세포 내로의 침입효율을 증가시켜 혈액을 통하여 간 내의 종양 세포로의 유입을 용이하게 할 수 있다.

상기 아데노바이러스는 높은 유전자 전달효율, 미분화세포로 유전자를 전달하는 능력 및 높은 역가의 바이러스 저장물 제조의 용이성으로 인해 유망한 유전자 치료용 벡터로 인정받고 있다. 또한 세포의 증식에 관계없이 다양한 세포를 감염시킬 수 있으며 또한 감염 후 숙주의 유전자에 통합되지 않으므로 삽입성 돌연변이의 위험이 없으므로 암치료를 위한 치료 유전자 전달 매체로 적합하다. 하지만, 이러한 아데노바이러스가 유전자 치료에 사용되기 위해서는 바이러스가 체내에서 스스로 증식하여 온몸에 감염됨으로써 또 다른 질병이 유발되지 않도록 바이러스 증식에 사용되는 유전자를 제거하는 과정을 필요로 한다. 따라서, 바이러스가 스스로 정상세포 내에서 증식하지 못하도록 아데노바이러스 게놈 중에서 상기 바이러스 증식에 사용되는 유전자를 결손시켜 유전자 치료에 사용할 수 있다.

한편, 상기 아데노비리다에는 마스트아데노바이러스(Mastadenovirus) 속의 동물성 아데노바이러스를 모두 포함한다. 특히, 인간의 아데노 바이러스는 A-F 아속(subgenera) 및 이의 개개의 혈청형을 포함하며, A-F 아속은 인간의 아데노바이러스 제1형, 제2형, 제3형, 제4형, 제4a형, 제5형, 제6형, 제7형, 제8형, 제9형, 제10형, 제11형(Ad11A 및 Ad11P), 제12형, 제13형, 제14형, 제15형, 제16형, 제17형, 제18형, 제19형, 제19a형, 제20형, 제21형, 제22형, 제23형, 제24형, 제25형, 제26형, 제27형, 제28형, 제29형, 제30형, 제31형, 제32형, 제33형, 제34형, 제34a형, 제35형, 제35p형, 제36형, 제37형, 제38형, 제39형, 제40형, 제41형, 제42형, 제43형, 제44형, 제45형, 제46형, 제47형, 제48형 및 제91형을 포함하나, 이에 제한되는 것은 아니다. 본 발명에서 아데노바이러스는 E1 및 E3이 결실된 아데노바이러스일 수 있으며, 이는 천연형의 아데노바이러스로부터 바이러스의 증식에 관여하는 부위가 제거된 아데노바이러스를 의미한다. 본 발명에서는 숙주세포에 형질감염시킨 후 바이러스 자체가 증식하는 것을 방지하기 위하여 E1 및 E3이 결실된 아데노바이러스를 기본 골격으로 사용할 수 있으며, 이를 통해 복제불가능한 재조합 아데노바이러스를 제조할 수 있다. 특히, 본 발명의 재조합 아데노바이러스는 복제불가능하며 간에 선택적으로 작용하는 것일 수 있다.

본 발명의 재조합 아데노바이러스는 프로모터, 트랜스-스플라이싱 라이보자임 및 암치료 유전자를 포함하는 것일 수 있으며, 추가로 조절 유도체를 가지는 것일 수 있고, 상기 프로모터는 조직-특이적 프로모터일 수 있다. 특히, 서열번호 47의 염기서열을 가지는 재조합 아데노바이러스일 수 있다.

본 발명의 용어 "발현 카세트"는 프로모터와 트랜스-스플라이싱 라이보자임-목적 유전자를 포함하고 있고, 트랜스-스플라이싱 라이보자임-목적 유전자의 각 말단에 SD/SA 서열 및 WPRE 서열이 각각 5' 말단과 3' 말단에 존재하며, 트랜스-스플라이싱 라이보자임-목적 유전자를 발현시킬 수 있는 단위 카세트를 의미한다.

본 발명에서 라이보자임-목적 유전자 발현 카세트는 상기 라이보자임과 목적 유전자가 연결된 서열에 전사체의 수준을 조절하는 서열, 즉 조절 유도체를 추가로 포함하는 것일 수 있으며 이에 제한되는 것은 아니나, 본 발명에서는 특히 스플라이싱 공여/스플라이싱 수여 서열(splicing donor/splicing acceptor sequence, SD/SA sequence) 및/또는 WPRE(Woodchuck hepatitis virus Posttranscriptional Regulatory Element)인 것을 특징으로 한다.

본 발명에서 라이보자임-목적 유전자 발현 카세트는, 목적 유전자의 양 말단에 스플라이싱 공여/스플라이싱 수여 서열(splicing donor/splicing acceptor sequence, SD/SA sequence) 및 WPRE(Woodchuck hepatitis virus Posttranscriptional Regulatory Element)이 각각 연결된 것일 수 있다. SD/SA는 전사 시작(transcription initiation)과 RNA ploymerase Ⅱ의 프로세싱(processing) 및 mRNA의 핵에서 세포질로의 이동(nucleocytoplasmic export)을 증가시키며 WPRE는 mRNA의 프로세싱과 핵에서 세포질로의 이동을 증가시킴으로써 각각 pre-mRNA 수준을 증가시킬 수 있다. 본 발명에서 상기 발현 카세트는 라이보자임-목적 유전자 발현 카세트의 5' 말단에 스플라이싱 공여/스플라이싱 수여 서열이 연결되고, 3' 말단에 WPRE가 연결된 것일 수 있다. 이러한 구성을 통하여 세포 내에서 라이보자임의 RNA 수준이 현저히 증가되고, 전사체 양이 증가함으로써, 세포 및 생체 내에서 암세포의 사멸도가 증가할 뿐 아니라 숙주 세포에 미치는 독성은 오히려 감소하는 것을 확인하였다. 본 발명과 같은 아데노바이러스에서 SD/SA 서열을 사용하는 구성, 및 SD/SA를 WPRE를 동시에 사용하는 구성은 본 발명자들에 의해 최초로 개발된 것이다.

본 발명에서 상기 SD/SA 서열은 RNA 전사체의 인트론을 제거하는 스플라이싱 반응에 있어서 잘려나가는 인트론의 시작부분과 끝나는 부분에 해당하는 서열을 의미하며, 일반적으로 SD서열은 인트론 5' 말단의 GU 서열일 수 있으며, SA서열은 인트론의 3' 말단의 AG 서열일 수 있다. 본 발명에서 SD/SA 서열은 서열번호 1의 핵산 서열을 가질 수 있으나, 목적 유전자 발현 카세트 내에 존재하면서 목적 유전자의 발현을 촉진시킬 수 있는 한 이에 제한되지 않는다. SD/SA 서열이 일부 유전자의 발현을 증진시킬 수 있음에 대해서는 알려진 바 있으나, 라이보자임의 발현을 증진시킬 수 있음은 기존에 알려진 바 없으며 본 발명에서 처음 확인하였다.

본 발명에서 상기 WPRE는 DNA 상에 발현을 촉진하는 3차 구조를 유도하여, 유전자의 발현을 증가시키는 서열을 의미한다. 본 발명에서 WPRE는 서열번호 3의 핵산서열을 가질 수 있으나, 목적 유전자 발현 카세트 내에 존재하면서 목적 유전자의 발현을 촉진시킬 수 있는 한 이에 제한되지 않는다.

본 발명의 용어 "프로모터"는 DNA의 일부분으로 전사를 개시할 수 있도록 RNA 중합효소의 결합에 관여한다. 일반적으로 표적 유전자와 동일 가닥상에 표적 유전자에 인접하여 이의 상류에 위치하며, RNA 중합효소 또는 RNA 중합효소를 도입하는 단백질 이른바 전사인자(transcription factor)가 결합하는 자리로서 상기 효소 또는 단백질이 올바른 전사시작 부위에 위치하도록 유도할 수 있다. 즉, 센스 가닥(sense strand) 상에서 전사하고자 하는 유전자의 5' 부위에 위치하여 RNA 중합효소가 직접 또는 전사인자를 통해 해당 위치에 결합하여 표적 유전자에 대한 mRNA 합성을 개시하도록 유도하는 것으로 특정한 유전자 서열을 갖는다. 유전자의 발현을 높이기 위하여 보편적인 프로모터(universal promoter)인 레트로바이러스의 LTR, 로우스 사르코마 바이러스(Rous Sarcoma Virus; RSV) 또는 사이토메갈로바이러스(cytomegalovirus; CMV) 프로모터를 이용할 수 있으나, 본 발명에서는 조직-특이적 프로모터를 이용할 수 있다.

본 발명에서 용어 "조직-특이적 프로모터"란 조직에 따라 특이적으로 프로모터 다운스트림 (downstream) 유전자의 mRNA로의 전사 개시 활성을 가지는, 암호화 영역의 업스트림 (upstream)의 비해독되는 핵산 서열을 말한다. 조직 특이적으로 프로모터 하위 유전자의 전사를 개시하도록 하는 핵산 서열은 조직에 따라 다양한 프로모터 서열이 제한 없이 포함될 수 있으며, 그 예로 간세포 특이적 프로모터인 PEPCK (phosphoenolpyruvate carboxykinase) 프로모터, 아포리포프로테인 E(apolipoprotein E) 프로모터, 혈청 알부민 프로모터, 간암 특이적 AFP(alphafetoprotein) 프로모터, 대장암 특이적 CEA(carcinoembryonic antigen) 프로모터, 또는 전립선암 특이적 PSA(Prostate-specific antigen) 프로모터가 있다. 본 발명에서는 이에 제한되는 것은 아니나, 특히 간조직 특이적인 PEPCK 프로모터일 수 있다. 본 발명에서 상기 PEPCK 프로모터는 서열번호 7의 프로모터일 수 있으며, 서열번호 8의 PEPCK 프로모터에 작용하는 인핸서를 추가로 포함하는 것일 수 있다.

본 발명의 용어 "암특이적 유전자"는 본 발명에 따른 암세포에서만 특이적으로 발현되거나 또는 현저하게 과발현되는 유전자를 의미한다. 상기 암특이적 유전자는 본 발명에 따른 라이보자임이 암특이적으로 작용할 수 있는 특징을 부가할 수 있다. 이러한 암특이적 유전자의 대표적인 예로는, TERT(Telomerase reverse transcriptase)의 mRNA, AFP(alphafetoprotein) mRNA, CEA(carcinoembryonic antigen) mRNA, PSA(Prostate-specific antigen) mRNA, 또는 CKAP2(Cytoskeleton-associated protein 2) mRNA 등이 사용 가능하나, 바람직하게는 TERT(Telomerase reverse transcriptase) mRNA를 사용할 수 있다.

본 발명의 용어 "TERT(Telomerase reverse transcriptase)"는 암 세포의 영속성(immortality) 및 증식(proliferation) 능력을 조절하는 가장 중요한 효소 중의 하나로서, 염색체에 말단소립 구조를 형성해 염색체 끝을 보호하는 역할을 통해 세포의 노화를 억제하는 효소를 의미한다. 정상적인 세포에서는 세포가 분열할 때마다 말단소립의 길이가 조금씩 줄어들어 결국 유전물질이 손실되고, 세포가 사멸하게 되는 기작을 갖는다. 그러나, 암세포에서는 이 효소가 말단소립을 계속적으로 연장시켜 주기 때문에 세포가 사멸하지 않으며, 암세포의 불멸성에 직접 기여함으로써 암을 치료하는데 중대한 장애 요소로 알려져 있다. 이러한, 텔로머라제(telomerase)는 무한히 복제되는 생식세포, 조혈세포 및 암세포에서 80 내지 90%의 텔로머라제 활성을 갖고 있지만, 암세포 주변의 정상세포들은 그 활성을 갖지 않는 특징을 갖는다. 본 발명에서는 암특이적 유전자로서 hTERT mRNA를 사용할 수 있으나, 이에 제한되지는 않는다.

본 발명의 용어 "라이보자임"은 효소처럼 작용하는 RNA 분자 또는 그 RNA 분자를 포함하는 단백질로 구성되는 분자로 RNA 효소 또는 촉매적 RNA라고도 불린다. 명확한 3차 구조를 갖는 RNA 분자로 화학반응을 수행하며 촉매적 또는 자기촉매적 특성을 가지며, 몇몇 라이보자임은 자기 또는 다른 RNA 분자를 절단하여 활성을 저해하는 것으로 밝혀졌으며, 다른 라이보자임은 리보솜의 아미노전달효소(aminotransferase) 활성을 촉매하는 것이 확인되었다. 이러한 라이보자임에는 망치머리(hammerhead) 라이보자임, VS 라이보자임 및 헤어핀(hairpin) 라이보자임 등이 포함된다. 본 발명에서 상기 라이보자임은 트랜스-스플라이싱 반응을 통해 암 특이적 유전자의 활성을 저해시켜서 결과적으로는 선택적인 항암효과를 나타낼 수 있을 뿐만 아니라 암치료 유전자와 접합된 형태로 발현되어 암치료 유전자를 활성화시킬 수 있다. 따라서, 암특이적 유전자를 불활성화시키고, 암치료 유전자를 활성화시킬 수 있는 활성을 나타낸다면 어떠한 형태의 것이라도 사용 가능하다.

본 발명의 목적상, 본 발명의 라이보자임은 상기에서 설명한 hTERT mRNA를 표적하는 라이보자임이며, hTERT가 과다발현되는 암세포, 특히 간암세포를 표적으로 하여 hTERT mRNA를 특이적으로 절단하여 억제시키고 치료유전자인 HSVtk(Herpes simplex virus-thymidine kinase) 유전자를 특이적으로 발현시키는 역할을 한다. 즉, 본 발명의 상기 라이보자임은 아데노바이러스를 사용하여 간 내로 도달한 본 발명의 재조합 아데노바이러스가 암세포를 표적하는데 중요한 역할을 한다.

본 발명의 용어 "트랜스-스플라이싱(trans-splicing)"은 서로 다른 유전자로부터의 RNA를 연결하는 것을 의미한다. 바람직하게는 암에 특이적인 hTERT(human Telomerase reverse transcriptase)의 mRNA를 인지하여 트랜스-스플라이싱하는 능력이 검증된 hTERT 표적 트랜스-스플라이싱 그룹 I 라이보자임을 사용하는 것일 수 있고, 더욱 바람직하게는 Rib21 라이보자임(서열번호 5)을 사용하는 것일 수 있다.

한편, 본 발명자들은 상기 라이보자임과 함께 목적 유전자를 발현시킬 수 있는 재조합 아데노바이러스를 고안하였다. 즉, 암특이적 유전자에 특이적인 트랜스-스플라이싱 라이보자임을 통하여 라이보자임에 연결된 목적 유전자 발현카세트에 포함된 목적 유전자를 암특이적 유전자 전사체에 삽입하는 기능을 하는 재조합 아데노바이러스를 고안하였다.

본 발명의 용어 "목적 유전자"는 상기 라이보자임에 의하여 암특이적 유전자의 mRNA에 연결되어 발현이 유도되는 유전자를 의미하며, 본 발명에서는 치료용 유전자 또는 리포터 유전자일 수 있으나 이에 제한되지 않는다.

본 발명의 용어 "암치료 유전자(anti-cancer therapeutic gene)"는 암 세포 내에서 발현시에 치료학적 효과를 나타내는 폴리펩티드를 암호화하는 폴리뉴클레오타이드 서열을 의미한다. 본 발명에 있어서, 상기 암치료 유전자는 상기 라이보자임과 접합된 형태로 발현되거나 또는 독립적으로 발현되어, 항암활성을 나타낼 수 있다. 이러한 암치료 유전자의 예로는, 약제감수성 유전자, 세포사멸 유전자, 세포증식 억제 유전자, 세포독성 유전자, 종양 억제인자 유전자, 항원성 유전자, 사이토카인 유전자, 항신생 혈관 생성 유전자 등을 들 수 있으나, 이에 제한되지는 않을 뿐만 아니라, 본 발명에서는 상기 암치료 유전자를 단독적으로 사용하거나 또는 둘 이상 복합적으로 사용할 수도 있다.

상기 약제감수성 유전자(drug-sensitizing gene)는 독성이 없는 전구체(prodrug)를 독성물질로 전환시키는 효소에 대한 유전자로 유전자가 이입된 세포가 사멸하게 되므로 자살 유전자(suicide gene)로도 불린다. 즉, 정상세포에는 독성이 없는 전구체를 전신적으로 투여했을 때 암세포에만 전구체가 독성 대사체(toxic metabolite)로 전환되어 약제에 대한 감수성을 변화시킴으로써 암세포를 파괴시키는 방법이다. 대표적으로 HSVtk(Herpes simplex virus-thymidine kinase) 유전자와 간사이클로비르(ganciclovir), 대장균의 사이토신 탈아미노효소(cytosine deaminase, CD) 유전자와 5-플루오로시토신(5-fluorocytosine, 5-FC)가 가능하다.

상기 세포사멸 유전자(proapoptotic gene)는 발현되어 프로그램된 세포 사멸을 유도하는 뉴클레오타이드 서열을 말한다. 당업자에게 공지된 세포사멸 유전자로, p53, 아데노바이러스 E3-11.6K (Ad2 및 Ad5에서 유래) 또는 아데노바이러스 E3-10.5K (Ad에서 유래), 아데노바이러스 E4 유전자, p53 경로 유전자 및 카스파제를 코딩하는 유전자가 포함된다.

상기 세포증식 억제 유전자(cytostatic gene)는 세포 내에서 발현되어 세포 주기 도중에 세포 주기를 정지시키는 뉴클레오타이드 서열을 의미한다. 대표적으로 p21, 망막아세포종 유전자, E2F-Rb 융합 단백질 유전자, 사이클린-종속성 카이네이즈 억제인자를 코딩하는 유전자(예를 들면, p16, p15, p18 및 p19), 성장 중지 특이성 호메오박스(growth arrest specific homeobox, GAX) 유전자 등이 있다.

상기 세포독성 유전자(cytotoxic gene)는 세포 내에서 발현되어 독성 효과를 나타내는 뉴클레오타이드 서열을 말한다. 일예로, 슈도모나스 외독소(exotoxin), 리신 독소, 디프테리아 독소 등을 코딩하는 뉴클레오타이드 서열 등이 있다.

상기 종양 억제인자 유전자(tumor suppressor gene)는 표적 세포 내에서 발현되어 종양 표현형을 억제할 수 있거나 세포사멸을 유도할 수 있는 뉴클레오타이드 서열을 의미한다. 대표적으로 종양 괴사 인자(tumor necrosis factor-α, TNF-α), p53 유전자, APC 유전자, DPC-4/Smad4 유전자, BRCA-1 유전자, BRCA-2 유전자, WT-1 유전자, 망막아세포종 유전자, MMAC-1 유전자, 선종양 폴립증 코일 단백질(adenomatous polyposis coil protein), 결손된 결장 종양(DCC) 유전자, MMSC-2 유전자, NF-1 유전자, 염색체 3p21.3에 위치한 비인후 종양 억제인자 유전자, MTS1 유전자, CDK4 유전자, NF-1 유전자, NF-2 유전자, VHL 유전자 및 sPD-1(programmed death-1)가 포함된다.

상기 항원성 유전자(antigenic gene)는 표적 세포 내에서 발현되어 면역 시스템에서 인식할 수 있는 세포 표면 항원성 단백질을 생산하는 뉴클레오타이드 서열을 말한다. 당업자에게 공지된 항원성 유전자의 예에는 암태아성 항원 (carcinoembryonic antigen, CEA) 및 p53이 포함된다.

상기 사이토카인 유전자(cytokine gene)는 세포 내에서 발현되어 사이토카인을 생성하는 뉴클레오타이드 서열을 의미한다. 대표적으로 GM-CSF, 인터류킨(IL-1, IL-2, IL-4, IL-12, IL-10, IL-19, IL-20), 인터페론 α, β, γ(인터페론 α-2b) 및 인터페론 α-2α-1과 같은 융합체 등이 포함된다.

상기 항신생혈관 생성 유전자(anti-angiogenic gene)는 발현되어 항-신생혈관 생성 인자를 세포밖으로 방출하는 뉴클레오타이드 서열을 말한다. 그 예로 안지오스타틴, 혈관 내피 성장 인자(VEGF)의 억제 인자, 엔도스타틴 등이 포함된다.

본 발명에서 용어 "리포터 유전자"는 본 발명의 아데노바이러스의 감염 여부 또는 라이보자임 발현 효율을 모니터링하기 위해 사용되는 유전자로서 감염된 세포 또는 조직의 손상이 없이 모니터링할 수 있는 유전자는 제한 없이 사용될 수 있으나, 그 예로 루시퍼라제(luciferase), 녹색 형광 단백질 (GFP), 변형된 녹색 형광 단백질 (modified green fluorescent protein; mGFP), 증강된 녹색 형광 단백질 (enhanced green fluorescent protein; EGFP), 적색 형광 단백질 (RFP), 변형된 적색 형광 단백질 (modified red fluorescent protein; mRFP), 증강된 적색 형광 단백질 (ERFP), 청색 형광 단백질 (BFP), 증강된 청색 형광 단백질 (EBFP), 황색 형광 단백질 (YFP), 증강된 황색 형광 단백질 (EYFP), 남색 형광 단백질 (CFP) 또는 증강된 남색 형광 단백질 (ECFP)일 수 있다.

본 발명의 구체적인 일 실시예에 따르면, 본 발명자는 hTERT를 표적으로 작용하는 라이보자임에 접합된 형태로 리포터 유전자의 일종인 반딧불이 루시퍼라제(firefly luciferase) 또는 암치료 유전자의 일종인 HSVtk를 발현시킬 수 있는 재조합 아데노바이러스를 제작하였다. 이에 반딧불이 루시퍼라제(firefly luciferase)를 발현시킬 수 있는 재조합 아데노바이러스로 라이보자임 발현 효율을 확인하였다(실시예 5 및 도 2 참고). 그 결과, SD/SA 서열 및/또는 WPRE를 구성으로 포함한 경우 이를 포함하지 않는 경우보다 라이보자임 발현 효율이 현저히 증가하는 것을 확인하였으며, 특히 SD/SA 서열이 라이보자임의 발현 효율을 증진시킬 수 있다는 것은 본 발명에서 처음 밝히었다. 또한, SD/SA 서열 및 WPRE 서열을 모두 포함할 때 SD/SA 서열 또는 WPRE 서열을 단독으로 포함하는 경우보다 발현 효율이 현저히 증가하는 것을 확인하였다(도 2).

또한, 본 발명의 암치료 유전자로 HSVtk를 발현시킬 수 있는 재조합 아데노바이러스로 본 발명의 재조합 아데노바이러스의 항암효과를 확인하였다. 구체적으로는, TERT를 표적으로 작용하는 라이보자임에 접합된 형태로 암치료 유전자의 일종인 HSVtk를 발현시킬 수 있고, SD/SA 서열 및/또는 WPRE를 포함하여 높은 발현 효율을 가지는 재조합 아데노바이러스를 제작하였고, 이를 암세포 및 동물의 암에 처리하였을 때, 직접적인 암세포 독성(도 6) 및 항암 활성(도 8 및 도 9)을 나타내는 것을 확인하였다. 또한, 이러한 결과를 통해 상기 트랜스-스플라이싱 반응을 통해 다수의 암치료 유전자를 발현시킬 경우, 암 치료 효과가 현저하게 증가시킬 수 있음을 확인하였다.

따라서, 바람직하게는 본 발명의 재조합 아데노바이러스는 약제감수성 유전자, 세포사멸 유전자, 세포증식 억제 유전자, 세포독성 유전자, 종양 억제인자 유전자, 항원성 유전자, 사이토카인 유전자 및 항신생 혈관 생성 유전자로 이루어진 군에서 선택되는 암치료 유전자를 포함하고, 더욱 바람직하게는 암치료 유전자로 HSVtk(Human Simplex Virus thymidine kinase)를 포함하는 것이다.

본 발명의 용어, "HSVtk(Herpes simplex virus-thymidine kinase)"은 단순 포진 바이러스로부터 유래되는 티미딘 인산화 효소를 의미한다. 이 효소는 독성이 없는 전구체(prodrug)를 독성물질로 전환시키므로서, 그 유전자가 이입된 세포가 사멸하게 하는 약제감수성 유전자의 대표적인 하나이다. 본 발명에 있어 HSVtk 유전자는 본 발명에 따른 라이보자임에 접합된 형태로 발현되어 항암활성을 나타내는 암치료 유전자로 사용되어질 수 있다. 이러한 HSVtk 유전자는 바람직하게는 서열번호 6으로 표시되는 염기서열을 가질 수 있으며, 진뱅크(genbank) 등록번호 AAP13943, P03176, AAA45811, P04407, Q9QNF7, KIBET3, P17402, P06478, P06479, AAB30917, P08333, BAB84107, AAP13885, AAL73990, AAG40842, BAB11942, NP_044624, NP_044492, CAB06747 등에 기재된 것일 수 있다.

또 하나의 양태로서, 본 발명은 상기 재조합 아데노바이러스가 도입된 숙주 세포에 관한 것이다.

본 발명에서 용어 "도입"은 형질감염(transfection) 또는 형질도입(transduction)에 의해 외래 DNA를 세포로 유입시키는 것을 의미한다. 형질감염은 칼슘 포스페이트-DNA 공침전법, DEAE-덱스트란-매개 형질감염법, 폴리브렌-매개 형질감염법, 전기충격법, 미세주사법, 리포좀 융합법, 리포펙타민 및 원형질체 융합법 등의 당분야에 공지된 여러 방법에 의해 수행될 수 있다. 또한, 형질도입은 감염(infection)을 수단으로 하여 바이러스 또는 바이러스 벡터 입자를 사용하여 세포 내로 유전자를 전달시키는 것을 의미한다.

본 발명에서 용어, "숙주 세포"는 본 발명의 아데노바이러스를 제조할 수 있는 숙주 세포는 제한 없이 포함되나, 포유류 세포 또는 조류 세포일 수 있으며, 예시적 포유류 세포는 돼지류 세포, 인간 세포, 소류 세포 및 조류 세포를 포함하나, 이에 국한되는 것은 아니다. 본 발명의 일 구현예에 따르면 293 세포주를 사용하여 아데노바이러스를 증폭,제작하였다.

본 발명의 다른 실시양태로서, 본 발명은 상기 재조합 아데노바이러스를 유효성분으로 포함하는 암 예방 또는 치료용 약학 조성물을 제공한다.

본 발명의 용어 "암"은 세포의 정상적인 분열, 분화 및 사멸의 조절 기능에 문제가 발생하여 비정상적으로는 과다 증식하여 주위 조직 및 장기에 침윤하여 덩어리를 형성하고 기존의 구조를 파괴하거나 변형시킨 상태를 의미하며, 이러한 예로 피부, 소화기, 비뇨기, 생식기, 호흡기, 순환기, 뇌 또는 신경계의 암이 있으며, 구체적으로 폐암, 비소세포성 폐암, 결장암, 골암, 췌장암, 피부암, 두부 또는 경부 암, 자궁암, 난소암, 직장암, 위암, 항문부근암, 결장암, 유방암, 나팔관암, 자궁내막암, 자궁경부암, 질암, 음문암, 호지킨병 (Hodgkin's disease), 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관암, 신장세포 암종, 신장골반암종, 중추신경계 (central nervous system, CNS) 종양, 1차 중추신경계 림프종, 척수 종양, 뇌간 신경교종 또는 뇌하수체 선종 등일 수 있으나 이에 한정되지는 않는다.

본 발명의 용어, "예방"은 본 발명에 따른 재조합 아데노바이러스 또는 조성물의 투여로 암을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.

본 발명의 용어, "치료"는 본 발명에 따른 재조합 아데노바이러스 또는 조성물의 투여로 암이 호전되거나 이롭게 변경하는 모든 행위를 의미한다.

아울러, 본 발명의 암 예방 또는 치료용 약학 조성물은 약학적으로 허용가능한 담체, 부형제 또는 희석제를 추가로 포함할 수 있다.

본 발명의 약학 조성물에 사용될 수 있는 약학적으로 허용가능한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 칼슘 카보네이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시 벤조에이트, 탈크, 마그네슘 스테아레이트, 광물유 등을 들 수 있다.

본 발명의 약학 조성물은 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 제형화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 강황 또는 울금 추출물, 이로부터 분리된 리나로올 화합물 또는 이의 약학적으로 허용가능한 염에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘 카보네이트, 수크로즈 또는 락토스, 젤라틴 등을 혼합하여 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.

본 발명의 또 다른 실시양태로서, 본 발명은 상기 재조합 아데노바이러스 또는 약학 조성물을 치료를 필요로 하는 개체에 약학적으로 유효한 양으로 투여하는 단계를 포함하는, 개체의 암을 치료하는 방법을 제공한다.

본 발명의 용어 "약학적으로 유효한 양"은 의학적 치료에 적용가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 성병, 연령, 질병의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있다. 또한 본 발명의 약학 조성물은 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다. 구체적으로 본 발명의 약학 조성물은 경구투여 또는 정맥투여가 바람직하다.

본 발명의 용어 "개체"는 본 발명에 따른 치료용 조성물의 투여에 의해 증상이 호전될 수 있는 암을 가진 말, 양, 돼지, 염소, 낙타, 영양, 개 등의 동물 또는 인간을 포함한다. 본 발명에 따른 치료용 조성물을 개체에게 투여함으로써, 암을 효과적으로 예방 및 치료할 수 있다. 본 발명에 따른 상기 치료방법은 인간을 제외한 동물을 치료하는 방법일 수 있으나, 이에 제한되지 않는다. 즉, 인간의 경우 본 발명에 따른 치료용 조성물의 투여에 의해 증상이 호전될 수 있는 암을 가지는 것을 고려할 때, 인간의 치료에 있어서도 충분히 사용되어 질 수 있다.

본 발명의 용어 "투여"는 어떠한 적절한 방법으로 동물에게 소정의 물질을 도입하는 것을 의미하며, 본 발명에 따른 치료용 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 경구 또는 비경구 투여될 수 있다. 또한, 본 발명에 따른 치료용 조성물은 유효성분이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다.

본 발명에 따른 치료용 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 약학 조성물은 1일 1 내지 10 mg/kg으로, 바람직하게는 1 내지 5 mg/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다.

본 발명의 치료용 조성물은 단독으로, 또는 공지의 항암제를 병용 투여하거나 외과적 수술요법 등의 보조 치료 방법들과 병행하여 사용하여 항암 효과를 증대시킬 수 있다. 본 발명의 조성물과 함께 이용될 수 있는 화학 요법제(chemotherapeutic agent)는 시스플라틴(cisplatin), 카르보플라틴 carboplatin), 프로카르바진(procarbazine), 메클로레타민(mechlorethamine), 시클로포스파미드(cyclophosphamide), 이포스파미드 (ifosfamide), 멜팔란(melphalan), 클로라부실(chlorambucil), 비술판(bisulfan), 니트로소우레아 (nitrosourea), 디악티노마이신(dactinomycin), 다우노루비신(daunorubicin), 독소루비신(doxorubicin), 블레오마이신(bleomycin), 플리코마이신(plicomycin), 마이토마이신(mitomycin), 에토포시드(etoposide), 탁목시펜(tamoxifen), 택솔(taxol), 트랜스플라티눔(transplatinum), 5-플루오로우라실(5-fluorouracil), 빈크리스틴(vincristin), 빈블라스틴(vinblastin) 및 메토트렉세이트(methotrexate) 등을 포함할 수 있다. 또한, 발명의 조성물과 함께 이용될 수 있는 방사 요법은 X-선 조사 및 γ-선 조사 등이다.

본 발명의 재조합 아데노바이러스는 조직특이적인 프로모터 하에서도 그 발현증가 효과가 현저함을 확인하였으며, 숙주에 미치는 간독성은 오히려 현저히 감소함에 따라, 항암 효과가 높고, 숙주에 미치는 독성이 현저히 낮아 안전성이 문제가 되는 유전자 치료 분야에서 널리 활용될 수 있을 것이다.

도 1은 재조합 아데노바이러스 벡터의 구성을 나타내는 개략도이다. 구체적으로 도 1a는 SV40 프로모터를 가지는 재조합 아데노바이러스 벡터, 도 1b는 CMV 프로모터를 가지는 재조합 아데노바이러스 벡터, 도 1c는 PEPCK 프로모터를 가지는 재조합 아데노바이러스 벡터의 구성을 나타내는 개략도이다.
도 2는 리포터 유전자(루시퍼라제) 실험을 통하여 실험을 통하여 SD/SA 서열 및/또는 WPRE 구성이 목적 유전자의 발현에 미치는 영향을 확인한 도면이다. 구체적으로는 도 2a는 실험에 사용한 SD/SA 서열 및/또는 WPRE 구성을 포함하는 벡터의 개략도이고, 도 2b는 각 벡터에 따른 리포터 유전자인 루시퍼라제 발현 효율을 비교한 도면이다. 도면에서 확인할 수 있듯이, SD/SA 서열 및/또는 WPRE 구성을 포함시키는 경우 대조군에 비하여 발현 효율이 증가하는 것을 확인하였으며, 특히 SD/SA 서열과 WPRE 구성을 모두 포함하는 경우 발현 효율이 현저히 증가하는 것을 확인하였다.
도 3은 리포터 유전자(루시퍼라제) 실험을 통하여 SD/SA 서열 및/또는 WPRE 구성이 목적 유전자의 발현에 미치는 영향을 다양한 세포주에서 확인한 도면이다. 구체적으로는 도 3a는 SD/SA 서열 및/또는 WPRE 구성을 포함하는 벡터의 개략도이고, 도 3b는 hTERT를 발현하는 세포주인 HEK293, AGS, MCF7 및 Hep3B에서 본 발명의 각 벡터들의 리포터 유전자인 루시퍼라제 발현 효율을 비교한 도면이다. 도 3c는 hTERT를 발현하지 않는 세포주인 IMR90 세포주에서 벡터들의 발현 효율을 확인한 도면이다. 도면에서 확인할 수 있듯이, hTERT를 발현하는 다양한 세포주에서 SD/SA 서열 및/또는 WPRE 구성을 포함시키는 경우 대조군에 비하여 발현 효율이 증가하는 것을 확인하였으며, 특히 SD/SA 서열과 WPRE 구성을 모두 포함하는 경우 발현 효율이 현저히 증가하는 것을 확인한 반면, hTERT를 발현하지 않는 세포에서는 상기 효과가 나타나지 않음을 확인하였다.
도 4는 본 발명의 벡터들의 세포사 유도 효율을 확인한 도면이다. 구체적으로는 도 4a는 CMV 프로모터를 가지는 재조합 아데노바이러스 벡터, 도 4b는 PEPCK 프로모터를 가지는 재조합 아데노바이러스 벡터의 구성을 나타내는 개략도이다. 이들을 HEK 293 세포(도 4c), 또는 Hep3B 세포(도 4d)에 형질전환시켜 세포사 효율을 확인하였다.
도 5는 본 발명의 재조합 아데노바이러스의 세포사 유도 효율을 확인한 도면이다. 구체적으로 도 5a는 본 발명의 CMV 프로모터를 포함하는 재조합 아데노바이러스의 구성을 나타낸 개략도이다. 도 5b는 HT29 세포에, 도 5c는 Hep3B 세포에 다양한 농도(MOI)의 재조합 아데노바이러스를 처리하여 세포사 유도 효율을 확인한 도면이다.
도 6은 본 발명의 재조합 아데노바이러스의 세포사 유도 효율을 확인한 도면이다. 구체적으로 도 6a는 본 발명의 PEPCK 프로모터를 포함하는 재조합 아데노바이러스의 구성을 나타낸 개략도이다. 도 6b는 HepG2 세포에 다양한 농도(MOI)의 재조합 아데노바이러스를 처리하여 세포사 유도 효율을 확인한 도면이다.
도 7은 본 발명의 재조합 아데노바이러스의 전사체 수준을 확인하기 위해서 RPA(Ribonuclease Protection Assay) 실험을 진행한 결과를 보이는 도면이다. 구체적으로 도 7a는 RPA 실험의 원리를 도식화한 개략도이다. 도 7b는 RPA 실험을 위하여 제작한 RNA 프로브가 제대로 결합하는지를 확인한 도면이고, 도 7c는 HT29 세포에서 도 7d는 Hep3B에서 전사체들의 양을 확인하였다, 그 결과, SD/SA 서열과 WPRE를 포함하는 경우 전사체 양이 증가하는 것을 확인하였다.
도 8은 본 발명의 재조합 아데노바이러스의 효능을 in vivo 시스템에서 확인한 도면이다. 도 8a 및 도 8b는 먼저 아데노바이러스 독성을 확인한 도면으로 본 발명의 재조합 아데노바이러스를 투여한 뒤 7일째 혈액을 채집하여 간효소 수치(AST 및 ALT)를 확인한 도면(도 8a)과 투여 후 2일, 7일, 14일 후에 간조직을 H&E 염색을 통해 간 조직의 손상을 확인한 도면(도 8b)이다. 도 8c 및 도 8d는 간 내 다발초점성 HCC 모델에 본 발명의 재조합 아데노바이러스를 처리하여 간조직 손상 정도를 간효소 수치를 통하여 확인(도 8c)하고, 간 조직 H&E 및 TUNNEL 염색을 통하여 확인(도 8d)하였다. 도 8e는 간 조직을 절제하여 간의 육안 사진 및 H&E 염색 도면으로 확인한 것이며 이는 상기 간효소 수치 및 TUNNEL 염색과 일치하였다. 도 8f는 간조직 슬라이드를 이용하여 간 내 종양 무게를 비교한 도면으로, 특히 SD/SA 서열과 WPRE 구성을 모두 포함한 재조합 아데노바이러스에서는 종양이 거의 발견되지 않는 것을 확인하였다.
도 9는 다양한 동량의 기존 재조합 아데노바이러스(Ad-PRT)와 본 발명의 재조합 아데노바이러스(Ad-SD/SA+WPRE-PRT)를 투여한 다발초점성 HCC 모델에서 간조직 손상과 항암 효과를 비교한 도면이다. 간조직 손상을 육안 사진 및 H&E 염색 사진으로 확인하고(도 9a), 간 내 종양 무게를 비교하였으며(도 9b), 간조직 손상 정도를 간효소 수치를 통하여 확인(도 9c)하였다.

이하 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐 실시예에 의해 본 발명의 내용이 제한되는 것은 아니다.

실시예 1: 플라스미드 제조

본 발명에서 조직 특이적인 트랜스-스플라이싱 라이보자임(trans-splicing ribozyme) 발현을 유도하기 위하여, 조절 유도체인 SD/SA(Splicing Donor/Splicing Acceptor), 및/또는 WPRE(Woodchuck hepatitis virus Posttranscriptional Regulatory Element)를 이용하여 최적의 구성을 제조하였다.

구체적으로는, 기존에 개발되어 있던 hTERT(human telomerase reverse transcriptase) mRNA를 표적하는 트랜스-스플라이싱 라이보자임의 효율을 증가시키기 위해, 라이보자임-목적 유전자의 5' 말단 쪽에 SD/SA(Splicing donor/splicing acceptor site)를 포함 및/또는 라이보자임-목적 유전자의 3' 말단 쪽에 WPRE(woodchuck hepatitis virus posttransciptional regulatory element)를 포함하는 벡터를 제작하였다.

1-1. pSEAP SV40 벡터를 기반으로 한 플라스미드 제작

우선 SD/SA와 WPRE가 라이보자임 발현에 미치는 영향을 검증하기 위하여 pSEAP SV40 반딧불이 루시퍼라제 벡터(firefly luciferase vector)에 각각을 클로닝하여 리포터 유전자 어세이(reporter gene assay)로 효능을 검증하였고, pSEAP 벡터에 SD/SA, WPRE 및 반딧불이 루시퍼라제 유전자를 hTERT(human telomerase reverse transcriptase) 전사체에 타게팅하는 라이보자임을 삽입하였다.

구체적으로는, SD/SA 서열이 목적 유전자 앞에 위치한 pSEAP SD/SA SF 벡터, 상기 pSEAP SD/SA SF 벡터에 대한 대조군으로서 splicing site의 일부가 결실된 pSEAP SD/SA△61mer SF 벡터, 목적 유전자의 3' UTR에 정방향 WPRE sequence를 삽입한 pSEAP SF WPRE forward 벡터, 목적 유전자의 3' UTR에 역방향 WPRE sequence를 삽입한 pSEAP SF WPRE reverse 벡터, SD/SA 및 정방향 WPRE가 각각 목적 유전자의 3' UTR과 5' UTR에 위치한 pSEAP SD/SA SF WPRE forward 벡터까지 총 5개의 벡터를 제작하였다(도 1a, 서열번호 25 내지 서열번호 30).

상기 벡터에 사용되는 라이보자임은 기존 논문들(Molecular Therapy, 2005, 12 : pp824-834; Molecular Therapy, 2008, 16 : pp74-80; Clinical Cancer Research, 2008, 14 : pp281-290)에서 이용된 pCMV ribozyme TK를 주형으로 하여, phusion(Finnzymes) taq 폴리머라제를 이용하여 PCR 증폭하였다. 본 발명에서 사용된 프라이머는 하기 표 1에 정리하였다.

프라이머	서열(5' -> 3')	서열번호
AS300 hTERT Ribo NruⅠ forward	CCTCGCGAAAGGCCAGCACGTTCTTCGCGCCGCGCT	11
AS300 hTERT Ribo NruⅠ reverse	CCTCGCGAGTACTCCAAAACTAATCAATATACTTTCGCA	12
WPRE NotⅠ forward	AAGGAAAAAAGCGGCCGCAATCAACCTCTGGATTACAAA	13
WPRE NotⅠ reverse	AAGGAAAAAAGCGGCCGCGCGGGGAGGCGGCCCAAA	14
WPRE FseⅠ forward	GCGGCCGGCCAATCAACCTCTGGATTACAAA	15
WPRE FseⅠ reverse	GCGGCCGGCCGCGGGGAGGCGGCCCAAA	16
Ribo P8 BglⅡ reverse	GAAGATCTGTTGACTTAGGACTTGGCTGCGTGGTTAGGACCATGTC	17
Ribo P8 BglⅡ forward	GAAGATCTTCTGTTGATATGGATGCA	18
SDSA BglⅡ forward	GAAGATCTGAACTGAAAAACCAGAAAG	19
TK end BstBⅠ FseI reverse	CCCTTCGAAGCGGCCGGCCTCAGTTAGCCTCCCCCATCT	20
hTERT T7 forward	TAATACGACTCACTATAGGGCAGGCAGCGCTGCGTCCT	21
TK T7 forward	TAATACGACTCACTATAGGGATGGCTTCGTACCCCTGCCAT	22
TK T/S 219 reverse	GTGAGGACCGTCTATATAAACCCGCAGTAG	23
TK 350 reverse	GTGTAGATGTTCGCGATTGTCTCGGAAG	24

상기 PCR 증폭은 상기 주형 DNA와 프라이머(서열번호 11 및 서열번호 12), Taq 폴리머라제 및 반응용액을 포함하여, 먼저 98℃에서 5분간 정치한 후, 98℃에서 30 초, 58℃에서 30초, 72℃에서 1분으로 이루어진 사이클을 30번 반복한 후, 72℃에서 7분간 정치하여 이루어졌다. 상기 PCR 결과물은 페놀 추출/에탄올 침전(Phenol extraction/Ethanol Precipitation)을 이용하여 DNA를 수득하였다.

벡터와 상기 수득한 PCR 결과물 DNA를 제한효소 NruⅠ(Fermentas)를 이용하여 37 ℃에서 하룻밤 동안 제한효소 반응을 시킨 후, 페놀 추출/에탄올 침전으로 DNA를 정제하고, 아가로즈 겔을 이용하여 전기영동으로 분리하고 겔 아가로즈 겔 용출 키트(Agarose gel elution kit, BioBasic, Inc.)를 이용하여 원하는 DNA만을 수득하였다.

상기를 통해 제한효소로 잘린 벡터와 PCR로 증폭된 라이보자임 TK인 DNA insert를 얻은 후, 벡터 : insert를 1 : 10의 비율로 섞은 후 4℃에서 하룻밤 동안 T4 DNA ligase(Roche)를 이용하여 라이게이션 반응시켰다.

이렇게 수득한 라이게이션한 벡터를 DH5α E. coli competent cell에 열충격 형질전환 방법(Heat shock transformation)을 통하여 세포 내로 도입한 후, 앰피실린이 첨가된 agar plate에 골고루 깔아 37 ℃ 인큐베이터에서 16시간동안 배양시켰다. agar plate에 자란 콜로니를 amplicillin이 첨가된 LB 배지에 접종하여 mini-prep으로 DNA를 뽑아 insert가 삽입된 벡터를 포함하는 클론을 확인하였다.

1-2. pAVQ CMV Ribozyme TK 벡터를 기반으로 한 플라스미드 제작

상기 실시예 1-1에서 루시퍼라제 리포터 유전자로 활성을 확인하였던 SD/SA, WPRE element를 암치료에 이용하기 위하여 hTERT 특이적 ribozyme 3′exon 부위를 suicide 유전자 (HSV-TK 유전자를 선택)로 치환시킨 construct를 제작하였다. 우선 모든 세포에서 잘 발현되는 CMV 프로모터를 이용하는 벡터를 기본 골격으로 하여 제작하였다(서열번호 31 내지 서열번호 36).

구체적으로는, 상기 실시예 1-1에서 제조한 pSEAP 벡터에 삽입된 SD/SA와 WPRE를 pAVQ CMV Ribozyme TK 벡터에 삽입하였다. 상기 pSEAP 벡터 조성들과 유사한 형태로 pAVQ SD/SA CRT, pAVQ SD/SA△61mer CRT, pAVQ CRT WPRE forward, pAVQ CRT WPRE reverse, pAVQ SD/SA CRT WPRE forward 벡터를 각각 제작하였다.

상기 벡터들은 2 단계에 걸쳐 제작되었다. 먼저, 1차 cloning으로 pAdenoVator CMV5 IRES GFP transfer 벡터에서 BglⅡ(Fermentas)와 BstBⅠ(NEB)로 잘라 IRES와 GFP 부분을 제거하여 준비한 벡터를 이용하였다. DNA insert는 pAVQ CMV ribozyme TK를 주형으로 라이보자임 중간에 있는 BglⅡ 제한효소 위치부터 HSV-TK까지 5'쪽에 BglⅡ, 3'쪽에 FseⅠ과 BstBⅠ제한효소 서열을 가지는 프라이머(서열번호 18 및 서열번호 20)를 이용하여 PCR 증폭하였다. 상기 PCR 결과물은 BglⅡ(Fermentas)와 BstBⅠ(NEB) 제한효소로 잘라 준비하였고, 벡터와 1: 10의 비율로 섞어 라이게이션하고, 형질전환을 통해 클론을 얻었다.

상기 클로닝된 1차 벡터에 각각의 DNA insert를 넣어 2차 클로닝을 하였다. 구체적으로, pAVQ SD/SA CRT 벡터 및 pAVQ SD/SA△61mer CRT 벡터 클로닝 시에는 1차 벡터를 BglⅡ(Fermentas) 제한효소로 잘라 준비하였고, DNA insert는 SD/SA site부터 라이보자임 중간까지 BglⅡ 제한효소 서열을 포함한 프라이머로 증폭하여 제한효소 BglⅡ(Fermentas)로 잘라 준비한 후, 벡터와 1:10으로 라이게이션하였고 형질전환을 통해 클론을 얻었다. pAVQ CRT WPRE forward 벡터와 pAVQ CRT WPRE reverse 벡터 클로닝 시에는 DNA insert인 WPRE를 pSEAP SF WPRE를 주형으로 FseⅠ 제한효소 서열을 포함하는 프라이머를 이용하여 PCR로 증폭하여 준비하였고, 벡터는 SD/SA를 포함하지 않는 CMV Ribozyme TK를 이용하였다. 벡터와 DNA insert를 제한효소 FseⅠ(NEB) 제한효소로 각각 잘라 준비하였고, 1:10 비율로 라이게이션하고 형질전환을 통해 정방향과 역방향 클론을 얻었다. pAVQ SD/SA CRT WPRE forward 벡터의 클로닝은 앞에서 클로닝된 pAVQ SD/SA CRT 벡터를 이용하여 벡터와 insert인 WPRE를 제한효소 FseⅠ(NEB) 제한효소로 잘라 준비하였고, 라이게이션하고 형질전환을 통해 정방향 클론을 얻었다.

1-3. pAVQ CMV Ribozyme TK 벡터를 기반으로 PEPCK 프로모터를 포함한 한 플라스미드 제작

상기 실시예 1-1에서는 리포터 유전자를 이용하여 활성을 확인하고, 실시예 1-2에서는 모든 세포에서 발현되는 프로모터를 이용한 벡터를 이용한 construct를 제작하였는바, 이를 이용하여 간세포 특이적인 PEPCK 프로모터를 이용한 벡터를 제작하였다(서열번호 37 내지 서열번호 41).

pAVQ PEPCK Ribozyme TK 벡터에 상기 실시예 1-2에 개시된 방법과 유사한 방법으로 SD/SA와 WPRE를 클로닝하였다. 상기 실시예 1-2에서 제작한 벡터와 유사한 형태이나 프로모터만이 다른 pAVQ SD/SA PRT, pAVQ SD/SA△61mer PRT, pAVQ PRT WPRE forward, pAVQ PRT WPRE reverse, pAVQ SD/SA PRT WPRE forward 벡터를 각각 제작하였다.

구체적으로, SD/SA의 클로닝 시에는 벡터는 pAVQ PEPCK Ribozyme TK 벡터를 제한효소 BglⅡ(Fermentas)로 잘라 라이보자임의 antisense 부분부터 라이보자임의 중간 부위를 제거하여 준비하였고, insert는 클로닝된 pAVQ SD/SA CRT 벡터, pAVQ SD/SA△61mer CRT 벡터에서 제한 효소 BglⅡ(Fermentas)로 잘라 SD/SA부터 라이보자임 중간 부위를 얻어 준비하였다. 벡터와 insert를 각각 1 : 10으로 라이게이션하고 형질전환을 통해 클론을 얻었다. WPRE 클로닝 시에는 벡터는 pAVQ PEPCK Ribozyme TK 벡터, pAVQ SD/SA PEPCK Ribozyme TK 벡터를 제한효소 NotⅠ(Fermentas)으로 잘라 준비하였고, insert는 클로닝 된 pAVQ CRT WPRE forward를 주형으로 NotI 제한효소 서열을 포함하는 프라이머로 증폭한 후 제한효소 NotⅠ(Fermentas)로 잘라 준비하였다. 벡터와 insert를 각각 1 : 10으로 라이게이션하고 형질전환을 통해 클론을 얻었다.

실시예 2: 재조합 아데노바이러스의 제작

본 발명에서 사용하는 아데노바이러스 벡터를 제작하기 위해서, 상기 실시예 1에서 pAdenoVator transfer 벡터(Qbiogene)에 클로닝된 벡터들을 pAdenoVator △E1/E3 backbone 벡터(Qbiogene)와 함께 BJ5183 E. coli competent cell에 동시 형질전환 시켰다. Transfer 벡터는 제한효소 PmeⅠ(NEB)로 선형화(Linearization)한 후, 페놀 추출/에탄올 침전을 통해 정제하여 준비하였고, 해당 벡터 DNA 1㎍과 pAdenoVator △E1/E3 backbone 벡터 100 ng을 Electrophoresis 방법으로 BJ5183에 동시 형질전환시켰다.

BJ5183에서 상동재조합(homologous recombination)이 일어난 재조합 벡터들은 제한효소 PacI(NEB)으로 선형화하여 페놀 추출/에탄올 침전으로 정제하였고, 이를 293 세포주(Human embryonic kidney)에 calcium phosphate를 이용하여 트랜스펙션하였다. 293 세포주에서 증폭시킨 재조합 아데노바이러스들은 염화세슘수배원심분리법(cesium chloride gradient centrifugation)을 통해 38000rpm으로 원심 분리하여 정제하였고, 이렇게 얻은 바이러스는 2시간, 2시간, 16시간으로 투석(dialysis, dH₂O 1600 ml, 투석완충용액; dialysis buffer : 100mM Tris-Cl pH7.5, 10mM MgCl₂ 200ml, 100% 글리세롤 200ml)한 후 -80℃에 보관하였다. 재조합 아데노바이러스들의 역사(titer)는 TCID50(tissue culture infectious dose for 50% of the cells) 방법을 이용하여 pfu(plaque forming units)을 결정하였다.

Ad-SD/SA CMV Ribozyme HSV-TK, Ad-CMV Ribozyme HSV-TK WPRE(forward), Ad-SD/SA CMV Ribozyme HSV-TK WPRE(forward),Ad-PEPCK SD/SA Ribozyme HSV-TK, Ad-PEPCK Ribozyme HSV-TK WPRE, 및 Ad-PEPCK SD/SA Ribozyme HSV-TK WPRE를 제작하였다(서열번호 42 내지 서열번호 47).

실시예 3: 세포 배양

본 발명에서는 인간 태아 간세포주 293 세포(Human embryonic kidney), 인간 간암 세포주 Hep3B 세포 및 HepG2 세포(Human hepatocellular carcinoma), 인간 위암 세포주 AGS 세포(Human gastric adenocarcinoma), 인간 대장암 세포주 HT-29 세포(Human colorectal adenocarcinoma), 인간 유방암 세포주 MCF-7 세포(human breast adenocarcinoma), 인간 폐 섬유아세포주 IMR90 세포(Human lung normal fibroblast)를 이용하였다.

상기 세포는 10% FBS 와 1% 페니실린/스트렙토마이신을 첨가한 MEM (minimum essential medium)/ DMEM (Dulbecco's modified eagle medium) 배지를 이용하여, 37 ℃, 5% CO₂ 조건이 유지되는 인큐베이터에서 배양하였다.

2~3일에 한번씩 새로운 100 mm 배양접시에 계대배양하였다. 구체적으로는, 상기 세포들이 부착된 배양접시를 1xPBS(Phosphate buffered saline, 8g NaCl, 0.2g KCl, 1.14g Na₂HPO₄, 0.2g KH₄PO₄/L)로 세척한 후, 1xTrypsin/EDTA(8.2g NaCl, 0.2g KCl, 1.14g Na₂HPO₄, 0.2 g KH2PO4, 0.029g Na₂EDTA·dH₂O, 1g trypsin, pH 7.35/L) 1ml을 처리하여 CO₂ 인큐베이터에 1분간 두었다. 배지 4mL로 트립신을 불활성화시킨 후 1500 rpm 2분 30초간 원심 분리하여, 상층액을 제거하고 배지에 재현탁하여 계대배양을 진행하였다.

실시예 4 : 형질주입( Transfection )

본 발명에서 아데노바이러스를 형질주입하는 방법은 하기와 같다.

형질주입 전날 세포를 2x10⁵ cells/well 농도로 12-well 배양접시에 접종하여 배양접시에 세포를 부착시켰다. 이에 리포좀(liposome)을 이용하여 형질주입하였다. 형질주입 용액은 Mirus의 TransIT-LT1 용액을 이용하였다. 100 ㎕의 무혈청 배지에 3 ㎕의 TransIT-LT1 용액을 넣고 파이펫으로 가볍게 섞어, 20분간 정치시켰다. 이 후, 500 ng의 DNA를 상기 배지로 희석한 TransIT-LT1 용액에 넣어 잘 섞은 후 상온에서 30분간 정치하여, DNA liposome 형태 복합체를 형성한다. 상기 TransIT-LT1 용액-DNA 복합체(100 ㎕씩)를 세포 위에 방울방울 골고루 떨어뜨린 다음, 배양 접시에 고루 퍼지도록 흔들어 섞어주고, 37 ℃, 5% CO₂ 조건이 유지되는 인큐베이터에서 24시간 동안 배양하였다.

실시예 5: 루시퍼라제 발현 측정 실험

본 발명의 라이보자임이 기존에 있던 pSEAP SRF(SV40 Ribozyme Firefly lucifease)보다 높은 활성을 나타내는 지 검증하기 위하여 리포터 어세이(reporter assay)를 수행하였다. 제작한 각각의 벡터를 TK-R.Luci 벡터 (TK 프로모터 하에 Renillar 루시퍼라제를 발현하는 벡터, 내부 대조군)와 함께 hTERT를 발현하는 세포주인 HEK 293 세포에 동시-형질주입(co-transfection)한 후 목적 유전자 활성을 pSEAP SRF (SV40 프로모터 하에 라이보자임과 반딧불이 루시퍼라제를 발현하는 벡터) 및 pSEAP SF (SV 프로모터 하에 반딧불이 루시퍼라제를 발현하는 벡터, 양성 대조군) 와 비교, 관찰하였다.

구체적으로는, 형질주입 후 24시간 후에 이전의 배지를 제거하고, 1 x PBS로 세척하였다. 1 x 용해완충액(lysis buffer)을 100 ㎕ 넣고, 상온에서 15 분간 용해시킨 후, 세포를 수득한 뒤, 13000 rpm으로 2분간 원심 분리하여 상층액 만을 새 튜브에 옮겼다.

Luminometer 튜브에 상기 수득한 세포 용혈액(cell lysate) 20 ㎕를 넣고 LAR Ⅱ (Luciferase assay reagent Ⅱ, Promega) 100 ㎕를 넣고 섞은 후 Luminometer로 읽었다. 다시 여기에 Stop & Glo reagent mix (Stop & Glo substrate + Stop & Glo buffer)를 100 ㎕씩 넣고 섞은 후 Luminometer로 측정하였다.

그 결과 SD/SA 및/또는 WPRE가 존재하는 경우 비교군에 비하여 목적 유전자의 활성이 높아지는 것을 확인하였다. 특히, 특히 SD/SA와 WPRE가 함께 존재하는 경우 목적 유전자 활성이 현저히 증가되는 것을 확인함으로써 목적 유전자의 활성이 현저히 높아지는 것을 확인하였다(도 2b).

한편, 다양한 세포주에서, 즉 293 세포 외에도 hTERT를 발현하는 세포주인 AGS, MCF7, Hep3B에서도 SD/SA, WPRE를 도입한 벡터의 목적 유전자 활성을 확인하였다. 상기 hTERT를 발현하는 세포주들에서는 SD/SA와 WPRE를 도입한 경우, 목적 유전자의 활성이 증가하는 것을 확인할 수 있었다. SD/SA를 도입한 경우 약 2~3배, WPRE를 도입한 경우 약 3 내지 5배 증가하였으며, MCF7과 Hep3B 세포의 경우는 양성 대조군인 pSEAP SF보다도 SD/SA와 WPRE가 함께 있는 벡터를 주입한 경우 목적 유전자 발현이 더욱 증가되는 것을 확인하였다(도 3b). 또한, hTERT를 발현하지 않는 세포인 IMR90에서는 라이보자임에 의해 조절되어 루시퍼라제 활성이 거의 나타나지 않음을 확인하였다(도 3c).

실시예 6: 자살 유전자 활성 측정 실험( Suicide gene activity assay )

상기에서 리포터 유전자로 활성을 확인하였던 SD/SA, WPRE 유전자를 암치료(cancer therapy)에 이용하기 위하여 hTERT 특이 ribozyme 3′exon 부위를 약제감수성 유전자(HSV-TK 유전자)로 치환시킨 벡터를 제작하였고, 이를 검증하기 위해 자살 유전자 활성 측정 실험(suicide gene activity assay)을 수행하였다. TK(thymidine kinase) gene은 GCV(ganciclovir)와 함께 작용하여 세포사를 유도하는 suicide gene이다. GCV는 2′-deoxy-guanosine의 유사체(analogue)로서 발현된 TK에 의해 인산화되어 GCV-P가 되는데, GCV-P는 세포들 간의 gap junction을 통과하여 인접 세포(adjacent cells)에 이동할 수 있다(bystander effect). 그러면서 인산화 효소(mammalian kinase)들에 의해 GCV-PPP가 생성되는 데 GCV-PPP는 DNA에 끼여 들어갈 수는 있지만 DNA 폴리머라제에 의해 DNA 복제(replication)는 될 수 없어 DNA 폴리머라제에 의한 연장(elongation)이 종결(termination)되고 결국 세포사를 유도하게 된다.

상기 실시예 1에서 제작한 각각의 벡터를 대조군 GFP 벡터(internal control)와 함께 세포에 동시-형질주입(co-transfection)하였다. CMV 프로모터 세트는 HEK 293 세포주에, PEPCK 프로모터 세트는 Hep3B 세포에 형질주입하였다. 한편, 각 실험에서 음성 대조군으로 CL (pAVQ-CMV-LacZ), PL (pAVQ-PEPCK-LacZ)를 이용하였고, 양성 대조군으로는 CT (pAVQ-CMV-TK), PT (pAVQ-PEPCK-TK)를 이용하였다(도 4a, 및 도 4b). DNA 형질주입 24 시간 후에 각 세포마다 프로드럭(prodrug) 100 μM GCV (Ganciclovir; Cymevene, Roche)를 2일에 한번씩 총 3번 처리하고 그 다음 날 490 nm의 UV 형광을 쬐어 GFP spot 사진을 찍었다. 세포마다 여러 장의 사진을 찍어 평균 세포 수를 구한 후에 GCV 처리하지 않은 대조군의 GFP 수를 100으로 잡고 GCV 처리한 동일 DNA transfected GFP 수를 보정하여 GCV에 의한 독성을 배제하였다. 이렇게 보정한 벡터 대조군을 100으로 잡아 각 벡터 구조체에 대한 보정 값을 환산하여 상대비교하였다.

그 결과, CMV 프로모터 세트의 경우, 리포터 어세이에서 확인한 것처럼 기존에 개발되어 있던 CRT(CMV Ribozyme TK)에 비해서 SD/SA, WPRE를 함유하고 있는 벡터가 더 많은 세포사를 유도할 것이라고 예상하였으나, 별 차이를 보이지 않았고, 양성 대조군인 CT (CMV TK)와 다 비슷한 정도로 세포사가 유도되는 것을 확인할 수 있었다(도 4c). PEPCK 프로모터 세트의 경우, 양성 대조군인 PT(PEPCK TK)를 비롯하여 전반적으로 많은 활성을 나타내지는 않았으나, SD/SA 혹은 WPRE를 함유하고 있는 벡터를 주입한 경우, PRT (PEPCK Ribozyme TK)에 비해 높은 비율로 세포사를 유도함을 확인할 수 있었다(도 4d).

SD/SA, WPRE를 함유한 라이보자임 발현 아데노바이러스 벡터가 과연 hTERT를 발현되는 세포에서 특이적이며 보다 우수한 세포사를 유도하는지 CMV/PEPCK-Rib-TK와 상호 비교하였다(도 5a). hTERT가 발현되는 HT-29 세포와 Hep3B, HepG2 세포에 바이러스를 농도 비례하게 감염시킨 후, GCV 100μM을 이틀에 한 번씩 총 3번 처리하여 MTS assay를 수행하였다. 음성 대조군으로 Ad-CL (CMV LacZ), Ad-PL (PEPCK LacZ) 바이러스를 이용하였고, 양성 대조군으로 Ad-CT (CMV TK), Ad-PT (PEPCK TK) 바이러스를 이용하였다. CMV 프로모터의 경우, 기존에 개발된 Ad-CRT에 비해 WPRE, SD/SA WPRE를 함유한 벡터가 더 우수한 세포사를 유도하는 것을 확인하였고, Hep3B 세포에서는 양성 대조군인 Ad-CT와 비슷하게 세포사를 유도함을 확인하였다(도 5b). PEPCK 프로모터의 경우도 SD/SA와 WPRE를 함유한 라이보자임 변형체 발현 벡터가 기존의 Ad-PRT에 비해 더 우수한 세포사를 유도함을 확인하였고, Ad-SD/SA+ WPRE PRT는 기존 Ad-PRT의 1/5 양으로도 동등한 세포사 기능을 보이는 것을 확인하였다(도 5c).

실시예 7: 세포 증식율 측정 실험( Cell proliferation asssay )

본 발명의 바이러스를 다양한 농도로 처리하고 이에 따른 세포의 증식율을 측정하였다.

구체적으로는, 세포를 96-well 배양접시에 1 x 10⁴ cells/well의 농도로 접종하여 37℃, 5% CO₂ 인큐베이터에서 하룻밤 동안 배양한 후, 배양된 세포에 본 발명의 바이러스를 다양한 농도(Mmultiplicity-of-infectivity, MOI)로 감염시켰다. 약 24시간 동안 감염 후, 각 well 에 100μM GCV (Ganciclovir; Cymevene, Roche)를 2일에 한번 씩 총 3번 처리하여 5일간 배양하였다.

배지 100 ㎕에 EZ-Cytox WST assay reagent(DAEILLAB SERVICE)를 10 % 추가하여, 각 well에 첨가한 후 1~3 시간 동안 37 ℃, 5% CO₂ 인큐베이터에서 배양한 후, 450 nm에서 흡광도를 측정하였다.

그 결과, 도 5a의 바이러스들을 이용하여 도 5b, 도 5.c에서 볼 수 있듯이 hTERT를 발현하는 세포인 HT29와 Hep3B에서 바이러스 MOI에 따라 세포 사멸이 유도됨을 관찰하였다. 또한 도 6b에서와 같이 간 특이적인 PEPCK promoter를 가진 바이러스들에서도 바이러스 MOI에 따라 세포 사멸이 유도됨을 확인하였다. 주목할 점은 발현량이 많은 CMV 프로모터 하에서는 TK에 의한 효과가 포화가 되어 SD/SA와 WPRE를 포함하는 벡터와 그렇지 않은 벡터와의 세포 사멸 효과가 비슷한 반면, 도 6b에서 보듯이 CMV 프로모터보다 발현효율이 낮은 PEPCK 프로모터에서 SD/SA와 WPRE를 포함하는 벡터가 그렇지 않은 벡터에 비해 월등히 세포 사멸을 증가시킬 수 있다는 것을 확인하였다.

실시예 8: RNA 분리

본 발명의 바이러스에 감염된 세포에 대해서 각각의 전 RNA(total RNA)를 수득하였다. 구체적으로는 Tri-reagent(Molecular Research Center. Inc)를 이용하여 정제하였다. 제조사의 프로토콜에 따라, 35 mm 배양접시에 500 ㎕의 Tri-reagent를 처리하고 5분간 배양하여 세포를 떼어낸 후 100 ㎕의 클로로포름을 첨가하여 vortex하고 4℃에서 10분간 원심 분리하였다. 그 후 상층액을 새로운 튜브로 옮긴 후 에탄올 침전(ethanol precipitation)하였고, 남아있는 gDNA를 없애기 위해 DNase I(Roche)를 처리하였다.

실시예 9 : RPA( Ribonuclease protection assay )

앞에서 확인한 세포사의 증가가 SD/SA, WPRE에 의해 트랜스-스플라이싱 전사체(trans-splicing product)가 증가하기 때문인지를 알아보기 위해 RPA(ribonuclease protection assay)를 수행하였다. RPA는 특정 mRNA를 검출하는 방법으로써 노던 블랏 혼성화(Northern blot hybridization)처럼 정량적인 방법으로 사용되며, 엑손-인트론(exon-intron) 구조와 같은 구조적 형태(topological feature)를 측정하기 위해서도 사용되는 실험 방법이다. mRNA에 상보적인 RNA 프로브(probe)를 만들어서 RNA와 혼성화시킨 다음 단일 가닥 RNA(single strand RNA)를 특이하게 절단하는 RNase로 혼성화되지 않은 RNA를 제거한 후, 변성 아크릴아마이드 겔(denaturing acrylamide gel)에 전기 영동하여 분석한다. S1 뉴클레아제 맵핑(nuclease mapping)와 마찬가지로 확인되는 RNA 프로브의 크기로 엑손-인트론의 결합이나 전사 시작 부위를 추측할 수 있다. 그리고 RNA 프로브의 양을 test mRNA보다 다량 사용하면 자동 방사선 신호(autoradiographic signal)의 강도는 시료 내의 mRNA의 양에 비례하므로 mRNA의 양을 추측할 수 있다. 참고로, 본 발명에서는 본 발명의 바이러스에 의해 형질감염된 세포들의 RNA 상 변화를 확인하기 위해서 전 RNA(total RNA)를 분리하여 RPA 실험을 진행하였다.

먼저, RNA 프로브 제작을 위해 CMV Ribozyme TK에 의해 생성되는 트랜스-스플라이싱 전사물(trans-spliced molecule, TSM)에 상보적인 서열을 T7 프로모터가 있는 pJET 1.2/blunt 벡터(Fermentas)에 클로닝하였다. 그 후, 클로닝된 벡터를 제한효소 XbaI (Fermentas)로 제한효소 처리하여 선형화시킨 후 Bio-16-UTP(Ambion) 또는 [a-³²P] UTP(Perkin Elmer)로 표지하여 T7 RNA 폴리머라제(TAKARA)로 시험관내 전사(in vitro transcription)하였다. 프로브의 특이적 결합을 test하기 위한 test RNA는 TK와 TSM을 T7 프로모터 서열을 포함하는 프라이머로 증폭하여 그것을 주형으로 시험관내 전사(in vitro transcription)를 통하여 제작하였다(도 7a). 또한, 만들어진 프로브가 TK RNA와 TSM에 잘 결합하는지 알아보기 위해서 in vitro로 TK RNA와 TSM RNA를 제작하여 프로브에 결합하는 것을 확인하였다.

구체적으로, RPA를 위한 프로브와 프로브 검증을 위한 target RNA를 만들기 위한 시험관내 전사는 다음과 같이 수행하였다. 주형 DNA는 프로브의 경우 플라스미드 DNA를 제한효소 XbaI로 잘라 선형화하여 준비하였고, target RNA는 T7 프로모터 서열을 포함하는 프라이머로 PCR 증폭하여 DNA를 준비하였다. 상기 준비한 주형 DNA를 10X T7 RNA 폴리머라제 완충액과 10 mM ATP, GTP, CTP 및 UTP(Roche), 50 mM DTT, RNase inhibitor(Cosmo genetch), T7 폴리머라제(TAKARA)와 전체 부피 20 ㎕로 맞춰 섞어주고, 37 ℃에서 3시간 동안 배양하였다. 비오틴-표지 프로브(biotin-labeled probe)의 경우, UTP와 Bio-16-UTP(Ambion)의 비율을 6 : 4로 하여 섞어주었다. 동위원소-표지 프로브(Isotope-labeled probe)의 경우, 10 mM ATP, GTP, CTP와 200 μM UTP, 40μCi [a-³²P]UTP(Perkin Elmer)를 넣어 hot과 cool을 1: 4의 비율로 섞어주었다. 그 후 DNaseⅠ(Roche)을 처리하고 페놀 추출/에탄올 침전하여 6% 변성 아크릴아마이드 겔(denaturing acrylamide gel)로 분리하여 RNA 용출 완충액(RNA elution buffer, 0.5 M NH4OAc, 1 mM EDTA(pH 8.0), 0.2 % SDS]에서 4시간 배양하여 RNA를 얻었다.

Sample RNA는 각각의 바이러스를 HT29 세포 또는 Hep3B 세포에 감염시킨 48h 후 total RNA를 정제하여 얻었다. Probe test 시에는 probe RNA를 TK, TSM RNA와 1:3의 비율로 하였고, cell test시에는 total RNA 30μg과 1X 혼성화 완충액(hybridization buffer - 40mM Pipes, 400mM NaCl, 1mM EDTA, deionized formamide,80%(v/v)) 상에서 하룻밤 동안 혼성화하였다(O/N hybridization). 그 후 RNase digestion buffer(10mM Tris-Cl, 5mM EDTA, 300mM NaOAc, pH7.5) 상에서 RNase A와 RNase T1을 처리하여 혼성화되지 않은 단일가닥 RNA를 제거하고 proteinase K와 SDS를 처리하여 RNase를 제거하였고, 페놀 추출/에탄올 침전한 후 10% 변성 아크릴아마이드 겔(Denaturing acrylamide gel)에 전기 영동하여 분석하였다.

그 결과, 라이보자임에 의해 trans-splicing이 일어나게 되면 hTERT와 TK가 융합된 형태의 TSM에 프로브가 혼성화하고 (TK gene보다 높은 size의 밴드가 형성됨), 라이보자임이 없는 경우는 TK에만 혼성화하게 된다. 라이보자임이 있는 CRT, SD/SA CRT, WPRE CRT, SD/SA WPRE CRT에서 라이보자임이 없는 CMV-TK에 비해 높은 크기(size)의 밴드들이 나타났으며 CRT에 비해 SD/SA WPRE를 함유한 바이러스들이 TSM을 증가시킴을 확인할 수 있었다(도 7c 및 도 7d). 또한 Hep3B 세포에서 라이보자임의 목적이 되는 hTERT 역시 감소하는 것을 확인할 수 있었다(도 7d). 동일한 양의 바이러스를 사용하는 대조군으로는 VAI RNA를 사용하였으며, RNA 로딩 대조군으로는 U6 snRNA를 노던 블랏을 통해 확인하였다.

실시예 10: 노던 블랏팅 ( Northern blotting )

Ribonuclease protection assay를 통해 확인한 TSM의 증가가 동일한 양의 RNA와 바이러스를 처리한 결과임을 확인하기 위해 노던 블랏 실험(northern blot assay)을 수행하였다. 앞에서 언급한 RNA 분리 방법으로 전 RNA를 뽑아 10 ㎍을 8% 변성 아크릴아마이드 겔에 180 V로 1시간 동안 분리하였다. 전기영동으로 RNA를 분리한 겔을 0.25 X TBE(Tris Borate EDTA) 완충액에서 200 mA로 1시간 동안 나일론 멤브레인(nylon membrane)으로 이동(transfer)하였고, 그 후 1200J로 2번 UV를 주어 UV 교차-결합(cross-linking)으로 RNA를 멤브레인에 고정하였다.

1X 블락킹 완충액(Blocking buffer, Ambion)를 이용하여 1시간 동안 전-혼성화(pre-hybridization)를 한 후, 프로브(1차(서열번호 9): VAI probe ; 5' AAAAGGAGCGCTCCCCCG TTGTCTGACGTCGCACACC 3'-biotin - 50℃, 2차(서열번호 10): U6 probe ; 5' GAATTTGCGTGTCATCCTTGCGCAGGGGCCATGCTAA 3'-biotin - 60℃)를 혼성화하였다. 상기 혼성화를 거친 멤브레인을 1X 세척 완충액(Wash buffer, Ambion)으로 5분씩 2번 세척한 후 블락킹 완충액에 5분 2번, 30분 정치하였다.

그 후, 스트렙타비딘-알칼라인 포스파타아제(streptavidin-Alkaine phosphatase, Ambion)를 1X 블락킹 완충액에 희석하여 30분간 처리하고 블락킹 완충액에 10분간 정치하였다. 그리고 세척 완충액으로 5분씩 3번 세척한 후 1X Assay buffer(Ambion)를 2분씩 2번 처리하였고, 멤브레인에 CDP-Star(Ambion) 처리 후 은박지로 싸서 빛을 차단한 상태로 5분간 반응시켰다. CDP-Star를 종이 타월로 제거 후 멤브레인을 랩핑(wrapping)하여 카세트에 넣고 필름을 얹어 10분간 노출시킨 후, developer와 fixer를 이용하여 밴드를 확인하였다.

노던 블랏을 통하여 본 발명의 재조합 아데노바이러스의 전사체 수준을 확인하는 RPA(Ribonuclease Protection Assay) 실험을 진행하였다. 우선, RPA 실험을 위하여 제작한 RNA 프로브가 제대로 결합하는 것을 확인하였고(도 7b), HT29 세포에서 및 Hep3B에서 본 발명의 재조합 아데노바이러스에 의한 전사체들의 양을 확인한 결과, SD/SA 서열과 WPRE를 포함하는 경우 전사체 양이 증가하는 것을 확인하였다.

실시예 11 : 동물 실험

11-1. 독성 실험( toxicity test )

동물모델에서의 재조합 아데노바이러스의 독성을 확인하기 위해 4 내지 5주령 BALB/cAnNCrl 누드 마우스(Orient Bio Inc., 한국)를 구입하여 실험하였다. 본 발명의 SD/SA PRT, WPRE PRT, SD/SA+WPRE PRT 바이러스의 독성을 확인하였다. 기존에 암 억제 효과가 입증된 Ad-PRT 용량의 1/4인 2.5 x 10¹⁰vp의 adenovirus 및 PBS (n= 5, 각각)를 꼬리 혈관(tail vein)으로 투여한 뒤 2일, 7일, 14일 후에 H&E 염색을 통해 간 조직의 손상을 확인하였고, 7일째 혈액 샘플을 채집하여 간효소인 ALT와 AST 수준을 측정하였다.

그 결과, Ad-SD/SA PRT, Ad-WPRE PRT, Ad-SD/SA+WPRE PRT 실험군들은 전신 외관이 PBS 투여군과 비슷하였으며 간효소 (AST, ALT) 수치도 PBS 투여군과 비슷하였다. H&E 염색 결과, 2일째, 7일째 및 14일째의 간조직 소견도 Ad-SD/SA PRT, Ad-WPRE PRT, Ad-SD/SA+WPRE PRT 실험군들은 PBS 투여군과 비슷하게, 간세포 손상이 거의 관찰되지 않았다(도 8a 및 도 8b).

11-2. 항암효과 측정 실험( Anti - tumor assay )

본 발명의 바이러스의 항암효과를 측정하기 위하여, 누드 마우스에 Hep3B 세포를 I.S.(intra spleen) 주입하여 간내 다발초점성 HCC 모델(intrahepatic multifocal HCC model)을 만들었다.

구체적으로는, hTERT(+) Hep3B 세포주의 인체 간세포 암종(hepatocellular carcinoma, HCC)의 발생과 유사한 간내 다발초점성 HCC 모델(intraheptic multifocal HCC model)을 만들기 위하여, 누드 마우스의 왼쪽 복벽을 열고 지라의 피막(splenic capsule) 아래로 3 x 10⁶ 농도의 Hep3B 세포를 주입하였고, 접종 11일 후에, 간내 HCC 혹(intrahepatic HCC nodules)이 생성된 것을 확인하였다.

간내 다발초점성 HCC 모델에 SD/SA, WPRE 각각 혹은 동시에 함유한 hTERT 특이적 라이보자임 변형체를 삽입한 아데노바이러스 벡터(Ad-SD/SA PRT : 1.25 x 10¹⁰vp - 기존 Ad-PRT의 1/8 용량, Ad-WPRE PRT : 0.25 x 10¹⁰vp - 기존 Ad-PRT의 1/40 용량, Ad-SD/SA+WPRE PRT : 0.25 x 10¹⁰vp - 기존 Ad-PRT의 1/40 용량)와 Ad-PRT 바이러스(1 x 10¹¹ vp) 및 PBS를 각 군에 해당하는 마우스에 꼬리 혈관을 통하여 투여하였다(각 실험군 및 대조군 당 n = 5). 바이러스를 투여한 다음날부터 10일간 50mg/kg의 GCV(ganciclovir)를 하루에 2회 복강 내로 투여하고 다음날 채혈 후 희생하여 복강 및 간을 관찰 후 무게를 재고 육안 사진 촬영하였다. 상기에서 채집한 간 조직에 대하여 간 전체를 2mm의 두께로 잘라 파라핀블록 제작, H&E(hematoxylin & eosin) 염색 후 관찰, imaging scan으로 면적을 재어 간내 종양의 무게를 산출 (간의 무게x 종양의 fraction)하여 비교하였다.

Ad-SD/SA PRT, Ad-WPRE PRT, Ad-SD/SA+WPRE PRT group과 Ad-PRT group은 PBS 대조군과 함께 실험종료 시점까지 생존하였으며, PBS 대조군은 간내 HCC(intrahepatic HCC)의 수와 크기가 증가하여 간 전체가 거의 종양으로 대체되고 종양색전에 의한 혈관폐쇄로 인하여 주위 간 조직에 허혈성 손상 등으로 간효소(liver enzyme, GOT/GPT) 수치가 현저하게 증가된 것에 비하여, Ad-SD/SA PRT, Ad-WPRE PRT, Ad-SD/SA+WPRE PRT 실험군과 Ad-PRT 대조군은 간효소 (GOT/GPT) 수치가 미미하게 증가하였고 (P < 0.001, ANOVA test) Ad-SD/SA+WPRE PRT 실험군이 가장 간독성이 낮음을 확인하였다(도 8c).

절제 후 간의 육안소견상 PBS 대조군은 간이 거의 HCC 결절들로 대체되어 있었고, Ad-SD/SA PRT, Ad-WPRE PRT, Ad-SD/SA+WPRE PRT 및 Ad-PRT 실험군은 간 내에서 거의 결절이 관찰되지 않거나 소수의 결절들이 관찰되었으며, 결절 이외의 간조직은 검붉은 색조를 띠고, 매끈하였다(도 8e). 절제 간에 대한 조직학적 소견은 육안소견과 거의 일치하였으며, PBS 투여한 대조군은 남아있는 간조직에서 심한 간세포 고사/괴사 및 염증소견이 관찰되어 (도 8d, TUNNEL assay에서 양성으로 염색되는 apoptotic hepatocyte가 많이 관찰됨) 증가된 간효소 (GOT/GPT) 수치 (도 8c)와 일치하였다. Ad-SD/SA PRT, Ad-WPRE PRT 및 Ad-PRT 실험군의 간조직에서는 약한 정도의 간세포 괴사 및 염증 반응을 관찰할 수 있었으나, Ad-SD/SA+WPRE PRT 실험군에서는 거의 관찰되지 않았다. 간조직 슬라이드를 virtual microscope으로 사진 촬영한 후 Aperio Imagescope v10.2.2.2319으로 전체 간에 대한 종양 면적의 fraction을 잰 후 간 무게를 곱하여 종양무게를 측정한 결과 PBS 대조군에 비해 Ad-SD/SA PRT 실험군, Ad-WPRE PRT 실험군, Ad-SD/SA+WPRE PRT 실험군과 Ad-PRT 실험군의 간내 종양의 무게는 현저히 감소되어 있음을 확인하였고, (P<0.001, ANOVA test) 그 중 Ad-SD/SA+WPRE PRT 실험군이 가장 항암효과(antitumor efficacy)가 뛰어남을 보였다(도 8f).

한편, 동량의 아데노바이러스 주입시 항암 효과를 비교 분석하기 위해 Ad-PRT 및 Ad-SD/SA+WPRE PRT를 1 x 10⁹ pfu, 1 x 10⁸ pfu, 0.25 x 10⁸ pfu 로 각각 처리 후 간내 다발초점성 HCC 모델(intrahepatic multifocal HCC model)에서의 암 축소(tumor regression)를 관찰하였다. Ad-PRT의 경우는 1 x 10⁸ pfu를 처리한 경우 항암 효능이 현격히 저하되며, 0.25 x 10⁸ pfu 처리시에는 항암 효능이 거의 관찰되지 못하였다. 반면에 Ad-SD/SA+WPRE PRT의 경우는 0.25 x 10⁸ pfu를 처리한 경우에도 항암 효능이 그대로 유지되는 것을 관찰할 수 있었다. 따라서 라이보자임에 SD/SA 및 WPRE를 도입시 아데노바이러스 용량을 기존의 1/40로 줄여서 생체 내에 도입하여도, 효과적으로 항암 효능을 가지는 것을 확인하였다.

상기 동량의 아데노바이러스 주입시 간독성을 확인한 결과, Ad-PRT 및 Ad-SD/SA+WPRE PRT를 1 x 10⁸ pfu, 0.25 x 10⁸ pfu 로 각각 처리한 경우에 아무런 간독성이 관찰되지 않았다(도 9). 즉, 기존 아데노바이러스에 비하여 현저히 낮은 농도를 처리하여도 효과를 가질 뿐 아니라, 효과를 가지는 농도의 4배의 농도를 처리하여도 아무런 독성을 보이지 않는 것을 확인함에 따라, 본 발명의 재조합 아데노바이러스는 기존에 아데노바이러스와 유사한 정도의 간독성을 가지고 있는데에 비하여, 이를 실제 생체 내에 처리시에는 기존 아데노바이러스에 비해서 1/40에 달하는 현저히 낮은 농도로 처리할 수 있어 안전성이 월등히 높음을 확인하였다.

상술한 결과를 종합하면, 본 발명의 재조합 아데노바이러스는 SD/SA 및 WPRE를 포함하여, 라이보자임의 RNA 수준이 월등히 증가하며, 특히 조직특이적인 프로모터 하에서도 그 증가 효과가 현저함을 확인하였다. 또한, 이를 통해 기존 아데노바이러스에 비해 1/40에 달하는 현저히 낮은 농도의 바이러스를 처리해도 기존 아데노바이러스보다도 항암효과가 우수함을 확인하였으며, 그에 반하여 숙주에 미치는 간독성은 오히려 현저히 감소하는 것을 확인하였다. 이에 따라, 본 발명의 조직특이적인 프로모터를 포함하는 트랜스-스플라이싱 라이보자임을 이용한 항암용 아데노바이러스가 기존의 트랜스-스플라이싱 라이보자임을 이용한 항암용 아데노바이러스에 비하여 항암 효과가 현저히 높을 뿐만 아니라, 숙주에 미치는 독성 또한 현저히 낮아 생체 내 사용시 안전성이 가장 중요한 문제인 유전자 치료 분야에서 널리 사용될 수 있음을 확인하였다.

이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있음을 이해할 수 있다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 제한적인 것이 아닌 것으로 이해하여야 한다. 본 발명의 범위는 전술한 상세한 설명보다는 후술되는 특허 청구범위의 의미 및 범위, 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.

<110> Industry-Academic Cooperation Foundation, Dankook University <120> Recombinant adenovirus comprising regulated derivatives of tumor-targeting trans-splicing ribozyme and uses thereof <130> PA130677KR <160> 47 <170> KopatentIn 2.0 <210> 1 <211> 181 <212> DNA <213> Splicing Donor/Splicing Acceptor seq <400> 1 agatctgaac tgaaaaacca gaaagttaac tggtaagttt agtctttttg tcttttattt 60 caggtcccgg atccggtggt ggtgcaaatc aaagaactgc tcctcagtgg atgttgcctt 120 tacttctagg cctgtacgga agtgttactt ctgctctaaa agctgcggaa ttgtacccag 180 g 181 <210> 2 <211> 121 <212> DNA <213> SD/SA del 61mer <400> 2 gaactgaaaa accagaaagt taactggtaa gtttagtctt tttgtctttt atttcaggtc 60 ccggatccgg tggtggtgca aatcaaagaa ctgctcctca gtggatgttg cctttacttc 120 t 121 <210> 3 <211> 597 <212> DNA <213> WPRE forward <400> 3 ccaatcaacc tctggattac aaaatttgtg aaagattgac tggtattctt aactatgttg 60 ctccttttac gctatgtgga tacgctgctt taatgccttt gtatcatgct attgcttccc 120 gtatggcttt cattttctcc tccttgtata aatcctggtt gctgtctctt tatgaggagt 180 tgtggcccgt tgtcaggcaa cgtggcgtgg tgtgcactgt gtttgctgac gcaaccccca 240 ctggttgggg cattgccacc acctgtcagc tcctttccgg gactttcgct ttccccctcc 300 ctattgccac ggcggaactc atcgccgcct gccttgcccg ctgctggaca ggggctcggc 360 tgttgggcac tgacaattcc gtggtgttgt cggggaaatc atcgtccttt ccttggctgc 420 tcgcctgtgt tgccacctgg attctgcgcg ggacgtcctt ctgctacgtc ccttcggccc 480 tcaatccagc ggaccttcct tcccgcggcc tgctgccggc tctgcggcct cttccgcgtc 540 ttcgccttcg ccctcagacg agtcggatct ccctttgggc cgcctccccg cggccgg 597 <210> 4 <211> 589 <212> DNA <213> WPRE reverse <400> 4 gcggggaggc ggcccaaagg gagatccgac tcgtctgagg gcgaaggcga agacgcggaa 60 gaggccgcag agccggcagc aggccgcggg aaggaaggtc cgctggattg agggccgaag 120 ggacgtagca gaaggacgtc ccgcgcagaa tccaggtggc aacacaggcg agcagccaag 180 gaaaggacga tgatttcccc gacaacacca cggaattgtc agtgcccaac agccgagccc 240 ctgtccagca gcgggcaagg caggcggcga tgagttccgc cgtggcaata gggaggggga 300 aagcgaaagt cccggaaagg agctgacagg tggtggcaat gccccaacca gtgggggttg 360 cgtcagcaaa cacagtgcac accacgccac gttgcctgac aacgggccac aactcctcat 420 aaagagacag caaccaggat ttatacaagg aggagaaaat gaaagccata cgggaagcaa 480 tagcatgata caaaggcatt aaagcagcgt atccacatag cgtaaaagga gcaacatagt 540 taagaatacc agtcaatctt tcacaaattt tgtaatccag aggttgatt 589 <210> 5 <211> 417 <212> DNA <213> Rib21 <400> 5 agcttcgttt tgcggcagga aaagttatca ggcatgcacc tggtagctag tctttaaacc 60 aatagattgc atcggtttaa aaggcaagac cgtcaaattg cgggaaaggg gtcaacagcc 120 gttcagtacc aagtctcagg ggaaactttg agatggcctt gcaaagggta tggtaataag 180 ctgacggaca tggtcctaac cacgcagcca agtcctaagt caacagatct tctgttgata 240 tggatgcagt tcacagacta aatgtcggtc ggggaagatg tattcttctc ataagatata 300 gtcggacctc tccttaatgg gagctagcgg atgaagtgat gcaacactgg agccgctggg 360 aactaatttg tatgcgaaag tatattgatt agttttggag tactcgaaaa cgcccac 417 <210> 6 <211> 1144 <212> DNA <213> HSV-TK <400> 6 catggcttcg tacccctgcc atcaacacgc gtctgcgttc gaccaggctg cgcgttctcg 60 cggccatagc aaccgacgta cggcgttgcg ccctcgccgg cagcaagaag ccacggaagt 120 ccgcctggag cagaaaatgc ccacgctact gcgggtttat atagacggtc ctcacgggat 180 ggggaaaacc accaccacgc aactgctggt ggccctgggt tcgcgcgacg atatcgtcta 240 cgtacccgag ccgatgactt actggcaggt gctgggggct tccgagacaa tcgcgaacat 300 ctacaccaca caacaccgcc tcgaccaggg tgagatatcg gccggggacg cggcggtggt 360 aatgacaagc gcccagataa caatgggcat gccttatgcc gtgaccgacg ccgttctggc 420 tcctcatgtc gggggggagg ctgggagttc acatgccccg cccccggccc tcaccctcat 480 cttcgaccgc catcccatcg ccgccctcct gtgctacccg gccgcgcgat accttatggg 540 cagcatgacc ccccaggccg tgctggcgtt cgtggccctc atcccgccga ccttgcccgg 600 cacaaacatc gtgttggggg cccttccgga ggacagacac atcgaccgcc tggccaaacg 660 ccagcgcccc ggcgagcggc ttgacctggc tatgctggcc gcgattcgcc gcgtttacgg 720 gctgcttgcc aatacggtgc ggtatctgca gggcggcggg tcgtggtggg aggattgggg 780 acagctttcg gggacggccg tgccgcccca gggtgccgag ccccagagca acgcgggccc 840 acgaccccat atcggggaca cgttatttac cctgtttcgg gcccccgagt tgctggcccc 900 caacggcgac ctgtataacg tgtttgcctg ggccttggac gtcttggcca aacgcctccg 960 tcccatgcac gtctttatcc tggattacga ccaatcgccc gccggctgcc gggacgccct 1020 gctgcaactt acctccggga tggtccagac ccacgtcacc accccaggct ccataccgac 1080 gatctgcgac ctggcgcgca cgtttgcccg ggagatgggg gaggctaact gaggccggcc 1140 gctt 1144 <210> 7 <211> 227 <212> DNA <213> PEPCK promoter <400> 7 cgggtgttcc tgaagggggg ctataaaagg gggtgggggc gcgttcgtcc tcactctctt 60 ccgcatcgct gtctgcgagg gccagctgtt ggggtgagta ctccctctga aaagcgggca 120 tgacttctgc gctaagattg tcagtttcca aaaacgagga ggatttgata ttcacctggc 180 ccgcggtgat gcctttgagg gtggccgcat ccatctggtc agaaaag 227 <210> 8 <211> 416 <212> DNA <213> PEPCK enhancer <400> 8 taccgcagcc ggtgggcccg taaatcacac ctattaccgg gtgcaactgg tagttaagag 60 agctgcagct gccgtcatcc ctgagcaggg gggccacttc gttaagcatg tccctgactc 120 gcatgttttc cctgaccaaa tccgccagaa ggcgctcgcc gcccagcgat agcagttctt 180 gcaaggaagc aaagtttttc aacggtttga gaccgtccgc cgtaggcatg cttttgagcg 240 tttgaccaag cagttccagg cggtcccaca gctcggtcac ctgctctacg gcatctcgat 300 ccagcatatc tcctcgtttc gcgggttggg gcggctttcg ctgtacggca gtagtcggtg 360 ctcgtccaga cgggccaggg tcatgtcttt ccacgggcgc agggtcctcg tcagcg 416 <210> 9 <211> 37 <212> DNA <213> Artificial Sequence <220> <223> probe for VAI <400> 9 aaaaggagcg ctcccccgtt gtctgacgtc gcacacc 37 <210> 10 <211> 37 <212> DNA <213> Artificial Sequence <220> <223> probe for U6 <400> 10 gaatttgcgt gtcatccttg cgcaggggcc atgctaa 37 <210> 11 <211> 36 <212> DNA <213> Artificial Sequence <220> <223> AS300 hTERT Ribo NruI forward <400> 11 cctcgcgaaa ggccagcacg ttcttcgcgc cgcgct 36 <210> 12 <211> 39 <212> DNA <213> Artificial Sequence <220> <223> AS300 hTERT Ribo NruI reverse <400> 12 cctcgcgagt actccaaaac taatcaatat actttcgca 39 <210> 13 <211> 39 <212> DNA <213> Artificial Sequence <220> <223> WPRE NotI forward <400> 13 aaggaaaaaa gcggccgcaa tcaacctctg gattacaaa 39 <210> 14 <211> 36 <212> DNA <213> Artificial Sequence <220> <223> WPRE NotI reverse <400> 14 aaggaaaaaa gcggccgcgc ggggaggcgg cccaaa 36 <210> 15 <211> 31 <212> DNA <213> Artificial Sequence <220> <223> WPRE FseI forward <400> 15 gcggccggcc aatcaacctc tggattacaa a 31 <210> 16 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> WPRE FseI reverse <400> 16 gcggccggcc gcggggaggc ggcccaaa 28 <210> 17 <211> 46 <212> DNA <213> Artificial Sequence <220> <223> Ribo P8 BglII reverse <400> 17 gaagatctgt tgacttagga cttggctgcg tggttaggac catgtc 46 <210> 18 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> Ribo P8 BglII forward <400> 18 gaagatcttc tgttgatatg gatgca 26 <210> 19 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> SDSA BglII forward <400> 19 gaagatctga actgaaaaac cagaaag 27 <210> 20 <211> 39 <212> DNA <213> Artificial Sequence <220> <223> TK end BstBI FseI reverse <400> 20 cccttcgaag cggccggcct cagttagcct cccccatct 39 <210> 21 <211> 38 <212> DNA <213> Artificial Sequence <220> <223> hTERT T7 forward <400> 21 taatacgact cactataggg caggcagcgc tgcgtcct 38 <210> 22 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> TK T7 forward <400> 22 taatacgact cactataggg atggcttcgt acccctgcca t 41 <210> 23 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> TK T/S 219 reverse <400> 23 gtgaggaccg tctatataaa cccgcagtag 30 <210> 24 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> TK 350 reverse <400> 24 gtgtagatgt tcgcgattgt ctcggaag 28 <210> 25 <211> 5736 <212> DNA <213> Artificial Sequence <220> <223> pSEAP SV40 Ribozyme F.luci(SRF) <400> 25 ggtaccgagc tcttacgcgt gctagcccgg gctcgagatc tgcgatctgc atctcaatta 60 gtcagcaacc atagtcccgc ccctaactcc gcccatcccg cccctaactc cgcccagttc 120 cgcccattct ccgccccatc gctgactaat tttttttatt tatgcagagg ccgaggccgc 180 ctcggcctct gagctattcc agaagtagtg aggaggcttt tttggaggcc taggcttttg 240 caaaaagctt cgaatcgcga aaggccagca cgttcttcgc gccgcgctcg cacagcctct 300 gcagcactcg ggccaccagc tccttcaggc aggacacctg gcggaaggag ggggcggcgg 360 ggggcggccg tgcgtcccag ggcacgcaca ccaggcactg ggccaccagc gcgcggaaag 420 ccgccgggtc cccgcgctgc accagccgcc agccctgggg ccccaggcgc cgcacgaacg 480 tggccagcgg cagcacctcg cggtagtggc tgcgcagcag ggagcgcacg gctaggcagc 540 ggggagcgcg cggcatcgcg ggggtggccg gggccagggc ttcccaagct tcgttttgcg 600 gcaggaaaag ttatcaggca tgcacctggt agctagtctt taaaccaata gattgcatcg 660 gtttaaaagg caagaccgtc aaattgcggg aaaggggtca acagccgttc agtaccaagt 720 ctcaggggaa actttgagat ggccttgcaa agggtatggt aataagctga cggacatggt 780 cctaaccacg cagccaagtc ctaagtcaac agatcttctg ttgatatgga tgcagttcac 840 agactaaatg tcggtcgggg aagatgtatt cttctcataa gatatagtcg gacctctcct 900 taatgggagc tagcggatga agtgatgcaa cactggagcc gctgggaact aatttgtatg 960 cgaaagtata ttgattagtt ttggagtact cgcgaaaacg cccaccatgg aagacgccaa 1020 aaacataaag aaaggcccgg cgccattcta tcctctagag gatggaaccg ctggagagca 1080 actgcataag gctatgaaga gatacgccct ggttcctgga acaattgctt ttacagatgc 1140 acatatcgag gtgaacatca cgtacgcgga atacttcgaa atgtccgttc ggttggcaga 1200 agctatgaaa cgatatgggc tgaatacaaa tcacagaatc gtcgtatgca gtgaaaactc 1260 tcttcaattc tttatgccgg tgttgggcgc gttatttatc ggagttgcag ttgcgcccgc 1320 gaacgacatt tataatgaac gtgaattgct caacagtatg aacatttcgc agcctaccgt 1380 agtgtttgtt tccaaaaagg ggttgcaaaa aattttgaac gtgcaaaaaa aattaccaat 1440 aatccagaaa attattatca tggattctaa aacggattac cagggatttc agtcgatgta 1500 cacgttcgtc acatctcatc tacctcccgg ttttaatgaa tacgattttg taccagagtc 1560 ctttgatcgt gacaaaacaa ttgcactgat aatgaattcc tctggatcta ctgggttacc 1620 taagggtgtg gcccttccgc atagaactgc ctgcgtcaga ttctcgcatg ccagagatcc 1680 tatttttggc aatcaaatca ttccggatac tgcgatttta agtgttgttc cattccatca 1740 cggttttgga atgtttacta cactcggata tttgatatgt ggatttcgag tcgtcttaat 1800 gtatagattt gaagaagagc tgtttttacg atcccttcag gattacaaaa ttcaaagtgc 1860 gttgctagta ccaaccctat tttcattctt cgccaaaagc actctgattg acaaatacga 1920 tttatctaat ttacacgaaa ttgcttctgg gggcgcacct ctttcgaaag aagtcgggga 1980 agcggttgca aaacgcttcc atcttccagg gatacgacaa ggatatgggc tcactgagac 2040 tacatcagct attctgatta cacccgaggg ggatgataaa ccgggcgcgg tcggtaaagt 2100 tgttccattt tttgaagcga aggttgtgga tctggatacc gggaaaacgc tgggcgttaa 2160 tcagagaggc gaattatgtg tcagaggacc tatgattatg tccggttatg taaacaatcc 2220 ggaagcgacc aacgccttga ttgacaagga tggatggcta cattctggag acatagctta 2280 ctgggacgaa gacgaacact tcttcatagt tgaccgcttg aagtctttaa ttaaatacaa 2340 aggatatcag gtggcccccg ctgaattgga atcgatattg ttacaacacc ccaacatctt 2400 cgacgcgggc gtggcaggtc ttcccgacga tgacgccggt gaacttcccg ccgccgttgt 2460 tgttttggag cacggaaaga cgatgacgga aaaagagatc gtggattacg tggccagtca 2520 agtaacaacc gcgaaaaagt tgcgcggagg agttgtgttt gtggacgaag taccgaaagg 2580 tcttaccgga aaactcgacg caagaaaaat cagagagatc ctcataaagg ccaagaaggg 2640 cggaaagtcc aaattgtaag ctagagtcgg ggcggccggc cgcttcgagc agacatgata 2700 agatacattg atgagtttgg acaaaccaca actagaatgc agtgaaaaaa atgctttatt 2760 tgtgaaattt gtgatgctat tgctttattt gtaaccatta taagctgcaa taaacaagtt 2820 aacaacaaca attgcattca ttttatgttt caggttcagg gggaggtgtg ggaggttttt 2880 taaagcaagt aaaacctcta caaatgtggt aaaatcgata aggatccgtc gaccgatgcc 2940 cttgagagcc ttcaacccag tcagctcctt ccggtgggcg cggggcatga ctatcgtcgc 3000 cgcacttatg actgtcttct ttatcatgca actcgtagga caggtgccgg cagcgctctt 3060 ccgcttcctc gctcactgac tcgctgcgct cggtcgttcg gctgcggcga gcggtatcag 3120 ctcactcaaa ggcggtaata cggttatcca cagaatcagg ggataacgca ggaaagaaca 3180 tgtgagcaaa aggccagcaa aaggccagga accgtaaaaa ggccgcgttg ctggcgtttt 3240 tccataggct ccgcccccct gacgagcatc acaaaaatcg acgctcaagt cagaggtggc 3300 gaaacccgac aggactataa agataccagg cgtttccccc tggaagctcc ctcgtgcgct 3360 ctcctgttcc gaccctgccg cttaccggat acctgtccgc ctttctccct tcgggaagcg 3420 tggcgctttc tcatagctca cgctgtaggt atctcagttc ggtgtaggtc gttcgctcca 3480 agctgggctg tgtgcacgaa ccccccgttc agcccgaccg ctgcgcctta tccggtaact 3540 atcgtcttga gtccaacccg gtaagacacg acttatcgcc actggcagca gccactggta 3600 acaggattag cagagcgagg tatgtaggcg gtgctacaga gttcttgaag tggtggccta 3660 actacggcta cactagaagg acagtatttg gtatctgcgc tctgctgaag ccagttacct 3720 tcggaaaaag agttggtagc tcttgatccg gcaaacaaac caccgctggt agcggtggtt 3780 tttttgtttg caagcagcag attacgcgca gaaaaaaagg atctcaagaa gatcctttga 3840 tcttttctac ggggtctgac gctcagtgga acgaaaactc acgttaaggg attttggtca 3900 tgagattatc aaaaaggatc ttcacctaga tccttttaaa ttaaaaatga agttttaaat 3960 caatctaaag tatatatgag taaacttggt ctgacagtta ccaatgctta atcagtgagg 4020 cacctatctc agcgatctgt ctatttcgtt catccatagt tgcctgactc cccgtcgtgt 4080 agataactac gatacgggag ggcttaccat ctggccccag tgctgcaatg ataccgcgag 4140 acccacgctc accggctcca gatttatcag caataaacca gccagccgga agggccgagc 4200 gcagaagtgg tcctgcaact ttatccgcct ccatccagtc tattaattgt tgccgggaag 4260 ctagagtaag tagttcgcca gttaatagtt tgcgcaacgt tgttgccatt gctacaggca 4320 tcgtggtgtc acgctcgtcg tttggtatgg cttcattcag ctccggttcc caacgatcaa 4380 ggcgagttac atgatccccc atgttgtgca aaaaagcggt tagctccttc ggtcctccga 4440 tcgttgtcag aagtaagttg gccgcagtgt tatcactcat ggttatggca gcactgcata 4500 attctcttac tgtcatgcca tccgtaagat gcttttctgt gactggtgag tactcaacca 4560 agtcattctg agaatagtgt atgcggcgac cgagttgctc ttgcccggcg tcaatacggg 4620 ataataccgc gccacatagc agaactttaa aagtgctcat cattggaaaa cgttcttcgg 4680 ggcgaaaact ctcaaggatc ttaccgctgt tgagatccag ttcgatgtaa cccactcgtg 4740 cacccaactg atcttcagca tcttttactt tcaccagcgt ttctgggtga gcaaaaacag 4800 gaaggcaaaa tgccgcaaaa aagggaataa gggcgacacg gaaatgttga atactcatac 4860 tcttcctttt tcaatattat tgaagcattt atcagggtta ttgtctcatg agcggataca 4920 tatttgaatg tatttagaaa aataaacaaa taggggttcc gcgcacattt ccccgaaaag 4980 tgccacctga cgcgccctgt agcggcgcat taagcgcggc gggtgtggtg gttacgcgca 5040 gcgtgaccgc tacacttgcc agcgccctag cgcccgctcc tttcgctttc ttcccttcct 5100 ttctcgccac gttcgccggc tttccccgtc aagctctaaa tcgggggctc cctttagggt 5160 tccgatttag tgctttacgg cacctcgacc ccaaaaaact tgattagggt gatggttcac 5220 gtagtgggcc atcgccctga tagacggttt ttcgcccttt gacgttggag tccacgttct 5280 ttaatagtgg actcttgttc caaactggaa caacactcaa ccctatctcg gtctattctt 5340 ttgatttata agggattttg ccgatttcgg cctattggtt aaaaaatgag ctgatttaac 5400 aaaaatttaa cgcgaatttt aacaaaatat taacgtttac aatttcccat tcgccattca 5460 ggctgcgcaa ctgttgggaa gggcgatcgg tgcgggcctc ttcgctatta cgccagccca 5520 agctaccatg ataagtaagt aatattaagg tacgggaggt acttggagcg gccgcaataa 5580 aatatcttta ttttcattac atctgtgtgt tggttttttg tgtgaatcga tagtactaac 5640 atacgctctc catcaaaaca aaacgaaaca aaacaaacta gcaaaatagg ctgtccccag 5700 tgcaagtgca ggtgccagaa catttctcta tcgata 5736 <210> 26 <211> 5914 <212> DNA <213> Artificial Sequence <220> <223> pSEAP SV40 SD/SA Ribozyme F.luci(SD/SA SRF) <400> 26 ggtaccgagc tcttacgcgt gctagcccgg gctcgagatc tgcgatctgc atctcaatta 60 gtcagcaacc atagtcccgc ccctaactcc gcccatcccg cccctaactc cgcccagttc 120 cgcccattct ccgccccatc gctgactaat tttttttatt tatgcagagg ccgaggccgc 180 ctcggcctct gagctattcc agaagtagtg aggaggcttt tttggaggcc tgaactgaaa 240 aaccagaaag ttaactggta agtttagtct ttttgtcttt tatttcaggt cccggatccg 300 gtggtggtgc aaatcaaaga actgctcctc agtggatgtt gcctttactt ctaggcctgt 360 acggaagtgt tacttctgct ctaaaagctg cggaattgta cccaggccta ggcttttgca 420 aaaagcttcg aatcgcgaaa ggccagcacg ttcttcgcgc cgcgctcgca cagcctctgc 480 agcactcggg ccaccagctc cttcaggcag gacacctggc ggaaggaggg ggcggcgggg 540 ggcggccgtg cgtcccaggg cacgcacacc aggcactggg ccaccagcgc gcggaaagcc 600 gccgggtccc cgcgctgcac cagccgccag ccctggggcc ccaggcgccg cacgaacgtg 660 gccagcggca gcacctcgcg gtagtggctg cgcagcaggg agcgcacggc taggcagcgg 720 ggagcgcgcg gcatcgcggg ggtggccggg gccagggctt cccaagcttc gttttgcggc 780 aggaaaagtt atcaggcatg cacctggtag ctagtcttta aaccaataga ttgcatcggt 840 ttaaaaggca agaccgtcaa attgcgggaa aggggtcaac agccgttcag taccaagtct 900 caggggaaac tttgagatgg ccttgcaaag ggtatggtaa taagctgacg gacatggtcc 960 taaccacgca gccaagtcct aagtcaacag atcttctgtt gatatggatg cagttcacag 1020 actaaatgtc ggtcggggaa gatgtattct tctcataaga tatagtcgga cctctcctta 1080 atgggagcta gcggatgaag tgatgcaaca ctggagccgc tgggaactaa tttgtatgcg 1140 aaagtatatt gattagtttt ggagtactcg cgaaaacgcc caccatggaa gacgccaaaa 1200 acataaagaa aggcccggcg ccattctatc ctctagagga tggaaccgct ggagagcaac 1260 tgcataaggc tatgaagaga tacgccctgg ttcctggaac aattgctttt acagatgcac 1320 atatcgaggt gaacatcacg tacgcggaat acttcgaaat gtccgttcgg ttggcagaag 1380 ctatgaaacg atatgggctg aatacaaatc acagaatcgt cgtatgcagt gaaaactctc 1440 ttcaattctt tatgccggtg ttgggcgcgt tatttatcgg agttgcagtt gcgcccgcga 1500 acgacattta taatgaacgt gaattgctca acagtatgaa catttcgcag cctaccgtag 1560 tgtttgtttc caaaaagggg ttgcaaaaaa ttttgaacgt gcaaaaaaaa ttaccaataa 1620 tccagaaaat tattatcatg gattctaaaa cggattacca gggatttcag tcgatgtaca 1680 cgttcgtcac atctcatcta cctcccggtt ttaatgaata cgattttgta ccagagtcct 1740 ttgatcgtga caaaacaatt gcactgataa tgaattcctc tggatctact gggttaccta 1800 agggtgtggc ccttccgcat agaactgcct gcgtcagatt ctcgcatgcc agagatccta 1860 tttttggcaa tcaaatcatt ccggatactg cgattttaag tgttgttcca ttccatcacg 1920 gttttggaat gtttactaca ctcggatatt tgatatgtgg atttcgagtc gtcttaatgt 1980 atagatttga agaagagctg tttttacgat cccttcagga ttacaaaatt caaagtgcgt 2040 tgctagtacc aaccctattt tcattcttcg ccaaaagcac tctgattgac aaatacgatt 2100 tatctaattt acacgaaatt gcttctgggg gcgcacctct ttcgaaagaa gtcggggaag 2160 cggttgcaaa acgcttccat cttccaggga tacgacaagg atatgggctc actgagacta 2220 catcagctat tctgattaca cccgaggggg atgataaacc gggcgcggtc ggtaaagttg 2280 ttccattttt tgaagcgaag gttgtggatc tggataccgg gaaaacgctg ggcgttaatc 2340 agagaggcga attatgtgtc agaggaccta tgattatgtc cggttatgta aacaatccgg 2400 aagcgaccaa cgccttgatt gacaaggatg gatggctaca ttctggagac atagcttact 2460 gggacgaaga cgaacacttc ttcatagttg accgcttgaa gtctttaatt aaatacaaag 2520 gatatcaggt ggcccccgct gaattggaat cgatattgtt acaacacccc aacatcttcg 2580 acgcgggcgt ggcaggtctt cccgacgatg acgccggtga acttcccgcc gccgttgttg 2640 ttttggagca cggaaagacg atgacggaaa aagagatcgt ggattacgtg gccagtcaag 2700 taacaaccgc gaaaaagttg cgcggaggag ttgtgtttgt ggacgaagta ccgaaaggtc 2760 ttaccggaaa actcgacgca agaaaaatca gagagatcct cataaaggcc aagaagggcg 2820 gaaagtccaa attgtaagct agagtcgggg cggccggccg cttcgagcag acatgataag 2880 atacattgat gagtttggac aaaccacaac tagaatgcag tgaaaaaaat gctttatttg 2940 tgaaatttgt gatgctattg ctttatttgt aaccattata agctgcaata aacaagttaa 3000 caacaacaat tgcattcatt ttatgtttca ggttcagggg gaggtgtggg aggtttttta 3060 aagcaagtaa aacctctaca aatgtggtaa aatcgataag gatccgtcga ccgatgccct 3120 tgagagcctt caacccagtc agctccttcc ggtgggcgcg gggcatgact atcgtcgccg 3180 cacttatgac tgtcttcttt atcatgcaac tcgtaggaca ggtgccggca gcgctcttcc 3240 gcttcctcgc tcactgactc gctgcgctcg gtcgttcggc tgcggcgagc ggtatcagct 3300 cactcaaagg cggtaatacg gttatccaca gaatcagggg ataacgcagg aaagaacatg 3360 tgagcaaaag gccagcaaaa ggccaggaac cgtaaaaagg ccgcgttgct ggcgtttttc 3420 cataggctcc gcccccctga cgagcatcac aaaaatcgac gctcaagtca gaggtggcga 3480 aacccgacag gactataaag ataccaggcg tttccccctg gaagctccct cgtgcgctct 3540 cctgttccga ccctgccgct taccggatac ctgtccgcct ttctcccttc gggaagcgtg 3600 gcgctttctc atagctcacg ctgtaggtat ctcagttcgg tgtaggtcgt tcgctccaag 3660 ctgggctgtg tgcacgaacc ccccgttcag cccgaccgct gcgccttatc cggtaactat 3720 cgtcttgagt ccaacccggt aagacacgac ttatcgccac tggcagcagc cactggtaac 3780 aggattagca gagcgaggta tgtaggcggt gctacagagt tcttgaagtg gtggcctaac 3840 tacggctaca ctagaaggac agtatttggt atctgcgctc tgctgaagcc agttaccttc 3900 ggaaaaagag ttggtagctc ttgatccggc aaacaaacca ccgctggtag cggtggtttt 3960 tttgtttgca agcagcagat tacgcgcaga aaaaaaggat ctcaagaaga tcctttgatc 4020 ttttctacgg ggtctgacgc tcagtggaac gaaaactcac gttaagggat tttggtcatg 4080 agattatcaa aaaggatctt cacctagatc cttttaaatt aaaaatgaag ttttaaatca 4140 atctaaagta tatatgagta aacttggtct gacagttacc aatgcttaat cagtgaggca 4200 cctatctcag cgatctgtct atttcgttca tccatagttg cctgactccc cgtcgtgtag 4260 ataactacga tacgggaggg cttaccatct ggccccagtg ctgcaatgat accgcgagac 4320 ccacgctcac cggctccaga tttatcagca ataaaccagc cagccggaag ggccgagcgc 4380 agaagtggtc ctgcaacttt atccgcctcc atccagtcta ttaattgttg ccgggaagct 4440 agagtaagta gttcgccagt taatagtttg cgcaacgttg ttgccattgc tacaggcatc 4500 gtggtgtcac gctcgtcgtt tggtatggct tcattcagct ccggttccca acgatcaagg 4560 cgagttacat gatcccccat gttgtgcaaa aaagcggtta gctccttcgg tcctccgatc 4620 gttgtcagaa gtaagttggc cgcagtgtta tcactcatgg ttatggcagc actgcataat 4680 tctcttactg tcatgccatc cgtaagatgc ttttctgtga ctggtgagta ctcaaccaag 4740 tcattctgag aatagtgtat gcggcgaccg agttgctctt gcccggcgtc aatacgggat 4800 aataccgcgc cacatagcag aactttaaaa gtgctcatca ttggaaaacg ttcttcgggg 4860 cgaaaactct caaggatctt accgctgttg agatccagtt cgatgtaacc cactcgtgca 4920 cccaactgat cttcagcatc ttttactttc accagcgttt ctgggtgagc aaaaacagga 4980 aggcaaaatg ccgcaaaaaa gggaataagg gcgacacgga aatgttgaat actcatactc 5040 ttcctttttc aatattattg aagcatttat cagggttatt gtctcatgag cggatacata 5100 tttgaatgta tttagaaaaa taaacaaata ggggttccgc gcacatttcc ccgaaaagtg 5160 ccacctgacg cgccctgtag cggcgcatta agcgcggcgg gtgtggtggt tacgcgcagc 5220 gtgaccgcta cacttgccag cgccctagcg cccgctcctt tcgctttctt cccttccttt 5280 ctcgccacgt tcgccggctt tccccgtcaa gctctaaatc gggggctccc tttagggttc 5340 cgatttagtg ctttacggca cctcgacccc aaaaaacttg attagggtga tggttcacgt 5400 agtgggccat cgccctgata gacggttttt cgccctttga cgttggagtc cacgttcttt 5460 aatagtggac tcttgttcca aactggaaca acactcaacc ctatctcggt ctattctttt 5520 gatttataag ggattttgcc gatttcggcc tattggttaa aaaatgagct gatttaacaa 5580 aaatttaacg cgaattttaa caaaatatta acgtttacaa tttcccattc gccattcagg 5640 ctgcgcaact gttgggaagg gcgatcggtg cgggcctctt cgctattacg ccagcccaag 5700 ctaccatgat aagtaagtaa tattaaggta cgggaggtac ttggagcggc cgcaataaaa 5760 tatctttatt ttcattacat ctgtgtgttg gttttttgtg tgaatcgata gtactaacat 5820 acgctctcca tcaaaacaaa acgaaacaaa acaaactagc aaaataggct gtccccagtg 5880 caagtgcagg tgccagaaca tttctctatc gata 5914 <210> 27 <211> 5863 <212> DNA <213> Artificial Sequence <220> <223> pSEAP SV40 SD/SA(del 61mer) Ribozyme F.luci(SD/SA del 61mer SRF) <400> 27 ggtaccgagc tcttacgcgt gctagcccgg gctcgagatc tgcgatctgc atctcaatta 60 gtcagcaacc atagtcccgc ccctaactcc gcccatcccg cccctaactc cgcccagttc 120 cgcccattct ccgccccatc gctgactaat tttttttatt tatgcagagg ccgaggccgc 180 ctcggcctct gagctattcc agaagtagtg aggaggcttt tttggaggcc tgaactgaaa 240 aaccagaaag ttaactggta agtttagtct ttttgtcttt tatttcaggt cccggatccg 300 gtggtggtgc aaatcaaaga actgctcctc agtggatgtt gcctttactt ctaggcctag 360 gcttttgcaa aaagcttcga atcgcgaaag gccagcacgt tcttcgcgcc gcgctcgcac 420 agcctctgca gcactcgggc caccagctcc ttcaggcagg acacctggcg gaaggagggg 480 gcggcggggg gcggccgtgc gtcccagggc acgcacacca ggcactgggc caccagcgcg 540 cggaaagccg ccgggtcccc gcgctgcacc agccgccagc cctggggccc caggcgccgc 600 acgaacgtgg ccagcggcag cacctcgcgg tagtggctgc gcagcaggga gcgcacggct 660 aggcagcggg gagcgcgcgg catcgcgggg gtggccgggg ccagggcttc ccaagcttcg 720 ttttgcggca ggaaaagtta tcaggcatgc acctggtagc tagtctttaa accaatagat 780 tgcatcggtt taaaaggcaa gaccgtcaaa ttgcgggaaa ggggtcaaca gccgttcagt 840 accaagtctc aggggaaact ttgagatggc cttgcaaagg gtatggtaat aagctgacgg 900 acatggtcct aaccacgcag ccaagtccta agtcaacaga tcttctgttg atatggatgc 960 agttcacaga ctaaatgtcg gtcggggaag atgtattctt ctcataagat atagtcggac 1020 ctctccttaa tgggagctag cggatgaagt gatgcaacac tggagccgct gggaactaat 1080 ttgtatgcga aagtatattg attagttttg gagtactcgc gaaaacgccc accatggaag 1140 acgccaaaaa cataaagaaa ggcccggcgc cattctatcc tctagaggat ggaaccgctg 1200 gagagcaact gcataaggct atgaagagat acgccctggt tcctggaaca attgctttta 1260 cagatgcaca tatcgaggtg aacatcacgt acgcggaata cttcgaaatg tccgttcggt 1320 tggcagaagc tatgaaacga tatgggctga atacaaatca cagaatcgtc gtatgcagtg 1380 aaaactctct tcaattcttt atgccggtgt tgggcgcgtt atttatcgga gttgcagttg 1440 cgcccgcgaa cgacatttat aatgaacgtg aattgctcaa cagtatgaac atttcgcagc 1500 ctaccgtagt gtttgtttcc aaaaaggggt tgcaaaaaat tttgaacgtg caaaaaaaat 1560 taccaataat ccagaaaatt attatcatgg attctaaaac ggattaccag ggatttcagt 1620 cgatgtacac gttcgtcaca tctcatctac ctcccggttt taatgaatac gattttgtac 1680 cagagtcctt tgatcgtgac aaaacaattg cactgataat gaattcctct ggatctactg 1740 ggttacctaa gggtgtggcc cttccgcata gaactgcctg cgtcagattc tcgcatgcca 1800 gagatcctat ttttggcaat caaatcattc cggatactgc gattttaagt gttgttccat 1860 tccatcacgg ttttggaatg tttactacac tcggatattt gatatgtgga tttcgagtcg 1920 tcttaatgta tagatttgaa gaagagctgt ttttacgatc ccttcaggat tacaaaattc 1980 aaagtgcgtt gctagtacca accctatttt cattcttcgc caaaagcact ctgattgaca 2040 aatacgattt atctaattta cacgaaattg cttctggggg cgcacctctt tcgaaagaag 2100 tcggggaagc ggttgcaaaa cgcttccatc ttccagggat acgacaagga tatgggctca 2160 ctgagactac atcagctatt ctgattacac ccgaggggga tgataaaccg ggcgcggtcg 2220 gtaaagttgt tccatttttt gaagcgaagg ttgtggatct ggataccggg aaaacgctgg 2280 gcgttaatca gagaggcgaa ttatgtgtca gaggacctat gattatgtcc ggttatgtaa 2340 acaatccgga agcgaccaac gccttgattg acaaggatgg atggctacat tctggagaca 2400 tagcttactg ggacgaagac gaacacttct tcatagttga ccgcttgaag tctttaatta 2460 aatacaaagg atatcaggtg gcccccgctg aattggaatc gatattgtta caacacccca 2520 acatcttcga cgcgggcgtg gcaggtcttc ccgacgatga cgccggtgaa cttcccgccg 2580 ccgttgttgt tttggagcac ggaaagacga tgacggaaaa agagatcgtg gattacgtgg 2640 ccagtcaagt aacaaccgcg aaaaagttgc gcggaggagt tgtgtttgtg gacgaagtac 2700 cgaaaggtct taccggaaaa ctcgacgcaa gaaaaatcag agagatcctc ataaaggcca 2760 agaagggcgg aaagtccaaa ttgtaagcta gagtcggggc ggccggccgc ttcgagcaga 2820 catgataaga tacattgatg agtttggaca aaccacaact agaatgcagt gaaaaaaatg 2880 ctttatttgt gaaatttgtg atgctattgc tttatttgta accattataa gctgcaataa 2940 acaagttaac aacaacaatt gcattcattt tatgtttcag gttcaggggg aggtgtggga 3000 ggttttttaa agcaagtaaa acctctacaa atgtggtaaa atcgataagg atccgtcgac 3060 cgatgccctt gagagccttc aacccagtca gctccttccg gtgggcgcgg ggcatgacta 3120 tcgtcgccgc acttatgact gtcttcttta tcatgcaact cgtaggacag gtgccggcag 3180 cgctcttccg cttcctcgct cactgactcg ctgcgctcgg tcgttcggct gcggcgagcg 3240 gtatcagctc actcaaaggc ggtaatacgg ttatccacag aatcagggga taacgcagga 3300 aagaacatgt gagcaaaagg ccagcaaaag gccaggaacc gtaaaaaggc cgcgttgctg 3360 gcgtttttcc ataggctccg cccccctgac gagcatcaca aaaatcgacg ctcaagtcag 3420 aggtggcgaa acccgacagg actataaaga taccaggcgt ttccccctgg aagctccctc 3480 gtgcgctctc ctgttccgac cctgccgctt accggatacc tgtccgcctt tctcccttcg 3540 ggaagcgtgg cgctttctca tagctcacgc tgtaggtatc tcagttcggt gtaggtcgtt 3600 cgctccaagc tgggctgtgt gcacgaaccc cccgttcagc ccgaccgctg cgccttatcc 3660 ggtaactatc gtcttgagtc caacccggta agacacgact tatcgccact ggcagcagcc 3720 actggtaaca ggattagcag agcgaggtat gtaggcggtg ctacagagtt cttgaagtgg 3780 tggcctaact acggctacac tagaaggaca gtatttggta tctgcgctct gctgaagcca 3840 gttaccttcg gaaaaagagt tggtagctct tgatccggca aacaaaccac cgctggtagc 3900 ggtggttttt ttgtttgcaa gcagcagatt acgcgcagaa aaaaaggatc tcaagaagat 3960 cctttgatct tttctacggg gtctgacgct cagtggaacg aaaactcacg ttaagggatt 4020 ttggtcatga gattatcaaa aaggatcttc acctagatcc ttttaaatta aaaatgaagt 4080 tttaaatcaa tctaaagtat atatgagtaa acttggtctg acagttacca atgcttaatc 4140 agtgaggcac ctatctcagc gatctgtcta tttcgttcat ccatagttgc ctgactcccc 4200 gtcgtgtaga taactacgat acgggagggc ttaccatctg gccccagtgc tgcaatgata 4260 ccgcgagacc cacgctcacc ggctccagat ttatcagcaa taaaccagcc agccggaagg 4320 gccgagcgca gaagtggtcc tgcaacttta tccgcctcca tccagtctat taattgttgc 4380 cgggaagcta gagtaagtag ttcgccagtt aatagtttgc gcaacgttgt tgccattgct 4440 acaggcatcg tggtgtcacg ctcgtcgttt ggtatggctt cattcagctc cggttcccaa 4500 cgatcaaggc gagttacatg atcccccatg ttgtgcaaaa aagcggttag ctccttcggt 4560 cctccgatcg ttgtcagaag taagttggcc gcagtgttat cactcatggt tatggcagca 4620 ctgcataatt ctcttactgt catgccatcc gtaagatgct tttctgtgac tggtgagtac 4680 tcaaccaagt cattctgaga atagtgtatg cggcgaccga gttgctcttg cccggcgtca 4740 atacgggata ataccgcgcc acatagcaga actttaaaag tgctcatcat tggaaaacgt 4800 tcttcggggc gaaaactctc aaggatctta ccgctgttga gatccagttc gatgtaaccc 4860 actcgtgcac ccaactgatc ttcagcatct tttactttca ccagcgtttc tgggtgagca 4920 aaaacaggaa ggcaaaatgc cgcaaaaaag ggaataaggg cgacacggaa atgttgaata 4980 ctcatactct tcctttttca atattattga agcatttatc agggttattg tctcatgagc 5040 ggatacatat ttgaatgtat ttagaaaaat aaacaaatag gggttccgcg cacatttccc 5100 cgaaaagtgc cacctgacgc gccctgtagc ggcgcattaa gcgcggcggg tgtggtggtt 5160 acgcgcagcg tgaccgctac acttgccagc gccctagcgc ccgctccttt cgctttcttc 5220 ccttcctttc tcgccacgtt cgccggcttt ccccgtcaag ctctaaatcg ggggctccct 5280 ttagggttcc gatttagtgc tttacggcac ctcgacccca aaaaacttga ttagggtgat 5340 ggttcacgta gtgggccatc gccctgatag acggtttttc gccctttgac gttggagtcc 5400 acgttcttta atagtggact cttgttccaa actggaacaa cactcaaccc tatctcggtc 5460 tattcttttg atttataagg gattttgccg atttcggcct attggttaaa aaatgagctg 5520 atttaacaaa aatttaacgc gaattttaac aaaatattaa cgtttacaat ttcccattcg 5580 ccattcaggc tgcgcaactg ttgggaaggg cgatcggtgc gggcctcttc gctattacgc 5640 cagcccaagc taccatgata agtaagtaat attaaggtac gggaggtact tggagcggcc 5700 gcaataaaat atctttattt tcattacatc tgtgtgttgg ttttttgtgt gaatcgatag 5760 tactaacata cgctctccat caaaacaaaa cgaaacaaaa caaactagca aaataggctg 5820 tccccagtgc aagtgcaggt gccagaacat ttctctatcg ata 5863 <210> 28 <211> 6333 <212> DNA <213> Artificial Sequence <220> <223> pSEAP SV40 Ribozyme F.luci WPRE (forward) <400> 28 ggtaccgagc tcttacgcgt gctagcccgg gctcgagatc tgcgatctgc atctcaatta 60 gtcagcaacc atagtcccgc ccctaactcc gcccatcccg cccctaactc cgcccagttc 120 cgcccattct ccgccccatc gctgactaat tttttttatt tatgcagagg ccgaggccgc 180 ctcggcctct gagctattcc agaagtagtg aggaggcttt tttggaggcc taggcttttg 240 caaaaagctt cgaatcgcga aaggccagca cgttcttcgc gccgcgctcg cacagcctct 300 gcagcactcg ggccaccagc tccttcaggc aggacacctg gcggaaggag ggggcggcgg 360 ggggcggccg tgcgtcccag ggcacgcaca ccaggcactg ggccaccagc gcgcggaaag 420 ccgccgggtc cccgcgctgc accagccgcc agccctgggg ccccaggcgc cgcacgaacg 480 tggccagcgg cagcacctcg cggtagtggc tgcgcagcag ggagcgcacg gctaggcagc 540 ggggagcgcg cggcatcgcg ggggtggccg gggccagggc ttcccaagct tcgttttgcg 600 gcaggaaaag ttatcaggca tgcacctggt agctagtctt taaaccaata gattgcatcg 660 gtttaaaagg caagaccgtc aaattgcggg aaaggggtca acagccgttc agtaccaagt 720 ctcaggggaa actttgagat ggccttgcaa agggtatggt aataagctga cggacatggt 780 cctaaccacg cagccaagtc ctaagtcaac agatcttctg ttgatatgga tgcagttcac 840 agactaaatg tcggtcgggg aagatgtatt cttctcataa gatatagtcg gacctctcct 900 taatgggagc tagcggatga agtgatgcaa cactggagcc gctgggaact aatttgtatg 960 cgaaagtata ttgattagtt ttggagtact cgcgaaaacg cccaccatgg aagacgccaa 1020 aaacataaag aaaggcccgg cgccattcta tcctctagag gatggaaccg ctggagagca 1080 actgcataag gctatgaaga gatacgccct ggttcctgga acaattgctt ttacagatgc 1140 acatatcgag gtgaacatca cgtacgcgga atacttcgaa atgtccgttc ggttggcaga 1200 agctatgaaa cgatatgggc tgaatacaaa tcacagaatc gtcgtatgca gtgaaaactc 1260 tcttcaattc tttatgccgg tgttgggcgc gttatttatc ggagttgcag ttgcgcccgc 1320 gaacgacatt tataatgaac gtgaattgct caacagtatg aacatttcgc agcctaccgt 1380 agtgtttgtt tccaaaaagg ggttgcaaaa aattttgaac gtgcaaaaaa aattaccaat 1440 aatccagaaa attattatca tggattctaa aacggattac cagggatttc agtcgatgta 1500 cacgttcgtc acatctcatc tacctcccgg ttttaatgaa tacgattttg taccagagtc 1560 ctttgatcgt gacaaaacaa ttgcactgat aatgaattcc tctggatcta ctgggttacc 1620 taagggtgtg gcccttccgc atagaactgc ctgcgtcaga ttctcgcatg ccagagatcc 1680 tatttttggc aatcaaatca ttccggatac tgcgatttta agtgttgttc cattccatca 1740 cggttttgga atgtttacta cactcggata tttgatatgt ggatttcgag tcgtcttaat 1800 gtatagattt gaagaagagc tgtttttacg atcccttcag gattacaaaa ttcaaagtgc 1860 gttgctagta ccaaccctat tttcattctt cgccaaaagc actctgattg acaaatacga 1920 tttatctaat ttacacgaaa ttgcttctgg gggcgcacct ctttcgaaag aagtcgggga 1980 agcggttgca aaacgcttcc atcttccagg gatacgacaa ggatatgggc tcactgagac 2040 tacatcagct attctgatta cacccgaggg ggatgataaa ccgggcgcgg tcggtaaagt 2100 tgttccattt tttgaagcga aggttgtgga tctggatacc gggaaaacgc tgggcgttaa 2160 tcagagaggc gaattatgtg tcagaggacc tatgattatg tccggttatg taaacaatcc 2220 ggaagcgacc aacgccttga ttgacaagga tggatggcta cattctggag acatagctta 2280 ctgggacgaa gacgaacact tcttcatagt tgaccgcttg aagtctttaa ttaaatacaa 2340 aggatatcag gtggcccccg ctgaattgga atcgatattg ttacaacacc ccaacatctt 2400 cgacgcgggc gtggcaggtc ttcccgacga tgacgccggt gaacttcccg ccgccgttgt 2460 tgttttggag cacggaaaga cgatgacgga aaaagagatc gtggattacg tggccagtca 2520 agtaacaacc gcgaaaaagt tgcgcggagg agttgtgttt gtggacgaag taccgaaagg 2580 tcttaccgga aaactcgacg caagaaaaat cagagagatc ctcataaagg ccaagaaggg 2640 cggaaagtcc aaattgtaag ctagagtcgg ggcggccggc caatcaacct ctggattaca 2700 aaatttgtga aagattgact ggtattctta actatgttgc tccttttacg ctatgtggat 2760 acgctgcttt aatgcctttg tatcatgcta ttgcttcccg tatggctttc attttctcct 2820 ccttgtataa atcctggttg ctgtctcttt atgaggagtt gtggcccgtt gtcaggcaac 2880 gtggcgtggt gtgcactgtg tttgctgacg caacccccac tggttggggc attgccacca 2940 cctgtcagct cctttccggg actttcgctt tccccctccc tattgccacg gcggaactca 3000 tcgccgcctg ccttgcccgc tgctggacag gggctcggct gttgggcact gacaattccg 3060 tggtgttgtc ggggaaatca tcgtcctttc cttggctgct cgcctgtgtt gccacctgga 3120 ttctgcgcgg gacgtccttc tgctacgtcc cttcggccct caatccagcg gaccttcctt 3180 cccgcggcct gctgccggct ctgcggcctc ttccgcgtct tcgccttcgc cctcagacga 3240 gtcggatctc cctttgggcc gcctccccgc ggccggccgc ttcgagcaga catgataaga 3300 tacattgatg agtttggaca aaccacaact agaatgcagt gaaaaaaatg ctttatttgt 3360 gaaatttgtg atgctattgc tttatttgta accattataa gctgcaataa acaagttaac 3420 aacaacaatt gcattcattt tatgtttcag gttcaggggg aggtgtggga ggttttttaa 3480 agcaagtaaa acctctacaa atgtggtaaa atcgataagg atccgtcgac cgatgccctt 3540 gagagccttc aacccagtca gctccttccg gtgggcgcgg ggcatgacta tcgtcgccgc 3600 acttatgact gtcttcttta tcatgcaact cgtaggacag gtgccggcag cgctcttccg 3660 cttcctcgct cactgactcg ctgcgctcgg tcgttcggct gcggcgagcg gtatcagctc 3720 actcaaaggc ggtaatacgg ttatccacag aatcagggga taacgcagga aagaacatgt 3780 gagcaaaagg ccagcaaaag gccaggaacc gtaaaaaggc cgcgttgctg gcgtttttcc 3840 ataggctccg cccccctgac gagcatcaca aaaatcgacg ctcaagtcag aggtggcgaa 3900 acccgacagg actataaaga taccaggcgt ttccccctgg aagctccctc gtgcgctctc 3960 ctgttccgac cctgccgctt accggatacc tgtccgcctt tctcccttcg ggaagcgtgg 4020 cgctttctca tagctcacgc tgtaggtatc tcagttcggt gtaggtcgtt cgctccaagc 4080 tgggctgtgt gcacgaaccc cccgttcagc ccgaccgctg cgccttatcc ggtaactatc 4140 gtcttgagtc caacccggta agacacgact tatcgccact ggcagcagcc actggtaaca 4200 ggattagcag agcgaggtat gtaggcggtg ctacagagtt cttgaagtgg tggcctaact 4260 acggctacac tagaaggaca gtatttggta tctgcgctct gctgaagcca gttaccttcg 4320 gaaaaagagt tggtagctct tgatccggca aacaaaccac cgctggtagc ggtggttttt 4380 ttgtttgcaa gcagcagatt acgcgcagaa aaaaaggatc tcaagaagat cctttgatct 4440 tttctacggg gtctgacgct cagtggaacg aaaactcacg ttaagggatt ttggtcatga 4500 gattatcaaa aaggatcttc acctagatcc ttttaaatta aaaatgaagt tttaaatcaa 4560 tctaaagtat atatgagtaa acttggtctg acagttacca atgcttaatc agtgaggcac 4620 ctatctcagc gatctgtcta tttcgttcat ccatagttgc ctgactcccc gtcgtgtaga 4680 taactacgat acgggagggc ttaccatctg gccccagtgc tgcaatgata ccgcgagacc 4740 cacgctcacc ggctccagat ttatcagcaa taaaccagcc agccggaagg gccgagcgca 4800 gaagtggtcc tgcaacttta tccgcctcca tccagtctat taattgttgc cgggaagcta 4860 gagtaagtag ttcgccagtt aatagtttgc gcaacgttgt tgccattgct acaggcatcg 4920 tggtgtcacg ctcgtcgttt ggtatggctt cattcagctc cggttcccaa cgatcaaggc 4980 gagttacatg atcccccatg ttgtgcaaaa aagcggttag ctccttcggt cctccgatcg 5040 ttgtcagaag taagttggcc gcagtgttat cactcatggt tatggcagca ctgcataatt 5100 ctcttactgt catgccatcc gtaagatgct tttctgtgac tggtgagtac tcaaccaagt 5160 cattctgaga atagtgtatg cggcgaccga gttgctcttg cccggcgtca atacgggata 5220 ataccgcgcc acatagcaga actttaaaag tgctcatcat tggaaaacgt tcttcggggc 5280 gaaaactctc aaggatctta ccgctgttga gatccagttc gatgtaaccc actcgtgcac 5340 ccaactgatc ttcagcatct tttactttca ccagcgtttc tgggtgagca aaaacaggaa 5400 ggcaaaatgc cgcaaaaaag ggaataaggg cgacacggaa atgttgaata ctcatactct 5460 tcctttttca atattattga agcatttatc agggttattg tctcatgagc ggatacatat 5520 ttgaatgtat ttagaaaaat aaacaaatag gggttccgcg cacatttccc cgaaaagtgc 5580 cacctgacgc gccctgtagc ggcgcattaa gcgcggcggg tgtggtggtt acgcgcagcg 5640 tgaccgctac acttgccagc gccctagcgc ccgctccttt cgctttcttc ccttcctttc 5700 tcgccacgtt cgccggcttt ccccgtcaag ctctaaatcg ggggctccct ttagggttcc 5760 gatttagtgc tttacggcac ctcgacccca aaaaacttga ttagggtgat ggttcacgta 5820 gtgggccatc gccctgatag acggtttttc gccctttgac gttggagtcc acgttcttta 5880 atagtggact cttgttccaa actggaacaa cactcaaccc tatctcggtc tattcttttg 5940 atttataagg gattttgccg atttcggcct attggttaaa aaatgagctg atttaacaaa 6000 aatttaacgc gaattttaac aaaatattaa cgtttacaat ttcccattcg ccattcaggc 6060 tgcgcaactg ttgggaaggg cgatcggtgc gggcctcttc gctattacgc cagcccaagc 6120 taccatgata agtaagtaat attaaggtac gggaggtact tggagcggcc gcaataaaat 6180 atctttattt tcattacatc tgtgtgttgg ttttttgtgt gaatcgatag tactaacata 6240 cgctctccat caaaacaaaa cgaaacaaaa caaactagca aaataggctg tccccagtgc 6300 aagtgcaggt gccagaacat ttctctatcg ata 6333 <210> 29 <211> 6333 <212> DNA <213> Artificial Sequence <220> <223> pSEAP SV40 Ribozyme F.luci WPRE(reverse) <400> 29 ggtaccgagc tcttacgcgt gctagcccgg gctcgagatc tgcgatctgc atctcaatta 60 gtcagcaacc atagtcccgc ccctaactcc gcccatcccg cccctaactc cgcccagttc 120 cgcccattct ccgccccatc gctgactaat tttttttatt tatgcagagg ccgaggccgc 180 ctcggcctct gagctattcc agaagtagtg aggaggcttt tttggaggcc taggcttttg 240 caaaaagctt cgaatcgcga aaggccagca cgttcttcgc gccgcgctcg cacagcctct 300 gcagcactcg ggccaccagc tccttcaggc aggacacctg gcggaaggag ggggcggcgg 360 ggggcggccg tgcgtcccag ggcacgcaca ccaggcactg ggccaccagc gcgcggaaag 420 ccgccgggtc cccgcgctgc accagccgcc agccctgggg ccccaggcgc cgcacgaacg 480 tggccagcgg cagcacctcg cggtagtggc tgcgcagcag ggagcgcacg gctaggcagc 540 ggggagcgcg cggcatcgcg ggggtggccg gggccagggc ttcccaagct tcgttttgcg 600 gcaggaaaag ttatcaggca tgcacctggt agctagtctt taaaccaata gattgcatcg 660 gtttaaaagg caagaccgtc aaattgcggg aaaggggtca acagccgttc agtaccaagt 720 ctcaggggaa actttgagat ggccttgcaa agggtatggt aataagctga cggacatggt 780 cctaaccacg cagccaagtc ctaagtcaac agatcttctg ttgatatgga tgcagttcac 840 agactaaatg tcggtcgggg aagatgtatt cttctcataa gatatagtcg gacctctcct 900 taatgggagc tagcggatga agtgatgcaa cactggagcc gctgggaact aatttgtatg 960 cgaaagtata ttgattagtt ttggagtact cgcgaaaacg cccaccatgg aagacgccaa 1020 aaacataaag aaaggcccgg cgccattcta tcctctagag gatggaaccg ctggagagca 1080 actgcataag gctatgaaga gatacgccct ggttcctgga acaattgctt ttacagatgc 1140 acatatcgag gtgaacatca cgtacgcgga atacttcgaa atgtccgttc ggttggcaga 1200 agctatgaaa cgatatgggc tgaatacaaa tcacagaatc gtcgtatgca gtgaaaactc 1260 tcttcaattc tttatgccgg tgttgggcgc gttatttatc ggagttgcag ttgcgcccgc 1320 gaacgacatt tataatgaac gtgaattgct caacagtatg aacatttcgc agcctaccgt 1380 agtgtttgtt tccaaaaagg ggttgcaaaa aattttgaac gtgcaaaaaa aattaccaat 1440 aatccagaaa attattatca tggattctaa aacggattac cagggatttc agtcgatgta 1500 cacgttcgtc acatctcatc tacctcccgg ttttaatgaa tacgattttg taccagagtc 1560 ctttgatcgt gacaaaacaa ttgcactgat aatgaattcc tctggatcta ctgggttacc 1620 taagggtgtg gcccttccgc atagaactgc ctgcgtcaga ttctcgcatg ccagagatcc 1680 tatttttggc aatcaaatca ttccggatac tgcgatttta agtgttgttc cattccatca 1740 cggttttgga atgtttacta cactcggata tttgatatgt ggatttcgag tcgtcttaat 1800 gtatagattt gaagaagagc tgtttttacg atcccttcag gattacaaaa ttcaaagtgc 1860 gttgctagta ccaaccctat tttcattctt cgccaaaagc actctgattg acaaatacga 1920 tttatctaat ttacacgaaa ttgcttctgg gggcgcacct ctttcgaaag aagtcgggga 1980 agcggttgca aaacgcttcc atcttccagg gatacgacaa ggatatgggc tcactgagac 2040 tacatcagct attctgatta cacccgaggg ggatgataaa ccgggcgcgg tcggtaaagt 2100 tgttccattt tttgaagcga aggttgtgga tctggatacc gggaaaacgc tgggcgttaa 2160 tcagagaggc gaattatgtg tcagaggacc tatgattatg tccggttatg taaacaatcc 2220 ggaagcgacc aacgccttga ttgacaagga tggatggcta cattctggag acatagctta 2280 ctgggacgaa gacgaacact tcttcatagt tgaccgcttg aagtctttaa ttaaatacaa 2340 aggatatcag gtggcccccg ctgaattgga atcgatattg ttacaacacc ccaacatctt 2400 cgacgcgggc gtggcaggtc ttcccgacga tgacgccggt gaacttcccg ccgccgttgt 2460 tgttttggag cacggaaaga cgatgacgga aaaagagatc gtggattacg tggccagtca 2520 agtaacaacc gcgaaaaagt tgcgcggagg agttgtgttt gtggacgaag taccgaaagg 2580 tcttaccgga aaactcgacg caagaaaaat cagagagatc ctcataaagg ccaagaaggg 2640 cggaaagtcc aaattgtaag ctagagtcgg ggcggccggc cgcggggagg cggcccaaag 2700 ggagatccga ctcgtctgag ggcgaaggcg aagacgcgga agaggccgca gagccggcag 2760 caggccgcgg gaaggaaggt ccgctggatt gagggccgaa gggacgtagc agaaggacgt 2820 cccgcgcaga atccaggtgg caacacaggc gagcagccaa ggaaaggacg atgatttccc 2880 cgacaacacc acggaattgt cagtgcccaa cagccgagcc cctgtccagc agcgggcaag 2940 gcaggcggcg atgagttccg ccgtggcaat agggaggggg aaagcgaaag tcccggaaag 3000 gagctgacag gtggtggcaa tgccccaacc agtgggggtt gcgtcagcaa acacagtgca 3060 caccacgcca cgttgcctga caacgggcca caactcctca taaagagaca gcaaccagga 3120 tttatacaag gaggagaaaa tgaaagccat acgggaagca atagcatgat acaaaggcat 3180 taaagcagcg tatccacata gcgtaaaagg agcaacatag ttaagaatac cagtcaatct 3240 ttcacaaatt ttgtaatcca gaggttgatt ggccggccgc ttcgagcaga catgataaga 3300 tacattgatg agtttggaca aaccacaact agaatgcagt gaaaaaaatg ctttatttgt 3360 gaaatttgtg atgctattgc tttatttgta accattataa gctgcaataa acaagttaac 3420 aacaacaatt gcattcattt tatgtttcag gttcaggggg aggtgtggga ggttttttaa 3480 agcaagtaaa acctctacaa atgtggtaaa atcgataagg atccgtcgac cgatgccctt 3540 gagagccttc aacccagtca gctccttccg gtgggcgcgg ggcatgacta tcgtcgccgc 3600 acttatgact gtcttcttta tcatgcaact cgtaggacag gtgccggcag cgctcttccg 3660 cttcctcgct cactgactcg ctgcgctcgg tcgttcggct gcggcgagcg gtatcagctc 3720 actcaaaggc ggtaatacgg ttatccacag aatcagggga taacgcagga aagaacatgt 3780 gagcaaaagg ccagcaaaag gccaggaacc gtaaaaaggc cgcgttgctg gcgtttttcc 3840 ataggctccg cccccctgac gagcatcaca aaaatcgacg ctcaagtcag aggtggcgaa 3900 acccgacagg actataaaga taccaggcgt ttccccctgg aagctccctc gtgcgctctc 3960 ctgttccgac cctgccgctt accggatacc tgtccgcctt tctcccttcg ggaagcgtgg 4020 cgctttctca tagctcacgc tgtaggtatc tcagttcggt gtaggtcgtt cgctccaagc 4080 tgggctgtgt gcacgaaccc cccgttcagc ccgaccgctg cgccttatcc ggtaactatc 4140 gtcttgagtc caacccggta agacacgact tatcgccact ggcagcagcc actggtaaca 4200 ggattagcag agcgaggtat gtaggcggtg ctacagagtt cttgaagtgg tggcctaact 4260 acggctacac tagaaggaca gtatttggta tctgcgctct gctgaagcca gttaccttcg 4320 gaaaaagagt tggtagctct tgatccggca aacaaaccac cgctggtagc ggtggttttt 4380 ttgtttgcaa gcagcagatt acgcgcagaa aaaaaggatc tcaagaagat cctttgatct 4440 tttctacggg gtctgacgct cagtggaacg aaaactcacg ttaagggatt ttggtcatga 4500 gattatcaaa aaggatcttc acctagatcc ttttaaatta aaaatgaagt tttaaatcaa 4560 tctaaagtat atatgagtaa acttggtctg acagttacca atgcttaatc agtgaggcac 4620 ctatctcagc gatctgtcta tttcgttcat ccatagttgc ctgactcccc gtcgtgtaga 4680 taactacgat acgggagggc ttaccatctg gccccagtgc tgcaatgata ccgcgagacc 4740 cacgctcacc ggctccagat ttatcagcaa taaaccagcc agccggaagg gccgagcgca 4800 gaagtggtcc tgcaacttta tccgcctcca tccagtctat taattgttgc cgggaagcta 4860 gagtaagtag ttcgccagtt aatagtttgc gcaacgttgt tgccattgct acaggcatcg 4920 tggtgtcacg ctcgtcgttt ggtatggctt cattcagctc cggttcccaa cgatcaaggc 4980 gagttacatg atcccccatg ttgtgcaaaa aagcggttag ctccttcggt cctccgatcg 5040 ttgtcagaag taagttggcc gcagtgttat cactcatggt tatggcagca ctgcataatt 5100 ctcttactgt catgccatcc gtaagatgct tttctgtgac tggtgagtac tcaaccaagt 5160 cattctgaga atagtgtatg cggcgaccga gttgctcttg cccggcgtca atacgggata 5220 ataccgcgcc acatagcaga actttaaaag tgctcatcat tggaaaacgt tcttcggggc 5280 gaaaactctc aaggatctta ccgctgttga gatccagttc gatgtaaccc actcgtgcac 5340 ccaactgatc ttcagcatct tttactttca ccagcgtttc tgggtgagca aaaacaggaa 5400 ggcaaaatgc cgcaaaaaag ggaataaggg cgacacggaa atgttgaata ctcatactct 5460 tcctttttca atattattga agcatttatc agggttattg tctcatgagc ggatacatat 5520 ttgaatgtat ttagaaaaat aaacaaatag gggttccgcg cacatttccc cgaaaagtgc 5580 cacctgacgc gccctgtagc ggcgcattaa gcgcggcggg tgtggtggtt acgcgcagcg 5640 tgaccgctac acttgccagc gccctagcgc ccgctccttt cgctttcttc ccttcctttc 5700 tcgccacgtt cgccggcttt ccccgtcaag ctctaaatcg ggggctccct ttagggttcc 5760 gatttagtgc tttacggcac ctcgacccca aaaaacttga ttagggtgat ggttcacgta 5820 gtgggccatc gccctgatag acggtttttc gccctttgac gttggagtcc acgttcttta 5880 atagtggact cttgttccaa actggaacaa cactcaaccc tatctcggtc tattcttttg 5940 atttataagg gattttgccg atttcggcct attggttaaa aaatgagctg atttaacaaa 6000 aatttaacgc gaattttaac aaaatattaa cgtttacaat ttcccattcg ccattcaggc 6060 tgcgcaactg ttgggaaggg cgatcggtgc gggcctcttc gctattacgc cagcccaagc 6120 taccatgata agtaagtaat attaaggtac gggaggtact tggagcggcc gcaataaaat 6180 atctttattt tcattacatc tgtgtgttgg ttttttgtgt gaatcgatag tactaacata 6240 cgctctccat caaaacaaaa cgaaacaaaa caaactagca aaataggctg tccccagtgc 6300 aagtgcaggt gccagaacat ttctctatcg ata 6333 <210> 30 <211> 6511 <212> DNA <213> Artificial Sequence <220> <223> pSEAP SV40 SD/SA Ribozyme F.luci WPRE(forward) <400> 30 ggtaccgagc tcttacgcgt gctagcccgg gctcgagatc tgcgatctgc atctcaatta 60 gtcagcaacc atagtcccgc ccctaactcc gcccatcccg cccctaactc cgcccagttc 120 cgcccattct ccgccccatc gctgactaat tttttttatt tatgcagagg ccgaggccgc 180 ctcggcctct gagctattcc agaagtagtg aggaggcttt tttggaggcc tgaactgaaa 240 aaccagaaag ttaactggta agtttagtct ttttgtcttt tatttcaggt cccggatccg 300 gtggtggtgc aaatcaaaga actgctcctc agtggatgtt gcctttactt ctaggcctgt 360 acggaagtgt tacttctgct ctaaaagctg cggaattgta cccaggccta ggcttttgca 420 aaaagcttcg aatcgcgaaa ggccagcacg ttcttcgcgc cgcgctcgca cagcctctgc 480 agcactcggg ccaccagctc cttcaggcag gacacctggc ggaaggaggg ggcggcgggg 540 ggcggccgtg cgtcccaggg cacgcacacc aggcactggg ccaccagcgc gcggaaagcc 600 gccgggtccc cgcgctgcac cagccgccag ccctggggcc ccaggcgccg cacgaacgtg 660 gccagcggca gcacctcgcg gtagtggctg cgcagcaggg agcgcacggc taggcagcgg 720 ggagcgcgcg gcatcgcggg ggtggccggg gccagggctt cccaagcttc gttttgcggc 780 aggaaaagtt atcaggcatg cacctggtag ctagtcttta aaccaataga ttgcatcggt 840 ttaaaaggca agaccgtcaa attgcgggaa aggggtcaac agccgttcag taccaagtct 900 caggggaaac tttgagatgg ccttgcaaag ggtatggtaa taagctgacg gacatggtcc 960 taaccacgca gccaagtcct aagtcaacag atcttctgtt gatatggatg cagttcacag 1020 actaaatgtc ggtcggggaa gatgtattct tctcataaga tatagtcgga cctctcctta 1080 atgggagcta gcggatgaag tgatgcaaca ctggagccgc tgggaactaa tttgtatgcg 1140 aaagtatatt gattagtttt ggagtactcg cgaaaacgcc caccatggaa gacgccaaaa 1200 acataaagaa aggcccggcg ccattctatc ctctagagga tggaaccgct ggagagcaac 1260 tgcataaggc tatgaagaga tacgccctgg ttcctggaac aattgctttt acagatgcac 1320 atatcgaggt gaacatcacg tacgcggaat acttcgaaat gtccgttcgg ttggcagaag 1380 ctatgaaacg atatgggctg aatacaaatc acagaatcgt cgtatgcagt gaaaactctc 1440 ttcaattctt tatgccggtg ttgggcgcgt tatttatcgg agttgcagtt gcgcccgcga 1500 acgacattta taatgaacgt gaattgctca acagtatgaa catttcgcag cctaccgtag 1560 tgtttgtttc caaaaagggg ttgcaaaaaa ttttgaacgt gcaaaaaaaa ttaccaataa 1620 tccagaaaat tattatcatg gattctaaaa cggattacca gggatttcag tcgatgtaca 1680 cgttcgtcac atctcatcta cctcccggtt ttaatgaata cgattttgta ccagagtcct 1740 ttgatcgtga caaaacaatt gcactgataa tgaattcctc tggatctact gggttaccta 1800 agggtgtggc ccttccgcat agaactgcct gcgtcagatt ctcgcatgcc agagatccta 1860 tttttggcaa tcaaatcatt ccggatactg cgattttaag tgttgttcca ttccatcacg 1920 gttttggaat gtttactaca ctcggatatt tgatatgtgg atttcgagtc gtcttaatgt 1980 atagatttga agaagagctg tttttacgat cccttcagga ttacaaaatt caaagtgcgt 2040 tgctagtacc aaccctattt tcattcttcg ccaaaagcac tctgattgac aaatacgatt 2100 tatctaattt acacgaaatt gcttctgggg gcgcacctct ttcgaaagaa gtcggggaag 2160 cggttgcaaa acgcttccat cttccaggga tacgacaagg atatgggctc actgagacta 2220 catcagctat tctgattaca cccgaggggg atgataaacc gggcgcggtc ggtaaagttg 2280 ttccattttt tgaagcgaag gttgtggatc tggataccgg gaaaacgctg ggcgttaatc 2340 agagaggcga attatgtgtc agaggaccta tgattatgtc cggttatgta aacaatccgg 2400 aagcgaccaa cgccttgatt gacaaggatg gatggctaca ttctggagac atagcttact 2460 gggacgaaga cgaacacttc ttcatagttg accgcttgaa gtctttaatt aaatacaaag 2520 gatatcaggt ggcccccgct gaattggaat cgatattgtt acaacacccc aacatcttcg 2580 acgcgggcgt ggcaggtctt cccgacgatg acgccggtga acttcccgcc gccgttgttg 2640 ttttggagca cggaaagacg atgacggaaa aagagatcgt ggattacgtg gccagtcaag 2700 taacaaccgc gaaaaagttg cgcggaggag ttgtgtttgt ggacgaagta ccgaaaggtc 2760 ttaccggaaa actcgacgca agaaaaatca gagagatcct cataaaggcc aagaagggcg 2820 gaaagtccaa attgtaagct agagtcgggg cggccggcca atcaacctct ggattacaaa 2880 atttgtgaaa gattgactgg tattcttaac tatgttgctc cttttacgct atgtggatac 2940 gctgctttaa tgcctttgta tcatgctatt gcttcccgta tggctttcat tttctcctcc 3000 ttgtataaat cctggttgct gtctctttat gaggagttgt ggcccgttgt caggcaacgt 3060 ggcgtggtgt gcactgtgtt tgctgacgca acccccactg gttggggcat tgccaccacc 3120 tgtcagctcc tttccgggac tttcgctttc cccctcccta ttgccacggc ggaactcatc 3180 gccgcctgcc ttgcccgctg ctggacaggg gctcggctgt tgggcactga caattccgtg 3240 gtgttgtcgg ggaaatcatc gtcctttcct tggctgctcg cctgtgttgc cacctggatt 3300 ctgcgcggga cgtccttctg ctacgtccct tcggccctca atccagcgga ccttccttcc 3360 cgcggcctgc tgccggctct gcggcctctt ccgcgtcttc gccttcgccc tcagacgagt 3420 cggatctccc tttgggccgc ctccccgcgg ccggccgctt cgagcagaca tgataagata 3480 cattgatgag tttggacaaa ccacaactag aatgcagtga aaaaaatgct ttatttgtga 3540 aatttgtgat gctattgctt tatttgtaac cattataagc tgcaataaac aagttaacaa 3600 caacaattgc attcatttta tgtttcaggt tcagggggag gtgtgggagg ttttttaaag 3660 caagtaaaac ctctacaaat gtggtaaaat cgataaggat ccgtcgaccg atgcccttga 3720 gagccttcaa cccagtcagc tccttccggt gggcgcgggg catgactatc gtcgccgcac 3780 ttatgactgt cttctttatc atgcaactcg taggacaggt gccggcagcg ctcttccgct 3840 tcctcgctca ctgactcgct gcgctcggtc gttcggctgc ggcgagcggt atcagctcac 3900 tcaaaggcgg taatacggtt atccacagaa tcaggggata acgcaggaaa gaacatgtga 3960 gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg cgttgctggc gtttttccat 4020 aggctccgcc cccctgacga gcatcacaaa aatcgacgct caagtcagag gtggcgaaac 4080 ccgacaggac tataaagata ccaggcgttt ccccctggaa gctccctcgt gcgctctcct 4140 gttccgaccc tgccgcttac cggatacctg tccgcctttc tcccttcggg aagcgtggcg 4200 ctttctcata gctcacgctg taggtatctc agttcggtgt aggtcgttcg ctccaagctg 4260 ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg ccttatccgg taactatcgt 4320 cttgagtcca acccggtaag acacgactta tcgccactgg cagcagccac tggtaacagg 4380 attagcagag cgaggtatgt aggcggtgct acagagttct tgaagtggtg gcctaactac 4440 ggctacacta gaaggacagt atttggtatc tgcgctctgc tgaagccagt taccttcgga 4500 aaaagagttg gtagctcttg atccggcaaa caaaccaccg ctggtagcgg tggttttttt 4560 gtttgcaagc agcagattac gcgcagaaaa aaaggatctc aagaagatcc tttgatcttt 4620 tctacggggt ctgacgctca gtggaacgaa aactcacgtt aagggatttt ggtcatgaga 4680 ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa aatgaagttt taaatcaatc 4740 taaagtatat atgagtaaac ttggtctgac agttaccaat gcttaatcag tgaggcacct 4800 atctcagcga tctgtctatt tcgttcatcc atagttgcct gactccccgt cgtgtagata 4860 actacgatac gggagggctt accatctggc cccagtgctg caatgatacc gcgagaccca 4920 cgctcaccgg ctccagattt atcagcaata aaccagccag ccggaagggc cgagcgcaga 4980 agtggtcctg caactttatc cgcctccatc cagtctatta attgttgccg ggaagctaga 5040 gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg ccattgctac aggcatcgtg 5100 gtgtcacgct cgtcgtttgg tatggcttca ttcagctccg gttcccaacg atcaaggcga 5160 gttacatgat cccccatgtt gtgcaaaaaa gcggttagct ccttcggtcc tccgatcgtt 5220 gtcagaagta agttggccgc agtgttatca ctcatggtta tggcagcact gcataattct 5280 cttactgtca tgccatccgt aagatgcttt tctgtgactg gtgagtactc aaccaagtca 5340 ttctgagaat agtgtatgcg gcgaccgagt tgctcttgcc cggcgtcaat acgggataat 5400 accgcgccac atagcagaac tttaaaagtg ctcatcattg gaaaacgttc ttcggggcga 5460 aaactctcaa ggatcttacc gctgttgaga tccagttcga tgtaacccac tcgtgcaccc 5520 aactgatctt cagcatcttt tactttcacc agcgtttctg ggtgagcaaa aacaggaagg 5580 caaaatgccg caaaaaaggg aataagggcg acacggaaat gttgaatact catactcttc 5640 ctttttcaat attattgaag catttatcag ggttattgtc tcatgagcgg atacatattt 5700 gaatgtattt agaaaaataa acaaataggg gttccgcgca catttccccg aaaagtgcca 5760 cctgacgcgc cctgtagcgg cgcattaagc gcggcgggtg tggtggttac gcgcagcgtg 5820 accgctacac ttgccagcgc cctagcgccc gctcctttcg ctttcttccc ttcctttctc 5880 gccacgttcg ccggctttcc ccgtcaagct ctaaatcggg ggctcccttt agggttccga 5940 tttagtgctt tacggcacct cgaccccaaa aaacttgatt agggtgatgg ttcacgtagt 6000 gggccatcgc cctgatagac ggtttttcgc cctttgacgt tggagtccac gttctttaat 6060 agtggactct tgttccaaac tggaacaaca ctcaacccta tctcggtcta ttcttttgat 6120 ttataaggga ttttgccgat ttcggcctat tggttaaaaa atgagctgat ttaacaaaaa 6180 tttaacgcga attttaacaa aatattaacg tttacaattt cccattcgcc attcaggctg 6240 cgcaactgtt gggaagggcg atcggtgcgg gcctcttcgc tattacgcca gcccaagcta 6300 ccatgataag taagtaatat taaggtacgg gaggtacttg gagcggccgc aataaaatat 6360 ctttattttc attacatctg tgtgttggtt ttttgtgtga atcgatagta ctaacatacg 6420 ctctccatca aaacaaaacg aaacaaaaca aactagcaaa ataggctgtc cccagtgcaa 6480 gtgcaggtgc cagaacattt ctctatcgat a 6511 <210> 31 <211> 9964 <212> DNA <213> Artificial Sequence <220> <223> pAVQ CMV Ribozyme HSV-TK <400> 31 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 ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag ttattaatag taatcaatta 540 cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt acggtaaatg 600 gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg acgtatgttc 660 ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat ttacggtaaa 720 ctgcccactt ggcagtacat caagtgtatc atatgccaag tccgccccct attgacgtca 780 atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttacgg gactttccta 840 cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg ttttggcagt 900 acaccaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc caccccattg 960 acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa tgtcgtaata 1020 accccgcccc gttgacgcaa atgggcggta ggcgtgtacg gtgggaggtc tatataagca 1080 gagctcgttt agtgaaccgt cagatcctca ctctcttccg catcgctgtc tgcgagggcc 1140 agctgttggg ctcgcggttg aggacaaact cttcgcggtc tttccagtac tcttggatcg 1200 gaaacccgtc ggcctccgaa cggtactccg ccaccgaggg acctgagcca gtccgcatcg 1260 accggatcgg aaaacctctc gagaaaggcg tctaaccagt cacagtcgca aggtaggctg 1320 agcaccgtgg cgggcggcag cgggtggcgg tcggggttgt ttctggcgga ggtgctgctg 1380 atgatgtaat taaagtaggc ggtcttgagc cggcggatgg tcgaggtgag gtgtggcagg 1440 cttgagatcc agctgttggg gtgagtactc cctctcaaaa gcgggcatga cttctgcgct 1500 aagattgtca gtttccaaaa acgaggagga tttgatattc acctggcccg atctggccat 1560 acacttgagt gacaatgaca tccactttgc ctttctctcc acaggtgtcc actcccaggt 1620 ccaagtttgg aagatccaag gccagcacgt tcttcgcgcc gcgctcgcac agcctctgca 1680 gcactcgggc caccagctcc ttcaggcagg acacctggcg gaaggagggg gcggcggggg 1740 gcggccgtgc gtcccagggc acgcacacca ggcactgggc caccagcgcg cggaaagccg 1800 ccgggtcccc gcgctgcacc agccgccagc cctggggccc caggcgccgc acgaacgtgg 1860 ccagcggcag cacctcgcgg tagtggctgc gcagcaggga gcgcacggct aggcagcggg 1920 gagcgcgcgg catcgcgggg gtggccgggg ccagggcttc ccaagcttcg ttttgcggca 1980 ggaaaagtta tcaggcatgc acctggtagc tagtctttaa accaatagat tgcatcggtt 2040 taaaaggcaa gaccgtcaaa ttgcgggaaa ggggtcaaca gccgttcagt accaagtctc 2100 aggggaaact ttgagatggc cttgcaaagg gtatggtaat aagctgacgg acatggtcct 2160 aaccacgcag ccaagtccta agtcaacaga tcttctgttg atatggatgc agttcacaga 2220 ctaaatgtcg gtcggggaag atgtattctt ctcataagat atagtcggac ctctccttaa 2280 tgggagctag cggatgaagt gatgcaacac tggagccgct gggaactaat ttgtatgcga 2340 aagtatattg attagttttg gagtactcga aaacgcccac catggcttcg tacccctgcc 2400 atcaacacgc gtctgcgttc gaccaggctg cgcgttctcg cggccatagc aaccgacgta 2460 cggcgttgcg ccctcgccgg cagcaagaag ccacggaagt ccgcctggag cagaaaatgc 2520 ccacgctact gcgggtttat atagacggtc ctcacgggat ggggaaaacc accaccacgc 2580 aactgctggt ggccctgggt tcgcgcgacg atatcgtcta cgtacccgag ccgatgactt 2640 actggcaggt gctgggggct tccgagacaa tcgcgaacat ctacaccaca caacaccgcc 2700 tcgaccaggg tgagatatcg gccggggacg cggcggtggt aatgacaagc gcccagataa 2760 caatgggcat gccttatgcc gtgaccgacg ccgttctggc tcctcatgtc gggggggagg 2820 ctgggagttc acatgccccg cccccggccc tcaccctcat cttcgaccgc catcccatcg 2880 ccgccctcct gtgctacccg gccgcgcgat accttatggg cagcatgacc ccccaggccg 2940 tgctggcgtt cgtggccctc atcccgccga ccttgcccgg cacaaacatc gtgttggggg 3000 cccttccgga ggacagacac atcgaccgcc tggccaaacg ccagcgcccc ggcgagcggc 3060 ttgacctggc tatgctggcc gcgattcgcc gcgtttacgg gctgcttgcc aatacggtgc 3120 ggtatctgca gggcggcggg tcgtggtggg aggattgggg acagctttcg gggacggccg 3180 tgccgcccca gggtgccgag ccccagagca acgcgggccc acgaccccat atcggggaca 3240 cgttatttac cctgtttcgg gcccccgagt tgctggcccc caacggcgac ctgtataacg 3300 tgtttgcctg ggccttggac gtcttggcca aacgcctccg tcccatgcac gtctttatcc 3360 tggattacga ccaatcgccc gccggctgcc gggacgccct gctgcaactt acctccggga 3420 tggtccagac ccacgtcacc accccaggct ccataccgac gatctgcgac ctggcgcgca 3480 cgtttgcccg ggagatgggg gaggctaact gattcgaaag atcccaacga aaagagagac 3540 cacatggtcc ttcttgagtt tgtaacagct gctgggatta cacatggcat ggatgaactg 3600 tacaactgag gatcccccga cctcgacctc tggctaataa aggaaattta ttttcattgc 3660 aatagtgtgt tggaattttt tgtgtctctc actcggaagg acatatggga gggcaaatca 3720 tttggtcgag atccctcgga gatcggatct gggcgtggtt aagggtggga aagaatatat 3780 aaggtggggg tcttatgtag ttttgtatct gttttgcagc agccgccgcc gccatgagca 3840 ccaactcgtt tgatggaagc attgtgagct catatttgac aacgcgcatg cccccatggg 3900 ccggggtgcg tcagaatgtg atgggctcca gcattgatgg tcgccccgtc ctgcccgcaa 3960 actctactac cttgacctac gagaccgtgt ctggaacgcc gttggagact gcagcctccg 4020 ccgccgcttc agccgctgca gccaccgccc gcgggattgt gactgacttt gctttcctga 4080 gcccgcttgc aagcagtgca gcttcccgtt catccgcccg cgatgacaag ttgacggctc 4140 ttttggcaca attggattct ttgacccggg aacttaatgt cgtttctcag cagctgttgg 4200 atctgcgcca gcaggtttct gccctgaagg cttcctcccc tcccaatgcg gtttaaaaca 4260 taaataaaaa accagactct gtttggattt ggatcaagca agtgtcttgc tgtctttatt 4320 taggggtttt gcgcgcgcgg taggcccggg accagcggtc tcggtcgttg agggtcctgt 4380 gtattttttc caggacgtgg taaaggtgac tctggatgtt cagatacatg ggcataagcc 4440 cgtctctggg gtggaggtag caccactgca gagcttcatg ctgcggggtg gtgttgtaga 4500 tgatccagtc gtagcaggag cgctgggcgt ggtgcctaaa aatgtctttc agtagcaagc 4560 tgattgccag gggcaggccc ttggtgtaag tgtttacaaa gcggttaagc tgggatgggt 4620 gcatacgtgg ggatatgaga tgcatcttgg actgtatttt taggttggct atgttcccag 4680 ccatatccct ccggggattc atgttgtgca gaaccaccag cacagtgtat ccggtgcact 4740 tgggaaattt gtcatgtagc ttagaaggaa atgcgtggaa gaacttggag acgcccttgt 4800 gacctccaag attttccatg cattcgtcca taatgatggc aatgggccca cgggcggcgg 4860 cctgggcgaa gatatttctg ggatcactaa cgtcatagtt gtgttccagg atgagatcgt 4920 cataggccat ttttacaaag cgcgggcgga gggtgccaga ctgcggtata atggttccat 4980 ccggcccagg ggcgtagtta ccctcacaga tttgcatttc ccacgctttg agttcagatg 5040 gggggatcat gtctacctgc ggggcgatga agaaaacggt ttccggggta ggggagatca 5100 gctgggaaga aagcaggttc ctgagcagct gcgacttacc gcagccggtg ggcccgtaaa 5160 tcacacctat taccgggtgc aactggtagt taagagagct gcagctgccg tcatccctga 5220 gcaggggggc cacttcgtta agcatgtccc tgactcgcat gttttccctg accaaatccg 5280 ccagaaggcg ctcgccgccc agcgatagca gttcttgcaa ggaagcaaag tttttcaacg 5340 gtttgagacc gtccgccgta ggcatgcttt tgagcgtttg accaagcagt tccaggcggt 5400 cccacagctc ggtcacctgc tctacggcat ctcgatccag catatctcct cgtttcgcgg 5460 gttggggcgg ctttcgctgt acggcagtag tcggtgctcg tccagacggg ccagggtcat 5520 gtctttccac gggcgcaggg tcctcgtcag cgtagtctgg gtcacggtga aggggtgcgc 5580 tccgggctgc gcgctggcca gggtgcgctt gaggctggtc ctgctggtgc tgaagcgctg 5640 ccggtcttcg ccctgcgcgt cggccaggta gcatttgacc atggtgtcat agtccagccc 5700 ctccgcggcg tggcccttgg cgcgcagctt gcccttggag gaggcgccgc acgaggggca 5760 gtgcagactt ttgagggcgt agagcttggg cgcgagaaat accgattccg gggagtaggc 5820 atccgcgccg caggccccgc agacggtctc gcattccacg agccaggtga gctctggccg 5880 ttcggggtca aaaaccaggt ttcccccatg ctttttgatg cgtttcttac ctctggtttc 5940 catgagccgg tgtccacgct cggtgacgaa aaggctgtcc gtgtccccgt atacagactt 6000 gagagggagt ttaaacgaat tcaatagctt gttgcatggg cggcgatata aaatgcaagg 6060 tgctgctcaa aaaatcaggc aaagcctcgc gcaaaaaaga aagcacatcg tagtcatgct 6120 catgcagata aaggcaggta agctccggaa ccaccacaga aaaagacacc atttttctct 6180 caaacatgtc tgcgggtttc tgcataaaca caaaataaaa taacaaaaaa acatttaaac 6240 attagaagcc tgtcttacaa caggaaaaac aacccttata agcataagac ggactacggc 6300 catgccggcg tgaccgtaaa aaaactggtc accgtgatta aaaagcacca ccgacagctc 6360 ctcggtcatg tccggagtca taatgtaaga ctcggtaaac acatcaggtt gattcatcgg 6420 tcagtgctaa aaagcgaccg aaatagcccg ggggaataca tacccgcagg cgtagagaca 6480 acattacagc ccccatagga ggtataacaa aattaatagg agagaaaaac acataaacac 6540 ctgaaaaacc ctcctgccta ggcaaaatag caccctcccg ctccagaaca acatacagcg 6600 cttcacagcg gcagcctaac agtcagcctt accagtaaaa aagaaaacct attaaaaaaa 6660 caccactcga cacggcacca gctcaatcag tcacagtgta aaaaagggcc aagtgcagag 6720 cgagtatata taggactaaa aaatgacgta acggttaaag tccacaaaaa acacccagaa 6780 aaccgcacgc gaacctacgc ccagaaacga aagccaaaaa acccacaact tcctcaaatc 6840 gtcacttccg ttttcccacg ttacgtaact tcccatttta agaaaactac aattcccaac 6900 acatacaagt tactccgccc taaaacctac gtcacccgcc ccgttcccac gccccgcgcc 6960 acgtcacaaa ctccaccccc tcattatcat attggcttca atccaaaata aggtatatta 7020 ttgatgatgt taattaacat gcatggatcc atatgcggtg tgaaataccg cacagatgcg 7080 taaggagaaa ataccgcatc aggcgctctt ccgcttcctc gctcactgac tcgctgcgct 7140 cggtcgttcg gctgcggcga gcggtatcag ctcactcaaa ggcggtaata cggttatcca 7200 cagaatcagg ggataacgca ggaaagaaca tgtgagcaaa aggccagcaa aaggccagga 7260 accgtaaaaa ggccgcgttg ctggcgtttt tccataggct ccgcccccct gacgagcatc 7320 acaaaaatcg acgctcaagt cagaggtggc gaaacccgac aggactataa agataccagg 7380 cgtttccccc tggaagctcc ctcgtgcgct ctcctgttcc gaccctgccg cttaccggat 7440 acctgtccgc ctttctccct tcgggaagcg tggcgctttc tcatagctca cgctgtaggt 7500 atctcagttc ggtgtaggtc gttcgctcca agctgggctg tgtgcacgaa ccccccgttc 7560 agcccgaccg ctgcgcctta tccggtaact atcgtcttga gtccaacccg gtaagacacg 7620 acttatcgcc actggcagca gccactggta acaggattag cagagcgagg tatgtaggcg 7680 gtgctacaga gttcttgaag tggtggccta actacggcta cactagaagg acagtatttg 7740 gtatctgcgc tctgctgaag ccagttacct tcggaaaaag agttggtagc tcttgatccg 7800 gcaaacaaac caccgctggt agcggtggtt tttttgtttg caagcagcag attacgcgca 7860 gaaaaaaagg atctcaagaa gatcctttga tcttttctac ggggtctgac gctcagtgga 7920 acgaaaactc acgttaaggg attttggtca tgagattatc aaaaaggatc ttcacctaga 7980 tccttttaaa ttaaaaatga agttttaaat caatctaaag tatatatgag taaacttggt 8040 ctgacagtta ccaatgctta atcagtgagg cacctatctc agcgatctgt ctatttcgtt 8100 catccatagt tgcctgactc cccgtcgtgt agataactac gatacgggag ggcttaccat 8160 ctggccccag tgctgcaatg ataccgcgag acccacgctc accggctcca gatttatcag 8220 caataaacca gccagccgga agggccgagc gcagaagtgg tcctgcaact ttatccgcct 8280 ccatccagtc tattaattgt tgccgggaag ctagagtaag tagttcgcca gttaatagtt 8340 tgcgcaacgt tgttgccatt gctgcagcca tgagattatc aaaaaggatc ttcacctaga 8400 tccttttcac gtagaaagcc agtccgcaga aacggtgctg accccggatg aatgtcagct 8460 actgggctat ctggacaagg gaaaacgcaa gcgcaaagag aaagcaggta gcttgcagtg 8520 ggcttacatg gcgatagcta gactgggcgg ttttatggac agcaagcgaa ccggaattgc 8580 cagctggggc gccctctggt aaggttggga agccctgcaa agtaaactgg atggctttct 8640 cgccgccaag gatctgatgg cgcaggggat caagctctga tcaagagaca ggatgaggat 8700 cgtttcgcat gattgaacaa gatggattgc acgcaggttc tccggccgct tgggtggaga 8760 ggctattcgg ctatgactgg gcacaacaga caatcggctg ctctgatgcc gccgtgttcc 8820 ggctgtcagc gcaggggcgc ccggttcttt ttgtcaagac cgacctgtcc ggtgccctga 8880 atgaactgca agacgaggca gcgcggctat cgtggctggc cacgacgggc gttccttgcg 8940 cagctgtgct cgacgttgtc actgaagcgg gaagggactg gctgctattg ggcgaagtgc 9000 cggggcagga tctcctgtca tctcaccttg ctcctgccga gaaagtatcc atcatggctg 9060 atgcaatgcg gcggctgcat acgcttgatc cggctacctg cccattcgac caccaagcga 9120 aacatcgcat cgagcgagca cgtactcgga tggaagccgg tcttgtcgat caggatgatc 9180 tggacgaaga gcatcagggg ctcgcgccag ccgaactgtt cgccaggctc aaggcgagca 9240 tgcccgacgg cgaggatctc gtcgtgaccc atggcgatgc ctgcttgccg aatatcatgg 9300 tggaaaatgg ccgcttttct ggattcatcg actgtggccg gctgggtgtg gcggaccgct 9360 atcaggacat agcgttggct acccgtgata ttgctgaaga gcttggcggc gaatgggctg 9420 accgcttcct cgtgctttac ggtatcgccg ctcccgattc gcagcgcatc gccttctatc 9480 gccttcttga cgagttcttc tgaattttgt taaaattttt gttaaatcag ctcatttttt 9540 aaccaatagg ccgaaatcgg caacatccct tataaatcaa aagaatagac cgcgataggg 9600 ttgagtgttg ttccagtttg gaacaagagt ccactattaa agaacgtgga ctccaacgtc 9660 aaagggcgaa aaaccgtcta tcagggcgat ggcccactac gtgaaccatc acccaaatca 9720 agttttttgc ggtcgaggtg ccgtaaagct ctaaatcgga accctaaagg gagcccccga 9780 tttagagctt gacggggaaa gccggcgaac gtggcgagaa aggaagggaa gaaagcgaaa 9840 ggagcgggcg ctagggcgct ggcaagtgta gcggtcacgc tgcgcgtaac caccacaccc 9900 gcgcgcttaa tgcgccgcta cagggcgcgt ccattcgcca ttcaggatcg aattaattct 9960 taat 9964 <210> 32 <211> 10181 <212> DNA <213> Artificial Sequence <220> <223> pAVQ SD/SA CMV Ribozyme HSV-TK <400> 32 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 ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag ttattaatag taatcaatta 540 cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt acggtaaatg 600 gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg acgtatgttc 660 ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat ttacggtaaa 720 ctgcccactt ggcagtacat caagtgtatc atatgccaag tccgccccct attgacgtca 780 atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttacgg gactttccta 840 cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg ttttggcagt 900 acaccaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc caccccattg 960 acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa tgtcgtaata 1020 accccgcccc gttgacgcaa atgggcggta ggcgtgtacg gtgggaggtc tatataagca 1080 gagctcgttt agtgaaccgt cagatcctca ctctcttccg catcgctgtc tgcgagggcc 1140 agctgttggg ctcgcggttg aggacaaact cttcgcggtc tttccagtac tcttggatcg 1200 gaaacccgtc ggcctccgaa cggtactccg ccaccgaggg acctgagcca gtccgcatcg 1260 accggatcgg aaaacctctc gagaaaggcg tctaaccagt cacagtcgca aggtaggctg 1320 agcaccgtgg cgggcggcag cgggtggcgg tcggggttgt ttctggcgga ggtgctgctg 1380 atgatgtaat taaagtaggc ggtcttgagc cggcggatgg tcgaggtgag gtgtggcagg 1440 cttgagatcc agctgttggg gtgagtactc cctctcaaaa gcgggcatga cttctgcgct 1500 aagattgtca gtttccaaaa acgaggagga tttgatattc acctggcccg atctggccat 1560 acacttgagt gacaatgaca tccactttgc ctttctctcc acaggtgtcc actcccaggt 1620 ccaagtttgg aagatctgaa ctgaaaaacc agaaagttaa ctggtaagtt tagtcttttt 1680 gtcttttatt tcaggtcccg gatccggtgg tggtgcaaat caaagaactg ctcctcagtg 1740 gatgttgcct ttacttctag gcctgtacgg aagtgttact tctgctctaa aagctgcgga 1800 attgtaccca ggcctaggct tttgcaaaaa gcttcgaatc gcgaaaggcc agcacgttct 1860 tcgcgccgcg ctcgcacagc ctctgcagca ctcgggccac cagctccttc aggcaggaca 1920 cctggcggaa ggagggggcg gcggggggcg gccgtgcgtc ccagggcacg cacaccaggc 1980 actgggccac cagcgcgcgg aaagccgccg ggtccccgcg ctgcaccagc cgccagccct 2040 ggggccccag gcgccgcacg aacgtggcca gcggcagcac ctcgcggtag tggctgcgca 2100 gcagggagcg cacggctagg cagcggggag cgcgcggcat cgcgggggtg gccggggcca 2160 gggcttccca agcttcgttt tgcggcagga aaagttatca ggcatgcacc tggtagctag 2220 tctttaaacc aatagattgc atcggtttaa aaggcaagac cgtcaaattg cgggaaaggg 2280 gtcaacagcc gttcagtacc aagtctcagg ggaaactttg agatggcctt gcaaagggta 2340 tggtaataag ctgacggaca tggtcctaac cacgcagcca agtcctaagt caacagatct 2400 tctgttgata tggatgcagt tcacagacta aatgtcggtc ggggaagatg tattcttctc 2460 ataagatata gtcggacctc tccttaatgg gagctagcgg atgaagtgat gcaacactgg 2520 agccgctggg aactaatttg tatgcgaaag tatattgatt agttttggag tactcgaaaa 2580 cgcccaccat ggcttcgtac ccctgccatc aacacgcgtc tgcgttcgac caggctgcgc 2640 gttctcgcgg ccatagcaac cgacgtacgg cgttgcgccc tcgccggcag caagaagcca 2700 cggaagtccg cctggagcag aaaatgccca cgctactgcg ggtttatata gacggtcctc 2760 acgggatggg gaaaaccacc accacgcaac tgctggtggc cctgggttcg cgcgacgata 2820 tcgtctacgt acccgagccg atgacttact ggcaggtgct gggggcttcc gagacaatcg 2880 cgaacatcta caccacacaa caccgcctcg accagggtga gatatcggcc ggggacgcgg 2940 cggtggtaat gacaagcgcc cagataacaa tgggcatgcc ttatgccgtg accgacgccg 3000 ttctggctcc tcatgtcggg ggggaggctg ggagttcaca tgccccgccc ccggccctca 3060 ccctcatctt cgaccgccat cccatcgccg ccctcctgtg ctacccggcc gcgcgatacc 3120 ttatgggcag catgaccccc caggccgtgc tggcgttcgt ggccctcatc ccgccgacct 3180 tgcccggcac aaacatcgtg ttgggggccc ttccggagga cagacacatc gaccgcctgg 3240 ccaaacgcca gcgccccggc gagcggcttg acctggctat gctggccgcg attcgccgcg 3300 tttacgggct gcttgccaat acggtgcggt atctgcaggg cggcgggtcg tggtgggagg 3360 attggggaca gctttcgggg acggccgtgc cgccccaggg tgccgagccc cagagcaacg 3420 cgggcccacg accccatatc ggggacacgt tatttaccct gtttcgggcc cccgagttgc 3480 tggcccccaa cggcgacctg tataacgtgt ttgcctgggc cttggacgtc ttggccaaac 3540 gcctccgtcc catgcacgtc tttatcctgg attacgacca atcgcccgcc ggctgccggg 3600 acgccctgct gcaacttacc tccgggatgg tccagaccca cgtcaccacc ccaggctcca 3660 taccgacgat ctgcgacctg gcgcgcacgt ttgcccggga gatgggggag gctaactgag 3720 gccggccgct tcgaaagatc ccaacgaaaa gagagaccac atggtccttc ttgagtttgt 3780 aacagctgct gggattacac atggcatgga tgaactgtac aactgaggat cccccgacct 3840 cgacctctgg ctaataaagg aaatttattt tcattgcaat agtgtgttgg aattttttgt 3900 gtctctcact cggaaggaca tatgggaggg caaatcattt ggtcgagatc cctcggagat 3960 cggatctggg cgtggttaag ggtgggaaag aatatataag gtgggggtct tatgtagttt 4020 tgtatctgtt ttgcagcagc cgccgccgcc atgagcacca actcgtttga tggaagcatt 4080 gtgagctcat atttgacaac gcgcatgccc ccatgggccg gggtgcgtca gaatgtgatg 4140 ggctccagca ttgatggtcg ccccgtcctg cccgcaaact ctactacctt gacctacgag 4200 accgtgtctg gaacgccgtt ggagactgca gcctccgccg ccgcttcagc cgctgcagcc 4260 accgcccgcg ggattgtgac tgactttgct ttcctgagcc cgcttgcaag cagtgcagct 4320 tcccgttcat ccgcccgcga tgacaagttg acggctcttt tggcacaatt ggattctttg 4380 acccgggaac ttaatgtcgt ttctcagcag ctgttggatc tgcgccagca ggtttctgcc 4440 ctgaaggctt cctcccctcc caatgcggtt taaaacataa ataaaaaacc agactctgtt 4500 tggatttgga tcaagcaagt gtcttgctgt ctttatttag gggttttgcg cgcgcggtag 4560 gcccgggacc agcggtctcg gtcgttgagg gtcctgtgta ttttttccag gacgtggtaa 4620 aggtgactct ggatgttcag atacatgggc ataagcccgt ctctggggtg gaggtagcac 4680 cactgcagag cttcatgctg cggggtggtg ttgtagatga tccagtcgta gcaggagcgc 4740 tgggcgtggt gcctaaaaat gtctttcagt agcaagctga ttgccagggg caggcccttg 4800 gtgtaagtgt ttacaaagcg gttaagctgg gatgggtgca tacgtgggga tatgagatgc 4860 atcttggact gtatttttag gttggctatg ttcccagcca tatccctccg gggattcatg 4920 ttgtgcagaa ccaccagcac agtgtatccg gtgcacttgg gaaatttgtc atgtagctta 4980 gaaggaaatg cgtggaagaa cttggagacg cccttgtgac ctccaagatt ttccatgcat 5040 tcgtccataa tgatggcaat gggcccacgg gcggcggcct gggcgaagat atttctggga 5100 tcactaacgt catagttgtg ttccaggatg agatcgtcat aggccatttt tacaaagcgc 5160 gggcggaggg tgccagactg cggtataatg gttccatccg gcccaggggc gtagttaccc 5220 tcacagattt gcatttccca cgctttgagt tcagatgggg ggatcatgtc tacctgcggg 5280 gcgatgaaga aaacggtttc cggggtaggg gagatcagct gggaagaaag caggttcctg 5340 agcagctgcg acttaccgca gccggtgggc ccgtaaatca cacctattac cgggtgcaac 5400 tggtagttaa gagagctgca gctgccgtca tccctgagca ggggggccac ttcgttaagc 5460 atgtccctga ctcgcatgtt ttccctgacc aaatccgcca gaaggcgctc gccgcccagc 5520 gatagcagtt cttgcaagga agcaaagttt ttcaacggtt tgagaccgtc cgccgtaggc 5580 atgcttttga gcgtttgacc aagcagttcc aggcggtccc acagctcggt cacctgctct 5640 acggcatctc gatccagcat atctcctcgt ttcgcgggtt ggggcggctt tcgctgtacg 5700 gcagtagtcg gtgctcgtcc agacgggcca gggtcatgtc tttccacggg cgcagggtcc 5760 tcgtcagcgt agtctgggtc acggtgaagg ggtgcgctcc gggctgcgcg ctggccaggg 5820 tgcgcttgag gctggtcctg ctggtgctga agcgctgccg gtcttcgccc tgcgcgtcgg 5880 ccaggtagca tttgaccatg gtgtcatagt ccagcccctc cgcggcgtgg cccttggcgc 5940 gcagcttgcc cttggaggag gcgccgcacg aggggcagtg cagacttttg agggcgtaga 6000 gcttgggcgc gagaaatacc gattccgggg agtaggcatc cgcgccgcag gccccgcaga 6060 cggtctcgca ttccacgagc caggtgagct ctggccgttc ggggtcaaaa accaggtttc 6120 ccccatgctt tttgatgcgt ttcttacctc tggtttccat gagccggtgt ccacgctcgg 6180 tgacgaaaag gctgtccgtg tccccgtata cagacttgag agggagttta aacgaattca 6240 atagcttgtt gcatgggcgg cgatataaaa tgcaaggtgc tgctcaaaaa atcaggcaaa 6300 gcctcgcgca aaaaagaaag cacatcgtag tcatgctcat gcagataaag gcaggtaagc 6360 tccggaacca ccacagaaaa agacaccatt tttctctcaa acatgtctgc gggtttctgc 6420 ataaacacaa aataaaataa caaaaaaaca tttaaacatt agaagcctgt cttacaacag 6480 gaaaaacaac ccttataagc ataagacgga ctacggccat gccggcgtga ccgtaaaaaa 6540 actggtcacc gtgattaaaa agcaccaccg acagctcctc ggtcatgtcc ggagtcataa 6600 tgtaagactc ggtaaacaca tcaggttgat tcatcggtca gtgctaaaaa gcgaccgaaa 6660 tagcccgggg gaatacatac ccgcaggcgt agagacaaca ttacagcccc cataggaggt 6720 ataacaaaat taataggaga gaaaaacaca taaacacctg aaaaaccctc ctgcctaggc 6780 aaaatagcac cctcccgctc cagaacaaca tacagcgctt cacagcggca gcctaacagt 6840 cagccttacc agtaaaaaag aaaacctatt aaaaaaacac cactcgacac ggcaccagct 6900 caatcagtca cagtgtaaaa aagggccaag tgcagagcga gtatatatag gactaaaaaa 6960 tgacgtaacg gttaaagtcc acaaaaaaca cccagaaaac cgcacgcgaa cctacgccca 7020 gaaacgaaag ccaaaaaacc cacaacttcc tcaaatcgtc acttccgttt tcccacgtta 7080 cgtaacttcc cattttaaga aaactacaat tcccaacaca tacaagttac tccgccctaa 7140 aacctacgtc acccgccccg ttcccacgcc ccgcgccacg tcacaaactc caccccctca 7200 ttatcatatt ggcttcaatc caaaataagg tatattattg atgatgttaa ttaacatgca 7260 tggatccata tgcggtgtga aataccgcac agatgcgtaa ggagaaaata ccgcatcagg 7320 cgctcttccg cttcctcgct cactgactcg ctgcgctcgg tcgttcggct gcggcgagcg 7380 gtatcagctc actcaaaggc ggtaatacgg ttatccacag aatcagggga taacgcagga 7440 aagaacatgt gagcaaaagg ccagcaaaag gccaggaacc gtaaaaaggc cgcgttgctg 7500 gcgtttttcc ataggctccg cccccctgac gagcatcaca aaaatcgacg ctcaagtcag 7560 aggtggcgaa acccgacagg actataaaga taccaggcgt ttccccctgg aagctccctc 7620 gtgcgctctc ctgttccgac cctgccgctt accggatacc tgtccgcctt tctcccttcg 7680 ggaagcgtgg cgctttctca tagctcacgc tgtaggtatc tcagttcggt gtaggtcgtt 7740 cgctccaagc tgggctgtgt gcacgaaccc cccgttcagc ccgaccgctg cgccttatcc 7800 ggtaactatc gtcttgagtc caacccggta agacacgact tatcgccact ggcagcagcc 7860 actggtaaca ggattagcag agcgaggtat gtaggcggtg ctacagagtt cttgaagtgg 7920 tggcctaact acggctacac tagaaggaca gtatttggta tctgcgctct gctgaagcca 7980 gttaccttcg gaaaaagagt tggtagctct tgatccggca aacaaaccac cgctggtagc 8040 ggtggttttt ttgtttgcaa gcagcagatt acgcgcagaa aaaaaggatc tcaagaagat 8100 cctttgatct tttctacggg gtctgacgct cagtggaacg aaaactcacg ttaagggatt 8160 ttggtcatga gattatcaaa aaggatcttc acctagatcc ttttaaatta aaaatgaagt 8220 tttaaatcaa tctaaagtat atatgagtaa acttggtctg acagttacca atgcttaatc 8280 agtgaggcac ctatctcagc gatctgtcta tttcgttcat ccatagttgc ctgactcccc 8340 gtcgtgtaga taactacgat acgggagggc ttaccatctg gccccagtgc tgcaatgata 8400 ccgcgagacc cacgctcacc ggctccagat ttatcagcaa taaaccagcc agccggaagg 8460 gccgagcgca gaagtggtcc tgcaacttta tccgcctcca tccagtctat taattgttgc 8520 cgggaagcta gagtaagtag ttcgccagtt aatagtttgc gcaacgttgt tgccattgct 8580 gcagccatga gattatcaaa aaggatcttc acctagatcc ttttcacgta gaaagccagt 8640 ccgcagaaac ggtgctgacc ccggatgaat gtcagctact gggctatctg gacaagggaa 8700 aacgcaagcg caaagagaaa gcaggtagct tgcagtgggc ttacatggcg atagctagac 8760 tgggcggttt tatggacagc aagcgaaccg gaattgccag ctggggcgcc ctctggtaag 8820 gttgggaagc cctgcaaagt aaactggatg gctttctcgc cgccaaggat ctgatggcgc 8880 aggggatcaa gctctgatca agagacagga tgaggatcgt ttcgcatgat tgaacaagat 8940 ggattgcacg caggttctcc ggccgcttgg gtggagaggc tattcggcta tgactgggca 9000 caacagacaa tcggctgctc tgatgccgcc gtgttccggc tgtcagcgca ggggcgcccg 9060 gttctttttg tcaagaccga cctgtccggt gccctgaatg aactgcaaga cgaggcagcg 9120 cggctatcgt ggctggccac gacgggcgtt ccttgcgcag ctgtgctcga cgttgtcact 9180 gaagcgggaa gggactggct gctattgggc gaagtgccgg ggcaggatct cctgtcatct 9240 caccttgctc ctgccgagaa agtatccatc atggctgatg caatgcggcg gctgcatacg 9300 cttgatccgg ctacctgccc attcgaccac caagcgaaac atcgcatcga gcgagcacgt 9360 actcggatgg aagccggtct tgtcgatcag gatgatctgg acgaagagca tcaggggctc 9420 gcgccagccg aactgttcgc caggctcaag gcgagcatgc ccgacggcga ggatctcgtc 9480 gtgacccatg gcgatgcctg cttgccgaat atcatggtgg aaaatggccg cttttctgga 9540 ttcatcgact gtggccggct gggtgtggcg gaccgctatc aggacatagc gttggctacc 9600 cgtgatattg ctgaagagct tggcggcgaa tgggctgacc gcttcctcgt gctttacggt 9660 atcgccgctc ccgattcgca gcgcatcgcc ttctatcgcc ttcttgacga gttcttctga 9720 attttgttaa aatttttgtt aaatcagctc attttttaac caataggccg aaatcggcaa 9780 catcccttat aaatcaaaag aatagaccgc gatagggttg agtgttgttc cagtttggaa 9840 caagagtcca ctattaaaga acgtggactc caacgtcaaa gggcgaaaaa ccgtctatca 9900 gggcgatggc ccactacgtg aaccatcacc caaatcaagt tttttgcggt cgaggtgccg 9960 taaagctcta aatcggaacc ctaaagggag cccccgattt agagcttgac ggggaaagcc 10020 ggcgaacgtg gcgagaaagg aagggaagaa agcgaaagga gcgggcgcta gggcgctggc 10080 aagtgtagcg gtcacgctgc gcgtaaccac cacacccgcg cgcttaatgc gccgctacag 10140 ggcgcgtcca ttcgccattc aggatcgaat taattcttaa t 10181 <210> 33 <211> 10130 <212> DNA <213> Artificial Sequence <220> <223> pAVQ SD/SA(del 61mer) CMV Ribozyme HSV-TK <400> 33 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 ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag ttattaatag taatcaatta 540 cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt acggtaaatg 600 gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg acgtatgttc 660 ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat ttacggtaaa 720 ctgcccactt ggcagtacat caagtgtatc atatgccaag tccgccccct attgacgtca 780 atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttacgg gactttccta 840 cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg ttttggcagt 900 acaccaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc caccccattg 960 acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa tgtcgtaata 1020 accccgcccc gttgacgcaa atgggcggta ggcgtgtacg gtgggaggtc tatataagca 1080 gagctcgttt agtgaaccgt cagatcctca ctctcttccg catcgctgtc tgcgagggcc 1140 agctgttggg ctcgcggttg aggacaaact cttcgcggtc tttccagtac tcttggatcg 1200 gaaacccgtc ggcctccgaa cggtactccg ccaccgaggg acctgagcca gtccgcatcg 1260 accggatcgg aaaacctctc gagaaaggcg tctaaccagt cacagtcgca aggtaggctg 1320 agcaccgtgg cgggcggcag cgggtggcgg tcggggttgt ttctggcgga ggtgctgctg 1380 atgatgtaat taaagtaggc ggtcttgagc cggcggatgg tcgaggtgag gtgtggcagg 1440 cttgagatcc agctgttggg gtgagtactc cctctcaaaa gcgggcatga cttctgcgct 1500 aagattgtca gtttccaaaa acgaggagga tttgatattc acctggcccg atctggccat 1560 acacttgagt gacaatgaca tccactttgc ctttctctcc acaggtgtcc actcccaggt 1620 ccaagtttgg aagatctgaa ctgaaaaacc agaaagttaa ctggtaagtt tagtcttttt 1680 gtcttttatt tcaggtcccg gatccggtgg tggtgcaaat caaagaactg ctcctcagtg 1740 gatgttgcct ttacttctag gcctaggctt ttgcaaaaag cttcgaatcg cgaaaggcca 1800 gcacgttctt cgcgccgcgc tcgcacagcc tctgcagcac tcgggccacc agctccttca 1860 ggcaggacac ctggcggaag gagggggcgg cggggggcgg ccgtgcgtcc cagggcacgc 1920 acaccaggca ctgggccacc agcgcgcgga aagccgccgg gtccccgcgc tgcaccagcc 1980 gccagccctg gggccccagg cgccgcacga acgtggccag cggcagcacc tcgcggtagt 2040 ggctgcgcag cagggagcgc acggctaggc agcggggagc gcgcggcatc gcgggggtgg 2100 ccggggccag ggcttcccaa gcttcgtttt gcggcaggaa aagttatcag gcatgcacct 2160 ggtagctagt ctttaaacca atagattgca tcggtttaaa aggcaagacc gtcaaattgc 2220 gggaaagggg tcaacagccg ttcagtacca agtctcaggg gaaactttga gatggccttg 2280 caaagggtat ggtaataagc tgacggacat ggtcctaacc acgcagccaa gtcctaagtc 2340 aacagatctt ctgttgatat ggatgcagtt cacagactaa atgtcggtcg gggaagatgt 2400 attcttctca taagatatag tcggacctct ccttaatggg agctagcgga tgaagtgatg 2460 caacactgga gccgctggga actaatttgt atgcgaaagt atattgatta gttttggagt 2520 actcgaaaac gcccaccatg gcttcgtacc cctgccatca acacgcgtct gcgttcgacc 2580 aggctgcgcg ttctcgcggc catagcaacc gacgtacggc gttgcgccct cgccggcagc 2640 aagaagccac ggaagtccgc ctggagcaga aaatgcccac gctactgcgg gtttatatag 2700 acggtcctca cgggatgggg aaaaccacca ccacgcaact gctggtggcc ctgggttcgc 2760 gcgacgatat cgtctacgta cccgagccga tgacttactg gcaggtgctg ggggcttccg 2820 agacaatcgc gaacatctac accacacaac accgcctcga ccagggtgag atatcggccg 2880 gggacgcggc ggtggtaatg acaagcgccc agataacaat gggcatgcct tatgccgtga 2940 ccgacgccgt tctggctcct catgtcgggg gggaggctgg gagttcacat gccccgcccc 3000 cggccctcac cctcatcttc gaccgccatc ccatcgccgc cctcctgtgc tacccggccg 3060 cgcgatacct tatgggcagc atgacccccc aggccgtgct ggcgttcgtg gccctcatcc 3120 cgccgacctt gcccggcaca aacatcgtgt tgggggccct tccggaggac agacacatcg 3180 accgcctggc caaacgccag cgccccggcg agcggcttga cctggctatg ctggccgcga 3240 ttcgccgcgt ttacgggctg cttgccaata cggtgcggta tctgcagggc ggcgggtcgt 3300 ggtgggagga ttggggacag ctttcgggga cggccgtgcc gccccagggt gccgagcccc 3360 agagcaacgc gggcccacga ccccatatcg gggacacgtt atttaccctg tttcgggccc 3420 ccgagttgct ggcccccaac ggcgacctgt ataacgtgtt tgcctgggcc ttggacgtct 3480 tggccaaacg cctccgtccc atgcacgtct ttatcctgga ttacgaccaa tcgcccgccg 3540 gctgccggga cgccctgctg caacttacct ccgggatggt ccagacccac gtcaccaccc 3600 caggctccat accgacgatc tgcgacctgg cgcgcacgtt tgcccgggag atgggggagg 3660 ctaactgagg ccggccgctt cgaaagatcc caacgaaaag agagaccaca tggtccttct 3720 tgagtttgta acagctgctg ggattacaca tggcatggat gaactgtaca actgaggatc 3780 ccccgacctc gacctctggc taataaagga aatttatttt cattgcaata gtgtgttgga 3840 attttttgtg tctctcactc ggaaggacat atgggagggc aaatcatttg gtcgagatcc 3900 ctcggagatc ggatctgggc gtggttaagg gtgggaaaga atatataagg tgggggtctt 3960 atgtagtttt gtatctgttt tgcagcagcc gccgccgcca tgagcaccaa ctcgtttgat 4020 ggaagcattg tgagctcata tttgacaacg cgcatgcccc catgggccgg ggtgcgtcag 4080 aatgtgatgg gctccagcat tgatggtcgc cccgtcctgc ccgcaaactc tactaccttg 4140 acctacgaga ccgtgtctgg aacgccgttg gagactgcag cctccgccgc cgcttcagcc 4200 gctgcagcca ccgcccgcgg gattgtgact gactttgctt tcctgagccc gcttgcaagc 4260 agtgcagctt cccgttcatc cgcccgcgat gacaagttga cggctctttt ggcacaattg 4320 gattctttga cccgggaact taatgtcgtt tctcagcagc tgttggatct gcgccagcag 4380 gtttctgccc tgaaggcttc ctcccctccc aatgcggttt aaaacataaa taaaaaacca 4440 gactctgttt ggatttggat caagcaagtg tcttgctgtc tttatttagg ggttttgcgc 4500 gcgcggtagg cccgggacca gcggtctcgg tcgttgaggg tcctgtgtat tttttccagg 4560 acgtggtaaa ggtgactctg gatgttcaga tacatgggca taagcccgtc tctggggtgg 4620 aggtagcacc actgcagagc ttcatgctgc ggggtggtgt tgtagatgat ccagtcgtag 4680 caggagcgct gggcgtggtg cctaaaaatg tctttcagta gcaagctgat tgccaggggc 4740 aggcccttgg tgtaagtgtt tacaaagcgg ttaagctggg atgggtgcat acgtggggat 4800 atgagatgca tcttggactg tatttttagg ttggctatgt tcccagccat atccctccgg 4860 ggattcatgt tgtgcagaac caccagcaca gtgtatccgg tgcacttggg aaatttgtca 4920 tgtagcttag aaggaaatgc gtggaagaac ttggagacgc ccttgtgacc tccaagattt 4980 tccatgcatt cgtccataat gatggcaatg ggcccacggg cggcggcctg ggcgaagata 5040 tttctgggat cactaacgtc atagttgtgt tccaggatga gatcgtcata ggccattttt 5100 acaaagcgcg ggcggagggt gccagactgc ggtataatgg ttccatccgg cccaggggcg 5160 tagttaccct cacagatttg catttcccac gctttgagtt cagatggggg gatcatgtct 5220 acctgcgggg cgatgaagaa aacggtttcc ggggtagggg agatcagctg ggaagaaagc 5280 aggttcctga gcagctgcga cttaccgcag ccggtgggcc cgtaaatcac acctattacc 5340 gggtgcaact ggtagttaag agagctgcag ctgccgtcat ccctgagcag gggggccact 5400 tcgttaagca tgtccctgac tcgcatgttt tccctgacca aatccgccag aaggcgctcg 5460 ccgcccagcg atagcagttc ttgcaaggaa gcaaagtttt tcaacggttt gagaccgtcc 5520 gccgtaggca tgcttttgag cgtttgacca agcagttcca ggcggtccca cagctcggtc 5580 acctgctcta cggcatctcg atccagcata tctcctcgtt tcgcgggttg gggcggcttt 5640 cgctgtacgg cagtagtcgg tgctcgtcca gacgggccag ggtcatgtct ttccacgggc 5700 gcagggtcct cgtcagcgta gtctgggtca cggtgaaggg gtgcgctccg ggctgcgcgc 5760 tggccagggt gcgcttgagg ctggtcctgc tggtgctgaa gcgctgccgg tcttcgccct 5820 gcgcgtcggc caggtagcat ttgaccatgg tgtcatagtc cagcccctcc gcggcgtggc 5880 ccttggcgcg cagcttgccc ttggaggagg cgccgcacga ggggcagtgc agacttttga 5940 gggcgtagag cttgggcgcg agaaataccg attccgggga gtaggcatcc gcgccgcagg 6000 ccccgcagac ggtctcgcat tccacgagcc aggtgagctc tggccgttcg gggtcaaaaa 6060 ccaggtttcc cccatgcttt ttgatgcgtt tcttacctct ggtttccatg agccggtgtc 6120 cacgctcggt gacgaaaagg ctgtccgtgt ccccgtatac agacttgaga gggagtttaa 6180 acgaattcaa tagcttgttg catgggcggc gatataaaat gcaaggtgct gctcaaaaaa 6240 tcaggcaaag cctcgcgcaa aaaagaaagc acatcgtagt catgctcatg cagataaagg 6300 caggtaagct ccggaaccac cacagaaaaa gacaccattt ttctctcaaa catgtctgcg 6360 ggtttctgca taaacacaaa ataaaataac aaaaaaacat ttaaacatta gaagcctgtc 6420 ttacaacagg aaaaacaacc cttataagca taagacggac tacggccatg ccggcgtgac 6480 cgtaaaaaaa ctggtcaccg tgattaaaaa gcaccaccga cagctcctcg gtcatgtccg 6540 gagtcataat gtaagactcg gtaaacacat caggttgatt catcggtcag tgctaaaaag 6600 cgaccgaaat agcccggggg aatacatacc cgcaggcgta gagacaacat tacagccccc 6660 ataggaggta taacaaaatt aataggagag aaaaacacat aaacacctga aaaaccctcc 6720 tgcctaggca aaatagcacc ctcccgctcc agaacaacat acagcgcttc acagcggcag 6780 cctaacagtc agccttacca gtaaaaaaga aaacctatta aaaaaacacc actcgacacg 6840 gcaccagctc aatcagtcac agtgtaaaaa agggccaagt gcagagcgag tatatatagg 6900 actaaaaaat gacgtaacgg ttaaagtcca caaaaaacac ccagaaaacc gcacgcgaac 6960 ctacgcccag aaacgaaagc caaaaaaccc acaacttcct caaatcgtca cttccgtttt 7020 cccacgttac gtaacttccc attttaagaa aactacaatt cccaacacat acaagttact 7080 ccgccctaaa acctacgtca cccgccccgt tcccacgccc cgcgccacgt cacaaactcc 7140 accccctcat tatcatattg gcttcaatcc aaaataaggt atattattga tgatgttaat 7200 taacatgcat ggatccatat gcggtgtgaa ataccgcaca gatgcgtaag gagaaaatac 7260 cgcatcaggc gctcttccgc ttcctcgctc actgactcgc tgcgctcggt cgttcggctg 7320 cggcgagcgg tatcagctca ctcaaaggcg gtaatacggt tatccacaga atcaggggat 7380 aacgcaggaa agaacatgtg agcaaaaggc cagcaaaagg ccaggaaccg taaaaaggcc 7440 gcgttgctgg cgtttttcca taggctccgc ccccctgacg agcatcacaa aaatcgacgc 7500 tcaagtcaga ggtggcgaaa cccgacagga ctataaagat accaggcgtt tccccctgga 7560 agctccctcg tgcgctctcc tgttccgacc ctgccgctta ccggatacct gtccgccttt 7620 ctcccttcgg gaagcgtggc gctttctcat agctcacgct gtaggtatct cagttcggtg 7680 taggtcgttc gctccaagct gggctgtgtg cacgaacccc ccgttcagcc cgaccgctgc 7740 gccttatccg gtaactatcg tcttgagtcc aacccggtaa gacacgactt atcgccactg 7800 gcagcagcca ctggtaacag gattagcaga gcgaggtatg taggcggtgc tacagagttc 7860 ttgaagtggt ggcctaacta cggctacact agaaggacag tatttggtat ctgcgctctg 7920 ctgaagccag ttaccttcgg aaaaagagtt ggtagctctt gatccggcaa acaaaccacc 7980 gctggtagcg gtggtttttt tgtttgcaag cagcagatta cgcgcagaaa aaaaggatct 8040 caagaagatc ctttgatctt ttctacgggg tctgacgctc agtggaacga aaactcacgt 8100 taagggattt tggtcatgag attatcaaaa aggatcttca cctagatcct tttaaattaa 8160 aaatgaagtt ttaaatcaat ctaaagtata tatgagtaaa cttggtctga cagttaccaa 8220 tgcttaatca gtgaggcacc tatctcagcg atctgtctat ttcgttcatc catagttgcc 8280 tgactccccg tcgtgtagat aactacgata cgggagggct taccatctgg ccccagtgct 8340 gcaatgatac cgcgagaccc acgctcaccg gctccagatt tatcagcaat aaaccagcca 8400 gccggaaggg ccgagcgcag aagtggtcct gcaactttat ccgcctccat ccagtctatt 8460 aattgttgcc gggaagctag agtaagtagt tcgccagtta atagtttgcg caacgttgtt 8520 gccattgctg cagccatgag attatcaaaa aggatcttca cctagatcct tttcacgtag 8580 aaagccagtc cgcagaaacg gtgctgaccc cggatgaatg tcagctactg ggctatctgg 8640 acaagggaaa acgcaagcgc aaagagaaag caggtagctt gcagtgggct tacatggcga 8700 tagctagact gggcggtttt atggacagca agcgaaccgg aattgccagc tggggcgccc 8760 tctggtaagg ttgggaagcc ctgcaaagta aactggatgg ctttctcgcc gccaaggatc 8820 tgatggcgca ggggatcaag ctctgatcaa gagacaggat gaggatcgtt tcgcatgatt 8880 gaacaagatg gattgcacgc aggttctccg gccgcttggg tggagaggct attcggctat 8940 gactgggcac aacagacaat cggctgctct gatgccgccg tgttccggct gtcagcgcag 9000 gggcgcccgg ttctttttgt caagaccgac ctgtccggtg ccctgaatga actgcaagac 9060 gaggcagcgc ggctatcgtg gctggccacg acgggcgttc cttgcgcagc tgtgctcgac 9120 gttgtcactg aagcgggaag ggactggctg ctattgggcg aagtgccggg gcaggatctc 9180 ctgtcatctc accttgctcc tgccgagaaa gtatccatca tggctgatgc aatgcggcgg 9240 ctgcatacgc ttgatccggc tacctgccca ttcgaccacc aagcgaaaca tcgcatcgag 9300 cgagcacgta ctcggatgga agccggtctt gtcgatcagg atgatctgga cgaagagcat 9360 caggggctcg cgccagccga actgttcgcc aggctcaagg cgagcatgcc cgacggcgag 9420 gatctcgtcg tgacccatgg cgatgcctgc ttgccgaata tcatggtgga aaatggccgc 9480 ttttctggat tcatcgactg tggccggctg ggtgtggcgg accgctatca ggacatagcg 9540 ttggctaccc gtgatattgc tgaagagctt ggcggcgaat gggctgaccg cttcctcgtg 9600 ctttacggta tcgccgctcc cgattcgcag cgcatcgcct tctatcgcct tcttgacgag 9660 ttcttctgaa ttttgttaaa atttttgtta aatcagctca ttttttaacc aataggccga 9720 aatcggcaac atcccttata aatcaaaaga atagaccgcg atagggttga gtgttgttcc 9780 agtttggaac aagagtccac tattaaagaa cgtggactcc aacgtcaaag ggcgaaaaac 9840 cgtctatcag ggcgatggcc cactacgtga accatcaccc aaatcaagtt ttttgcggtc 9900 gaggtgccgt aaagctctaa atcggaaccc taaagggagc ccccgattta gagcttgacg 9960 gggaaagccg gcgaacgtgg cgagaaagga agggaagaaa gcgaaaggag cgggcgctag 10020 ggcgctggca agtgtagcgg tcacgctgcg cgtaaccacc acacccgcgc gcttaatgcg 10080 ccgctacagg gcgcgtccat tcgccattca ggatcgaatt aattcttaat 10130 <210> 34 <211> 10571 <212> DNA <213> Artificial Sequence <220> <223> pAVQ CMV Ribozyme HSV-TK WPRE(forward) <400> 34 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 ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag ttattaatag taatcaatta 540 cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt acggtaaatg 600 gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg acgtatgttc 660 ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat ttacggtaaa 720 ctgcccactt ggcagtacat caagtgtatc atatgccaag tccgccccct attgacgtca 780 atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttacgg gactttccta 840 cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg ttttggcagt 900 acaccaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc caccccattg 960 acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa tgtcgtaata 1020 accccgcccc gttgacgcaa atgggcggta ggcgtgtacg gtgggaggtc tatataagca 1080 gagctcgttt agtgaaccgt cagatcctca ctctcttccg catcgctgtc tgcgagggcc 1140 agctgttggg ctcgcggttg aggacaaact cttcgcggtc tttccagtac tcttggatcg 1200 gaaacccgtc ggcctccgaa cggtactccg ccaccgaggg acctgagcca gtccgcatcg 1260 accggatcgg aaaacctctc gagaaaggcg tctaaccagt cacagtcgca aggtaggctg 1320 agcaccgtgg cgggcggcag cgggtggcgg tcggggttgt ttctggcgga ggtgctgctg 1380 atgatgtaat taaagtaggc ggtcttgagc cggcggatgg tcgaggtgag gtgtggcagg 1440 cttgagatcc agctgttggg gtgagtactc cctctcaaaa gcgggcatga cttctgcgct 1500 aagattgtca gtttccaaaa acgaggagga tttgatattc acctggcccg atctggccat 1560 acacttgagt gacaatgaca tccactttgc ctttctctcc acaggtgtcc actcccaggt 1620 ccaagtttgg aagatccaag gccagcacgt tcttcgcgcc gcgctcgcac agcctctgca 1680 gcactcgggc caccagctcc ttcaggcagg acacctggcg gaaggagggg gcggcggggg 1740 gcggccgtgc gtcccagggc acgcacacca ggcactgggc caccagcgcg cggaaagccg 1800 ccgggtcccc gcgctgcacc agccgccagc cctggggccc caggcgccgc acgaacgtgg 1860 ccagcggcag cacctcgcgg tagtggctgc gcagcaggga gcgcacggct aggcagcggg 1920 gagcgcgcgg catcgcgggg gtggccgggg ccagggcttc ccaagcttcg ttttgcggca 1980 ggaaaagtta tcaggcatgc acctggtagc tagtctttaa accaatagat tgcatcggtt 2040 taaaaggcaa gaccgtcaaa ttgcgggaaa ggggtcaaca gccgttcagt accaagtctc 2100 aggggaaact ttgagatggc cttgcaaagg gtatggtaat aagctgacgg acatggtcct 2160 aaccacgcag ccaagtccta agtcaacaga tcttctgttg atatggatgc agttcacaga 2220 ctaaatgtcg gtcggggaag atgtattctt ctcataagat atagtcggac ctctccttaa 2280 tgggagctag cggatgaagt gatgcaacac tggagccgct gggaactaat ttgtatgcga 2340 aagtatattg attagttttg gagtactcga aaacgcccac catggcttcg tacccctgcc 2400 atcaacacgc gtctgcgttc gaccaggctg cgcgttctcg cggccatagc aaccgacgta 2460 cggcgttgcg ccctcgccgg cagcaagaag ccacggaagt ccgcctggag cagaaaatgc 2520 ccacgctact gcgggtttat atagacggtc ctcacgggat ggggaaaacc accaccacgc 2580 aactgctggt ggccctgggt tcgcgcgacg atatcgtcta cgtacccgag ccgatgactt 2640 actggcaggt gctgggggct tccgagacaa tcgcgaacat ctacaccaca caacaccgcc 2700 tcgaccaggg tgagatatcg gccggggacg cggcggtggt aatgacaagc gcccagataa 2760 caatgggcat gccttatgcc gtgaccgacg ccgttctggc tcctcatgtc gggggggagg 2820 ctgggagttc acatgccccg cccccggccc tcaccctcat cttcgaccgc catcccatcg 2880 ccgccctcct gtgctacccg gccgcgcgat accttatggg cagcatgacc ccccaggccg 2940 tgctggcgtt cgtggccctc atcccgccga ccttgcccgg cacaaacatc gtgttggggg 3000 cccttccgga ggacagacac atcgaccgcc tggccaaacg ccagcgcccc ggcgagcggc 3060 ttgacctggc tatgctggcc gcgattcgcc gcgtttacgg gctgcttgcc aatacggtgc 3120 ggtatctgca gggcggcggg tcgtggtggg aggattgggg acagctttcg gggacggccg 3180 tgccgcccca gggtgccgag ccccagagca acgcgggccc acgaccccat atcggggaca 3240 cgttatttac cctgtttcgg gcccccgagt tgctggcccc caacggcgac ctgtataacg 3300 tgtttgcctg ggccttggac gtcttggcca aacgcctccg tcccatgcac gtctttatcc 3360 tggattacga ccaatcgccc gccggctgcc gggacgccct gctgcaactt acctccggga 3420 tggtccagac ccacgtcacc accccaggct ccataccgac gatctgcgac ctggcgcgca 3480 cgtttgcccg ggagatgggg gaggctaact gaggccggcc aatcaacctc tggattacaa 3540 aatttgtgaa agattgactg gtattcttaa ctatgttgct ccttttacgc tatgtggata 3600 cgctgcttta atgcctttgt atcatgctat tgcttcccgt atggctttca ttttctcctc 3660 cttgtataaa tcctggttgc tgtctcttta tgaggagttg tggcccgttg tcaggcaacg 3720 tggcgtggtg tgcactgtgt ttgctgacgc aacccccact ggttggggca ttgccaccac 3780 ctgtcagctc ctttccggga ctttcgcttt ccccctccct attgccacgg cggaactcat 3840 cgccgcctgc cttgcccgct gctggacagg ggctcggctg ttgggcactg acaattccgt 3900 ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc gcctgtgttg ccacctggat 3960 tctgcgcggg acgtccttct gctacgtccc ttcggccctc aatccagcgg accttccttc 4020 ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt cgccttcgcc ctcagacgag 4080 tcggatctcc ctttgggccg cctccccgcg gccggccgct tcgaaagatc ccaacgaaaa 4140 gagagaccac atggtccttc ttgagtttgt aacagctgct gggattacac atggcatgga 4200 tgaactgtac aactgaggat cccccgacct cgacctctgg ctaataaagg aaatttattt 4260 tcattgcaat agtgtgttgg aattttttgt gtctctcact cggaaggaca tatgggaggg 4320 caaatcattt ggtcgagatc cctcggagat cggatctggg cgtggttaag ggtgggaaag 4380 aatatataag gtgggggtct tatgtagttt tgtatctgtt ttgcagcagc cgccgccgcc 4440 atgagcacca actcgtttga tggaagcatt gtgagctcat atttgacaac gcgcatgccc 4500 ccatgggccg gggtgcgtca gaatgtgatg ggctccagca ttgatggtcg ccccgtcctg 4560 cccgcaaact ctactacctt gacctacgag accgtgtctg gaacgccgtt ggagactgca 4620 gcctccgccg ccgcttcagc cgctgcagcc accgcccgcg ggattgtgac tgactttgct 4680 ttcctgagcc cgcttgcaag cagtgcagct tcccgttcat ccgcccgcga tgacaagttg 4740 acggctcttt tggcacaatt ggattctttg acccgggaac ttaatgtcgt ttctcagcag 4800 ctgttggatc tgcgccagca ggtttctgcc ctgaaggctt cctcccctcc caatgcggtt 4860 taaaacataa ataaaaaacc agactctgtt tggatttgga tcaagcaagt gtcttgctgt 4920 ctttatttag gggttttgcg cgcgcggtag gcccgggacc agcggtctcg gtcgttgagg 4980 gtcctgtgta ttttttccag gacgtggtaa aggtgactct ggatgttcag atacatgggc 5040 ataagcccgt ctctggggtg gaggtagcac cactgcagag cttcatgctg cggggtggtg 5100 ttgtagatga tccagtcgta gcaggagcgc tgggcgtggt gcctaaaaat gtctttcagt 5160 agcaagctga ttgccagggg caggcccttg gtgtaagtgt ttacaaagcg gttaagctgg 5220 gatgggtgca tacgtgggga tatgagatgc atcttggact gtatttttag gttggctatg 5280 ttcccagcca tatccctccg gggattcatg ttgtgcagaa ccaccagcac agtgtatccg 5340 gtgcacttgg gaaatttgtc atgtagctta gaaggaaatg cgtggaagaa cttggagacg 5400 cccttgtgac ctccaagatt ttccatgcat tcgtccataa tgatggcaat gggcccacgg 5460 gcggcggcct gggcgaagat atttctggga tcactaacgt catagttgtg ttccaggatg 5520 agatcgtcat aggccatttt tacaaagcgc gggcggaggg tgccagactg cggtataatg 5580 gttccatccg gcccaggggc gtagttaccc tcacagattt gcatttccca cgctttgagt 5640 tcagatgggg ggatcatgtc tacctgcggg gcgatgaaga aaacggtttc cggggtaggg 5700 gagatcagct gggaagaaag caggttcctg agcagctgcg acttaccgca gccggtgggc 5760 ccgtaaatca cacctattac cgggtgcaac tggtagttaa gagagctgca gctgccgtca 5820 tccctgagca ggggggccac ttcgttaagc atgtccctga ctcgcatgtt ttccctgacc 5880 aaatccgcca gaaggcgctc gccgcccagc gatagcagtt cttgcaagga agcaaagttt 5940 ttcaacggtt tgagaccgtc cgccgtaggc atgcttttga gcgtttgacc aagcagttcc 6000 aggcggtccc acagctcggt cacctgctct acggcatctc gatccagcat atctcctcgt 6060 ttcgcgggtt ggggcggctt tcgctgtacg gcagtagtcg gtgctcgtcc agacgggcca 6120 gggtcatgtc tttccacggg cgcagggtcc tcgtcagcgt agtctgggtc acggtgaagg 6180 ggtgcgctcc gggctgcgcg ctggccaggg tgcgcttgag gctggtcctg ctggtgctga 6240 agcgctgccg gtcttcgccc tgcgcgtcgg ccaggtagca tttgaccatg gtgtcatagt 6300 ccagcccctc cgcggcgtgg cccttggcgc gcagcttgcc cttggaggag gcgccgcacg 6360 aggggcagtg cagacttttg agggcgtaga gcttgggcgc gagaaatacc gattccgggg 6420 agtaggcatc cgcgccgcag gccccgcaga cggtctcgca ttccacgagc caggtgagct 6480 ctggccgttc ggggtcaaaa accaggtttc ccccatgctt tttgatgcgt ttcttacctc 6540 tggtttccat gagccggtgt ccacgctcgg tgacgaaaag gctgtccgtg tccccgtata 6600 cagacttgag agggagttta aacgaattca atagcttgtt gcatgggcgg cgatataaaa 6660 tgcaaggtgc tgctcaaaaa atcaggcaaa gcctcgcgca aaaaagaaag cacatcgtag 6720 tcatgctcat gcagataaag gcaggtaagc tccggaacca ccacagaaaa agacaccatt 6780 tttctctcaa acatgtctgc gggtttctgc ataaacacaa aataaaataa caaaaaaaca 6840 tttaaacatt agaagcctgt cttacaacag gaaaaacaac ccttataagc ataagacgga 6900 ctacggccat gccggcgtga ccgtaaaaaa actggtcacc gtgattaaaa agcaccaccg 6960 acagctcctc ggtcatgtcc ggagtcataa tgtaagactc ggtaaacaca tcaggttgat 7020 tcatcggtca gtgctaaaaa gcgaccgaaa tagcccgggg gaatacatac ccgcaggcgt 7080 agagacaaca ttacagcccc cataggaggt ataacaaaat taataggaga gaaaaacaca 7140 taaacacctg aaaaaccctc ctgcctaggc aaaatagcac cctcccgctc cagaacaaca 7200 tacagcgctt cacagcggca gcctaacagt cagccttacc agtaaaaaag aaaacctatt 7260 aaaaaaacac cactcgacac ggcaccagct caatcagtca cagtgtaaaa aagggccaag 7320 tgcagagcga gtatatatag gactaaaaaa tgacgtaacg gttaaagtcc acaaaaaaca 7380 cccagaaaac cgcacgcgaa cctacgccca gaaacgaaag ccaaaaaacc cacaacttcc 7440 tcaaatcgtc acttccgttt tcccacgtta cgtaacttcc cattttaaga aaactacaat 7500 tcccaacaca tacaagttac tccgccctaa aacctacgtc acccgccccg ttcccacgcc 7560 ccgcgccacg tcacaaactc caccccctca ttatcatatt ggcttcaatc caaaataagg 7620 tatattattg atgatgttaa ttaacatgca tggatccata tgcggtgtga aataccgcac 7680 agatgcgtaa ggagaaaata ccgcatcagg cgctcttccg cttcctcgct cactgactcg 7740 ctgcgctcgg tcgttcggct gcggcgagcg gtatcagctc actcaaaggc ggtaatacgg 7800 ttatccacag aatcagggga taacgcagga aagaacatgt gagcaaaagg ccagcaaaag 7860 gccaggaacc gtaaaaaggc cgcgttgctg gcgtttttcc ataggctccg cccccctgac 7920 gagcatcaca aaaatcgacg ctcaagtcag aggtggcgaa acccgacagg actataaaga 7980 taccaggcgt ttccccctgg aagctccctc gtgcgctctc ctgttccgac cctgccgctt 8040 accggatacc tgtccgcctt tctcccttcg ggaagcgtgg cgctttctca tagctcacgc 8100 tgtaggtatc tcagttcggt gtaggtcgtt cgctccaagc tgggctgtgt gcacgaaccc 8160 cccgttcagc ccgaccgctg cgccttatcc ggtaactatc gtcttgagtc caacccggta 8220 agacacgact tatcgccact ggcagcagcc actggtaaca ggattagcag agcgaggtat 8280 gtaggcggtg ctacagagtt cttgaagtgg tggcctaact acggctacac tagaaggaca 8340 gtatttggta tctgcgctct gctgaagcca gttaccttcg gaaaaagagt tggtagctct 8400 tgatccggca aacaaaccac cgctggtagc ggtggttttt ttgtttgcaa gcagcagatt 8460 acgcgcagaa aaaaaggatc tcaagaagat cctttgatct tttctacggg gtctgacgct 8520 cagtggaacg aaaactcacg ttaagggatt ttggtcatga gattatcaaa aaggatcttc 8580 acctagatcc ttttaaatta aaaatgaagt tttaaatcaa tctaaagtat atatgagtaa 8640 acttggtctg acagttacca atgcttaatc agtgaggcac ctatctcagc gatctgtcta 8700 tttcgttcat ccatagttgc ctgactcccc gtcgtgtaga taactacgat acgggagggc 8760 ttaccatctg gccccagtgc tgcaatgata ccgcgagacc cacgctcacc ggctccagat 8820 ttatcagcaa taaaccagcc agccggaagg gccgagcgca gaagtggtcc tgcaacttta 8880 tccgcctcca tccagtctat taattgttgc cgggaagcta gagtaagtag ttcgccagtt 8940 aatagtttgc gcaacgttgt tgccattgct gcagccatga gattatcaaa aaggatcttc 9000 acctagatcc ttttcacgta gaaagccagt ccgcagaaac ggtgctgacc ccggatgaat 9060 gtcagctact gggctatctg gacaagggaa aacgcaagcg caaagagaaa gcaggtagct 9120 tgcagtgggc ttacatggcg atagctagac tgggcggttt tatggacagc aagcgaaccg 9180 gaattgccag ctggggcgcc ctctggtaag gttgggaagc cctgcaaagt aaactggatg 9240 gctttctcgc cgccaaggat ctgatggcgc aggggatcaa gctctgatca agagacagga 9300 tgaggatcgt ttcgcatgat tgaacaagat ggattgcacg caggttctcc ggccgcttgg 9360 gtggagaggc tattcggcta tgactgggca caacagacaa tcggctgctc tgatgccgcc 9420 gtgttccggc tgtcagcgca ggggcgcccg gttctttttg tcaagaccga cctgtccggt 9480 gccctgaatg aactgcaaga cgaggcagcg cggctatcgt ggctggccac gacgggcgtt 9540 ccttgcgcag ctgtgctcga cgttgtcact gaagcgggaa gggactggct gctattgggc 9600 gaagtgccgg ggcaggatct cctgtcatct caccttgctc ctgccgagaa agtatccatc 9660 atggctgatg caatgcggcg gctgcatacg cttgatccgg ctacctgccc attcgaccac 9720 caagcgaaac atcgcatcga gcgagcacgt actcggatgg aagccggtct tgtcgatcag 9780 gatgatctgg acgaagagca tcaggggctc gcgccagccg aactgttcgc caggctcaag 9840 gcgagcatgc ccgacggcga ggatctcgtc gtgacccatg gcgatgcctg cttgccgaat 9900 atcatggtgg aaaatggccg cttttctgga ttcatcgact gtggccggct gggtgtggcg 9960 gaccgctatc aggacatagc gttggctacc cgtgatattg ctgaagagct tggcggcgaa 10020 tgggctgacc gcttcctcgt gctttacggt atcgccgctc ccgattcgca gcgcatcgcc 10080 ttctatcgcc ttcttgacga gttcttctga attttgttaa aatttttgtt aaatcagctc 10140 attttttaac caataggccg aaatcggcaa catcccttat aaatcaaaag aatagaccgc 10200 gatagggttg agtgttgttc cagtttggaa caagagtcca ctattaaaga acgtggactc 10260 caacgtcaaa gggcgaaaaa ccgtctatca gggcgatggc ccactacgtg aaccatcacc 10320 caaatcaagt tttttgcggt cgaggtgccg taaagctcta aatcggaacc ctaaagggag 10380 cccccgattt agagcttgac ggggaaagcc ggcgaacgtg gcgagaaagg aagggaagaa 10440 agcgaaagga gcgggcgcta gggcgctggc aagtgtagcg gtcacgctgc gcgtaaccac 10500 cacacccgcg cgcttaatgc gccgctacag ggcgcgtcca ttcgccattc aggatcgaat 10560 taattcttaa t 10571 <210> 35 <211> 10571 <212> DNA <213> Artificial Sequence <220> <223> pAVQ CMV Ribozyme HSV-TK WPRE(reverse) <400> 35 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 ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag ttattaatag taatcaatta 540 cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt acggtaaatg 600 gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg acgtatgttc 660 ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat ttacggtaaa 720 ctgcccactt ggcagtacat caagtgtatc atatgccaag tccgccccct attgacgtca 780 atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttacgg gactttccta 840 cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg ttttggcagt 900 acaccaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc caccccattg 960 acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa tgtcgtaata 1020 accccgcccc gttgacgcaa atgggcggta ggcgtgtacg gtgggaggtc tatataagca 1080 gagctcgttt agtgaaccgt cagatcctca ctctcttccg catcgctgtc tgcgagggcc 1140 agctgttggg ctcgcggttg aggacaaact cttcgcggtc tttccagtac tcttggatcg 1200 gaaacccgtc ggcctccgaa cggtactccg ccaccgaggg acctgagcca gtccgcatcg 1260 accggatcgg aaaacctctc gagaaaggcg tctaaccagt cacagtcgca aggtaggctg 1320 agcaccgtgg cgggcggcag cgggtggcgg tcggggttgt ttctggcgga ggtgctgctg 1380 atgatgtaat taaagtaggc ggtcttgagc cggcggatgg tcgaggtgag gtgtggcagg 1440 cttgagatcc agctgttggg gtgagtactc cctctcaaaa gcgggcatga cttctgcgct 1500 aagattgtca gtttccaaaa acgaggagga tttgatattc acctggcccg atctggccat 1560 acacttgagt gacaatgaca tccactttgc ctttctctcc acaggtgtcc actcccaggt 1620 ccaagtttgg aagatccaag gccagcacgt tcttcgcgcc gcgctcgcac agcctctgca 1680 gcactcgggc caccagctcc ttcaggcagg acacctggcg gaaggagggg gcggcggggg 1740 gcggccgtgc gtcccagggc acgcacacca ggcactgggc caccagcgcg cggaaagccg 1800 ccgggtcccc gcgctgcacc agccgccagc cctggggccc caggcgccgc acgaacgtgg 1860 ccagcggcag cacctcgcgg tagtggctgc gcagcaggga gcgcacggct aggcagcggg 1920 gagcgcgcgg catcgcgggg gtggccgggg ccagggcttc ccaagcttcg ttttgcggca 1980 ggaaaagtta tcaggcatgc acctggtagc tagtctttaa accaatagat tgcatcggtt 2040 taaaaggcaa gaccgtcaaa ttgcgggaaa ggggtcaaca gccgttcagt accaagtctc 2100 aggggaaact ttgagatggc cttgcaaagg gtatggtaat aagctgacgg acatggtcct 2160 aaccacgcag ccaagtccta agtcaacaga tcttctgttg atatggatgc agttcacaga 2220 ctaaatgtcg gtcggggaag atgtattctt ctcataagat atagtcggac ctctccttaa 2280 tgggagctag cggatgaagt gatgcaacac tggagccgct gggaactaat ttgtatgcga 2340 aagtatattg attagttttg gagtactcga aaacgcccac catggcttcg tacccctgcc 2400 atcaacacgc gtctgcgttc gaccaggctg cgcgttctcg cggccatagc aaccgacgta 2460 cggcgttgcg ccctcgccgg cagcaagaag ccacggaagt ccgcctggag cagaaaatgc 2520 ccacgctact gcgggtttat atagacggtc ctcacgggat ggggaaaacc accaccacgc 2580 aactgctggt ggccctgggt tcgcgcgacg atatcgtcta cgtacccgag ccgatgactt 2640 actggcaggt gctgggggct tccgagacaa tcgcgaacat ctacaccaca caacaccgcc 2700 tcgaccaggg tgagatatcg gccggggacg cggcggtggt aatgacaagc gcccagataa 2760 caatgggcat gccttatgcc gtgaccgacg ccgttctggc tcctcatgtc gggggggagg 2820 ctgggagttc acatgccccg cccccggccc tcaccctcat cttcgaccgc catcccatcg 2880 ccgccctcct gtgctacccg gccgcgcgat accttatggg cagcatgacc ccccaggccg 2940 tgctggcgtt cgtggccctc atcccgccga ccttgcccgg cacaaacatc gtgttggggg 3000 cccttccgga ggacagacac atcgaccgcc tggccaaacg ccagcgcccc ggcgagcggc 3060 ttgacctggc tatgctggcc gcgattcgcc gcgtttacgg gctgcttgcc aatacggtgc 3120 ggtatctgca gggcggcggg tcgtggtggg aggattgggg acagctttcg gggacggccg 3180 tgccgcccca gggtgccgag ccccagagca acgcgggccc acgaccccat atcggggaca 3240 cgttatttac cctgtttcgg gcccccgagt tgctggcccc caacggcgac ctgtataacg 3300 tgtttgcctg ggccttggac gtcttggcca aacgcctccg tcccatgcac gtctttatcc 3360 tggattacga ccaatcgccc gccggctgcc gggacgccct gctgcaactt acctccggga 3420 tggtccagac ccacgtcacc accccaggct ccataccgac gatctgcgac ctggcgcgca 3480 cgtttgcccg ggagatgggg gaggctaact gaggccggcc gcggggaggc ggcccaaagg 3540 gagatccgac tcgtctgagg gcgaaggcga agacgcggaa gaggccgcag agccggcagc 3600 aggccgcggg aaggaaggtc cgctggattg agggccgaag ggacgtagca gaaggacgtc 3660 ccgcgcagaa tccaggtggc aacacaggcg agcagccaag gaaaggacga tgatttcccc 3720 gacaacacca cggaattgtc agtgcccaac agccgagccc ctgtccagca gcgggcaagg 3780 caggcggcga tgagttccgc cgtggcaata gggaggggga aagcgaaagt cccggaaagg 3840 agctgacagg tggtggcaat gccccaacca gtgggggttg cgtcagcaaa cacagtgcac 3900 accacgccac gttgcctgac aacgggccac aactcctcat aaagagacag caaccaggat 3960 ttatacaagg aggagaaaat gaaagccata cgggaagcaa tagcatgata caaaggcatt 4020 aaagcagcgt atccacatag cgtaaaagga gcaacatagt taagaatacc agtcaatctt 4080 tcacaaattt tgtaatccag aggttgattg gccggccgct tcgaaagatc ccaacgaaaa 4140 gagagaccac atggtccttc ttgagtttgt aacagctgct gggattacac atggcatgga 4200 tgaactgtac aactgaggat cccccgacct cgacctctgg ctaataaagg aaatttattt 4260 tcattgcaat agtgtgttgg aattttttgt gtctctcact cggaaggaca tatgggaggg 4320 caaatcattt ggtcgagatc cctcggagat cggatctggg cgtggttaag ggtgggaaag 4380 aatatataag gtgggggtct tatgtagttt tgtatctgtt ttgcagcagc cgccgccgcc 4440 atgagcacca actcgtttga tggaagcatt gtgagctcat atttgacaac gcgcatgccc 4500 ccatgggccg gggtgcgtca gaatgtgatg ggctccagca ttgatggtcg ccccgtcctg 4560 cccgcaaact ctactacctt gacctacgag accgtgtctg gaacgccgtt ggagactgca 4620 gcctccgccg ccgcttcagc cgctgcagcc accgcccgcg ggattgtgac tgactttgct 4680 ttcctgagcc cgcttgcaag cagtgcagct tcccgttcat ccgcccgcga tgacaagttg 4740 acggctcttt tggcacaatt ggattctttg acccgggaac ttaatgtcgt ttctcagcag 4800 ctgttggatc tgcgccagca ggtttctgcc ctgaaggctt cctcccctcc caatgcggtt 4860 taaaacataa ataaaaaacc agactctgtt tggatttgga tcaagcaagt gtcttgctgt 4920 ctttatttag gggttttgcg cgcgcggtag gcccgggacc agcggtctcg gtcgttgagg 4980 gtcctgtgta ttttttccag gacgtggtaa aggtgactct ggatgttcag atacatgggc 5040 ataagcccgt ctctggggtg gaggtagcac cactgcagag cttcatgctg cggggtggtg 5100 ttgtagatga tccagtcgta gcaggagcgc tgggcgtggt gcctaaaaat gtctttcagt 5160 agcaagctga ttgccagggg caggcccttg gtgtaagtgt ttacaaagcg gttaagctgg 5220 gatgggtgca tacgtgggga tatgagatgc atcttggact gtatttttag gttggctatg 5280 ttcccagcca tatccctccg gggattcatg ttgtgcagaa ccaccagcac agtgtatccg 5340 gtgcacttgg gaaatttgtc atgtagctta gaaggaaatg cgtggaagaa cttggagacg 5400 cccttgtgac ctccaagatt ttccatgcat tcgtccataa tgatggcaat gggcccacgg 5460 gcggcggcct gggcgaagat atttctggga tcactaacgt catagttgtg ttccaggatg 5520 agatcgtcat aggccatttt tacaaagcgc gggcggaggg tgccagactg cggtataatg 5580 gttccatccg gcccaggggc gtagttaccc tcacagattt gcatttccca cgctttgagt 5640 tcagatgggg ggatcatgtc tacctgcggg gcgatgaaga aaacggtttc cggggtaggg 5700 gagatcagct gggaagaaag caggttcctg agcagctgcg acttaccgca gccggtgggc 5760 ccgtaaatca cacctattac cgggtgcaac tggtagttaa gagagctgca gctgccgtca 5820 tccctgagca ggggggccac ttcgttaagc atgtccctga ctcgcatgtt ttccctgacc 5880 aaatccgcca gaaggcgctc gccgcccagc gatagcagtt cttgcaagga agcaaagttt 5940 ttcaacggtt tgagaccgtc cgccgtaggc atgcttttga gcgtttgacc aagcagttcc 6000 aggcggtccc acagctcggt cacctgctct acggcatctc gatccagcat atctcctcgt 6060 ttcgcgggtt ggggcggctt tcgctgtacg gcagtagtcg gtgctcgtcc agacgggcca 6120 gggtcatgtc tttccacggg cgcagggtcc tcgtcagcgt agtctgggtc acggtgaagg 6180 ggtgcgctcc gggctgcgcg ctggccaggg tgcgcttgag gctggtcctg ctggtgctga 6240 agcgctgccg gtcttcgccc tgcgcgtcgg ccaggtagca tttgaccatg gtgtcatagt 6300 ccagcccctc cgcggcgtgg cccttggcgc gcagcttgcc cttggaggag gcgccgcacg 6360 aggggcagtg cagacttttg agggcgtaga gcttgggcgc gagaaatacc gattccgggg 6420 agtaggcatc cgcgccgcag gccccgcaga cggtctcgca ttccacgagc caggtgagct 6480 ctggccgttc ggggtcaaaa accaggtttc ccccatgctt tttgatgcgt ttcttacctc 6540 tggtttccat gagccggtgt ccacgctcgg tgacgaaaag gctgtccgtg tccccgtata 6600 cagacttgag agggagttta aacgaattca atagcttgtt gcatgggcgg cgatataaaa 6660 tgcaaggtgc tgctcaaaaa atcaggcaaa gcctcgcgca aaaaagaaag cacatcgtag 6720 tcatgctcat gcagataaag gcaggtaagc tccggaacca ccacagaaaa agacaccatt 6780 tttctctcaa acatgtctgc gggtttctgc ataaacacaa aataaaataa caaaaaaaca 6840 tttaaacatt agaagcctgt cttacaacag gaaaaacaac ccttataagc ataagacgga 6900 ctacggccat gccggcgtga ccgtaaaaaa actggtcacc gtgattaaaa agcaccaccg 6960 acagctcctc ggtcatgtcc ggagtcataa tgtaagactc ggtaaacaca tcaggttgat 7020 tcatcggtca gtgctaaaaa gcgaccgaaa tagcccgggg gaatacatac ccgcaggcgt 7080 agagacaaca ttacagcccc cataggaggt ataacaaaat taataggaga gaaaaacaca 7140 taaacacctg aaaaaccctc ctgcctaggc aaaatagcac cctcccgctc cagaacaaca 7200 tacagcgctt cacagcggca gcctaacagt cagccttacc agtaaaaaag aaaacctatt 7260 aaaaaaacac cactcgacac ggcaccagct caatcagtca cagtgtaaaa aagggccaag 7320 tgcagagcga gtatatatag gactaaaaaa tgacgtaacg gttaaagtcc acaaaaaaca 7380 cccagaaaac cgcacgcgaa cctacgccca gaaacgaaag ccaaaaaacc cacaacttcc 7440 tcaaatcgtc acttccgttt tcccacgtta cgtaacttcc cattttaaga aaactacaat 7500 tcccaacaca tacaagttac tccgccctaa aacctacgtc acccgccccg ttcccacgcc 7560 ccgcgccacg tcacaaactc caccccctca ttatcatatt ggcttcaatc caaaataagg 7620 tatattattg atgatgttaa ttaacatgca tggatccata tgcggtgtga aataccgcac 7680 agatgcgtaa ggagaaaata ccgcatcagg cgctcttccg cttcctcgct cactgactcg 7740 ctgcgctcgg tcgttcggct gcggcgagcg gtatcagctc actcaaaggc ggtaatacgg 7800 ttatccacag aatcagggga taacgcagga aagaacatgt gagcaaaagg ccagcaaaag 7860 gccaggaacc gtaaaaaggc cgcgttgctg gcgtttttcc ataggctccg cccccctgac 7920 gagcatcaca aaaatcgacg ctcaagtcag aggtggcgaa acccgacagg actataaaga 7980 taccaggcgt ttccccctgg aagctccctc gtgcgctctc ctgttccgac cctgccgctt 8040 accggatacc tgtccgcctt tctcccttcg ggaagcgtgg cgctttctca tagctcacgc 8100 tgtaggtatc tcagttcggt gtaggtcgtt cgctccaagc tgggctgtgt gcacgaaccc 8160 cccgttcagc ccgaccgctg cgccttatcc ggtaactatc gtcttgagtc caacccggta 8220 agacacgact tatcgccact ggcagcagcc actggtaaca ggattagcag agcgaggtat 8280 gtaggcggtg ctacagagtt cttgaagtgg tggcctaact acggctacac tagaaggaca 8340 gtatttggta tctgcgctct gctgaagcca gttaccttcg gaaaaagagt tggtagctct 8400 tgatccggca aacaaaccac cgctggtagc ggtggttttt ttgtttgcaa gcagcagatt 8460 acgcgcagaa aaaaaggatc tcaagaagat cctttgatct tttctacggg gtctgacgct 8520 cagtggaacg aaaactcacg ttaagggatt ttggtcatga gattatcaaa aaggatcttc 8580 acctagatcc ttttaaatta aaaatgaagt tttaaatcaa tctaaagtat atatgagtaa 8640 acttggtctg acagttacca atgcttaatc agtgaggcac ctatctcagc gatctgtcta 8700 tttcgttcat ccatagttgc ctgactcccc gtcgtgtaga taactacgat acgggagggc 8760 ttaccatctg gccccagtgc tgcaatgata ccgcgagacc cacgctcacc ggctccagat 8820 ttatcagcaa taaaccagcc agccggaagg gccgagcgca gaagtggtcc tgcaacttta 8880 tccgcctcca tccagtctat taattgttgc cgggaagcta gagtaagtag ttcgccagtt 8940 aatagtttgc gcaacgttgt tgccattgct gcagccatga gattatcaaa aaggatcttc 9000 acctagatcc ttttcacgta gaaagccagt ccgcagaaac ggtgctgacc ccggatgaat 9060 gtcagctact gggctatctg gacaagggaa aacgcaagcg caaagagaaa gcaggtagct 9120 tgcagtgggc ttacatggcg atagctagac tgggcggttt tatggacagc aagcgaaccg 9180 gaattgccag ctggggcgcc ctctggtaag gttgggaagc cctgcaaagt aaactggatg 9240 gctttctcgc cgccaaggat ctgatggcgc aggggatcaa gctctgatca agagacagga 9300 tgaggatcgt ttcgcatgat tgaacaagat ggattgcacg caggttctcc ggccgcttgg 9360 gtggagaggc tattcggcta tgactgggca caacagacaa tcggctgctc tgatgccgcc 9420 gtgttccggc tgtcagcgca ggggcgcccg gttctttttg tcaagaccga cctgtccggt 9480 gccctgaatg aactgcaaga cgaggcagcg cggctatcgt ggctggccac gacgggcgtt 9540 ccttgcgcag ctgtgctcga cgttgtcact gaagcgggaa gggactggct gctattgggc 9600 gaagtgccgg ggcaggatct cctgtcatct caccttgctc ctgccgagaa agtatccatc 9660 atggctgatg caatgcggcg gctgcatacg cttgatccgg ctacctgccc attcgaccac 9720 caagcgaaac atcgcatcga gcgagcacgt actcggatgg aagccggtct tgtcgatcag 9780 gatgatctgg acgaagagca tcaggggctc gcgccagccg aactgttcgc caggctcaag 9840 gcgagcatgc ccgacggcga ggatctcgtc gtgacccatg gcgatgcctg cttgccgaat 9900 atcatggtgg aaaatggccg cttttctgga ttcatcgact gtggccggct gggtgtggcg 9960 gaccgctatc aggacatagc gttggctacc cgtgatattg ctgaagagct tggcggcgaa 10020 tgggctgacc gcttcctcgt gctttacggt atcgccgctc ccgattcgca gcgcatcgcc 10080 ttctatcgcc ttcttgacga gttcttctga attttgttaa aatttttgtt aaatcagctc 10140 attttttaac caataggccg aaatcggcaa catcccttat aaatcaaaag aatagaccgc 10200 gatagggttg agtgttgttc cagtttggaa caagagtcca ctattaaaga acgtggactc 10260 caacgtcaaa gggcgaaaaa ccgtctatca gggcgatggc ccactacgtg aaccatcacc 10320 caaatcaagt tttttgcggt cgaggtgccg taaagctcta aatcggaacc ctaaagggag 10380 cccccgattt agagcttgac ggggaaagcc ggcgaacgtg gcgagaaagg aagggaagaa 10440 agcgaaagga gcgggcgcta gggcgctggc aagtgtagcg gtcacgctgc gcgtaaccac 10500 cacacccgcg cgcttaatgc gccgctacag ggcgcgtcca ttcgccattc aggatcgaat 10560 taattcttaa t 10571 <210> 36 <211> 10778 <212> DNA <213> Artificial Sequence <220> <223> pAVQ SD/SA CMV Ribozyme HSV-TK WPRE(forward) <400> 36 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 ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag ttattaatag taatcaatta 540 cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt acggtaaatg 600 gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg acgtatgttc 660 ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat ttacggtaaa 720 ctgcccactt ggcagtacat caagtgtatc atatgccaag tccgccccct attgacgtca 780 atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttacgg gactttccta 840 cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg ttttggcagt 900 acaccaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc caccccattg 960 acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa tgtcgtaata 1020 accccgcccc gttgacgcaa atgggcggta ggcgtgtacg gtgggaggtc tatataagca 1080 gagctcgttt agtgaaccgt cagatcctca ctctcttccg catcgctgtc tgcgagggcc 1140 agctgttggg ctcgcggttg aggacaaact cttcgcggtc tttccagtac tcttggatcg 1200 gaaacccgtc ggcctccgaa cggtactccg ccaccgaggg acctgagcca gtccgcatcg 1260 accggatcgg aaaacctctc gagaaaggcg tctaaccagt cacagtcgca aggtaggctg 1320 agcaccgtgg cgggcggcag cgggtggcgg tcggggttgt ttctggcgga ggtgctgctg 1380 atgatgtaat taaagtaggc ggtcttgagc cggcggatgg tcgaggtgag gtgtggcagg 1440 cttgagatcc agctgttggg gtgagtactc cctctcaaaa gcgggcatga cttctgcgct 1500 aagattgtca gtttccaaaa acgaggagga tttgatattc acctggcccg atctggccat 1560 acacttgagt gacaatgaca tccactttgc ctttctctcc acaggtgtcc actcccaggt 1620 ccaagtttgg aagatctgaa ctgaaaaacc agaaagttaa ctggtaagtt tagtcttttt 1680 gtcttttatt tcaggtcccg gatccggtgg tggtgcaaat caaagaactg ctcctcagtg 1740 gatgttgcct ttacttctag gcctgtacgg aagtgttact tctgctctaa aagctgcgga 1800 attgtaccca ggcctaggct tttgcaaaaa gcttcgaatc gcgaaaggcc agcacgttct 1860 tcgcgccgcg ctcgcacagc ctctgcagca ctcgggccac cagctccttc aggcaggaca 1920 cctggcggaa ggagggggcg gcggggggcg gccgtgcgtc ccagggcacg cacaccaggc 1980 actgggccac cagcgcgcgg aaagccgccg ggtccccgcg ctgcaccagc cgccagccct 2040 ggggccccag gcgccgcacg aacgtggcca gcggcagcac ctcgcggtag tggctgcgca 2100 gcagggagcg cacggctagg cagcggggag cgcgcggcat cgcgggggtg gccggggcca 2160 gggcttccca agcttcgttt tgcggcagga aaagttatca ggcatgcacc tggtagctag 2220 tctttaaacc aatagattgc atcggtttaa aaggcaagac cgtcaaattg cgggaaaggg 2280 gtcaacagcc gttcagtacc aagtctcagg ggaaactttg agatggcctt gcaaagggta 2340 tggtaataag ctgacggaca tggtcctaac cacgcagcca agtcctaagt caacagatct 2400 tctgttgata tggatgcagt tcacagacta aatgtcggtc ggggaagatg tattcttctc 2460 ataagatata gtcggacctc tccttaatgg gagctagcgg atgaagtgat gcaacactgg 2520 agccgctggg aactaatttg tatgcgaaag tatattgatt agttttggag tactcgaaaa 2580 cgcccaccat ggcttcgtac ccctgccatc aacacgcgtc tgcgttcgac caggctgcgc 2640 gttctcgcgg ccatagcaac cgacgtacgg cgttgcgccc tcgccggcag caagaagcca 2700 cggaagtccg cctggagcag aaaatgccca cgctactgcg ggtttatata gacggtcctc 2760 acgggatggg gaaaaccacc accacgcaac tgctggtggc cctgggttcg cgcgacgata 2820 tcgtctacgt acccgagccg atgacttact ggcaggtgct gggggcttcc gagacaatcg 2880 cgaacatcta caccacacaa caccgcctcg accagggtga gatatcggcc ggggacgcgg 2940 cggtggtaat gacaagcgcc cagataacaa tgggcatgcc ttatgccgtg accgacgccg 3000 ttctggctcc tcatgtcggg ggggaggctg ggagttcaca tgccccgccc ccggccctca 3060 ccctcatctt cgaccgccat cccatcgccg ccctcctgtg ctacccggcc gcgcgatacc 3120 ttatgggcag catgaccccc caggccgtgc tggcgttcgt ggccctcatc ccgccgacct 3180 tgcccggcac aaacatcgtg ttgggggccc ttccggagga cagacacatc gaccgcctgg 3240 ccaaacgcca gcgccccggc gagcggcttg acctggctat gctggccgcg attcgccgcg 3300 tttacgggct gcttgccaat acggtgcggt atctgcaggg cggcgggtcg tggtgggagg 3360 attggggaca gctttcgggg acggccgtgc cgccccaggg tgccgagccc cagagcaacg 3420 cgggcccacg accccatatc ggggacacgt tatttaccct gtttcgggcc cccgagttgc 3480 tggcccccaa cggcgacctg tataacgtgt ttgcctgggc cttggacgtc ttggccaaac 3540 gcctccgtcc catgcacgtc tttatcctgg attacgacca atcgcccgcc ggctgccggg 3600 acgccctgct gcaacttacc tccgggatgg tccagaccca cgtcaccacc ccaggctcca 3660 taccgacgat ctgcgacctg gcgcgcacgt ttgcccggga gatgggggag gctaactgag 3720 gccggccaat caacctctgg attacaaaat ttgtgaaaga ttgactggta ttcttaacta 3780 tgttgctcct tttacgctat gtggatacgc tgctttaatg cctttgtatc atgctattgc 3840 ttcccgtatg gctttcattt tctcctcctt gtataaatcc tggttgctgt ctctttatga 3900 ggagttgtgg cccgttgtca ggcaacgtgg cgtggtgtgc actgtgtttg ctgacgcaac 3960 ccccactggt tggggcattg ccaccacctg tcagctcctt tccgggactt tcgctttccc 4020 cctccctatt gccacggcgg aactcatcgc cgcctgcctt gcccgctgct ggacaggggc 4080 tcggctgttg ggcactgaca attccgtggt gttgtcgggg aaatcatcgt cctttccttg 4140 gctgctcgcc tgtgttgcca cctggattct gcgcgggacg tccttctgct acgtcccttc 4200 ggccctcaat ccagcggacc ttccttcccg cggcctgctg ccggctctgc ggcctcttcc 4260 gcgtcttcgc cttcgccctc agacgagtcg gatctccctt tgggccgcct ccccgcggcc 4320 ggccgcttcg aaagatccca acgaaaagag agaccacatg gtccttcttg agtttgtaac 4380 agctgctggg attacacatg gcatggatga actgtacaac tgaggatccc ccgacctcga 4440 cctctggcta ataaaggaaa tttattttca ttgcaatagt gtgttggaat tttttgtgtc 4500 tctcactcgg aaggacatat gggagggcaa atcatttggt cgagatccct cggagatcgg 4560 atctgggcgt ggttaagggt gggaaagaat atataaggtg ggggtcttat gtagttttgt 4620 atctgttttg cagcagccgc cgccgccatg agcaccaact cgtttgatgg aagcattgtg 4680 agctcatatt tgacaacgcg catgccccca tgggccgggg tgcgtcagaa tgtgatgggc 4740 tccagcattg atggtcgccc cgtcctgccc gcaaactcta ctaccttgac ctacgagacc 4800 gtgtctggaa cgccgttgga gactgcagcc tccgccgccg cttcagccgc tgcagccacc 4860 gcccgcggga ttgtgactga ctttgctttc ctgagcccgc ttgcaagcag tgcagcttcc 4920 cgttcatccg cccgcgatga caagttgacg gctcttttgg cacaattgga ttctttgacc 4980 cgggaactta atgtcgtttc tcagcagctg ttggatctgc gccagcaggt ttctgccctg 5040 aaggcttcct cccctcccaa tgcggtttaa aacataaata aaaaaccaga ctctgtttgg 5100 atttggatca agcaagtgtc ttgctgtctt tatttagggg ttttgcgcgc gcggtaggcc 5160 cgggaccagc ggtctcggtc gttgagggtc ctgtgtattt tttccaggac gtggtaaagg 5220 tgactctgga tgttcagata catgggcata agcccgtctc tggggtggag gtagcaccac 5280 tgcagagctt catgctgcgg ggtggtgttg tagatgatcc agtcgtagca ggagcgctgg 5340 gcgtggtgcc taaaaatgtc tttcagtagc aagctgattg ccaggggcag gcccttggtg 5400 taagtgttta caaagcggtt aagctgggat gggtgcatac gtggggatat gagatgcatc 5460 ttggactgta tttttaggtt ggctatgttc ccagccatat ccctccgggg attcatgttg 5520 tgcagaacca ccagcacagt gtatccggtg cacttgggaa atttgtcatg tagcttagaa 5580 ggaaatgcgt ggaagaactt ggagacgccc ttgtgacctc caagattttc catgcattcg 5640 tccataatga tggcaatggg cccacgggcg gcggcctggg cgaagatatt tctgggatca 5700 ctaacgtcat agttgtgttc caggatgaga tcgtcatagg ccatttttac aaagcgcggg 5760 cggagggtgc cagactgcgg tataatggtt ccatccggcc caggggcgta gttaccctca 5820 cagatttgca tttcccacgc tttgagttca gatgggggga tcatgtctac ctgcggggcg 5880 atgaagaaaa cggtttccgg ggtaggggag atcagctggg aagaaagcag gttcctgagc 5940 agctgcgact taccgcagcc ggtgggcccg taaatcacac ctattaccgg gtgcaactgg 6000 tagttaagag agctgcagct gccgtcatcc ctgagcaggg gggccacttc gttaagcatg 6060 tccctgactc gcatgttttc cctgaccaaa tccgccagaa ggcgctcgcc gcccagcgat 6120 agcagttctt gcaaggaagc aaagtttttc aacggtttga gaccgtccgc cgtaggcatg 6180 cttttgagcg tttgaccaag cagttccagg cggtcccaca gctcggtcac ctgctctacg 6240 gcatctcgat ccagcatatc tcctcgtttc gcgggttggg gcggctttcg ctgtacggca 6300 gtagtcggtg ctcgtccaga cgggccaggg tcatgtcttt ccacgggcgc agggtcctcg 6360 tcagcgtagt ctgggtcacg gtgaaggggt gcgctccggg ctgcgcgctg gccagggtgc 6420 gcttgaggct ggtcctgctg gtgctgaagc gctgccggtc ttcgccctgc gcgtcggcca 6480 ggtagcattt gaccatggtg tcatagtcca gcccctccgc ggcgtggccc ttggcgcgca 6540 gcttgccctt ggaggaggcg ccgcacgagg ggcagtgcag acttttgagg gcgtagagct 6600 tgggcgcgag aaataccgat tccggggagt aggcatccgc gccgcaggcc ccgcagacgg 6660 tctcgcattc cacgagccag gtgagctctg gccgttcggg gtcaaaaacc aggtttcccc 6720 catgcttttt gatgcgtttc ttacctctgg tttccatgag ccggtgtcca cgctcggtga 6780 cgaaaaggct gtccgtgtcc ccgtatacag acttgagagg gagtttaaac gaattcaata 6840 gcttgttgca tgggcggcga tataaaatgc aaggtgctgc tcaaaaaatc aggcaaagcc 6900 tcgcgcaaaa aagaaagcac atcgtagtca tgctcatgca gataaaggca ggtaagctcc 6960 ggaaccacca cagaaaaaga caccattttt ctctcaaaca tgtctgcggg tttctgcata 7020 aacacaaaat aaaataacaa aaaaacattt aaacattaga agcctgtctt acaacaggaa 7080 aaacaaccct tataagcata agacggacta cggccatgcc ggcgtgaccg taaaaaaact 7140 ggtcaccgtg attaaaaagc accaccgaca gctcctcggt catgtccgga gtcataatgt 7200 aagactcggt aaacacatca ggttgattca tcggtcagtg ctaaaaagcg accgaaatag 7260 cccgggggaa tacatacccg caggcgtaga gacaacatta cagcccccat aggaggtata 7320 acaaaattaa taggagagaa aaacacataa acacctgaaa aaccctcctg cctaggcaaa 7380 atagcaccct cccgctccag aacaacatac agcgcttcac agcggcagcc taacagtcag 7440 ccttaccagt aaaaaagaaa acctattaaa aaaacaccac tcgacacggc accagctcaa 7500 tcagtcacag tgtaaaaaag ggccaagtgc agagcgagta tatataggac taaaaaatga 7560 cgtaacggtt aaagtccaca aaaaacaccc agaaaaccgc acgcgaacct acgcccagaa 7620 acgaaagcca aaaaacccac aacttcctca aatcgtcact tccgttttcc cacgttacgt 7680 aacttcccat tttaagaaaa ctacaattcc caacacatac aagttactcc gccctaaaac 7740 ctacgtcacc cgccccgttc ccacgccccg cgccacgtca caaactccac cccctcatta 7800 tcatattggc ttcaatccaa aataaggtat attattgatg atgttaatta acatgcatgg 7860 atccatatgc ggtgtgaaat accgcacaga tgcgtaagga gaaaataccg catcaggcgc 7920 tcttccgctt cctcgctcac tgactcgctg cgctcggtcg ttcggctgcg gcgagcggta 7980 tcagctcact caaaggcggt aatacggtta tccacagaat caggggataa cgcaggaaag 8040 aacatgtgag caaaaggcca gcaaaaggcc aggaaccgta aaaaggccgc gttgctggcg 8100 tttttccata ggctccgccc ccctgacgag catcacaaaa atcgacgctc aagtcagagg 8160 tggcgaaacc cgacaggact ataaagatac caggcgtttc cccctggaag ctccctcgtg 8220 cgctctcctg ttccgaccct gccgcttacc ggatacctgt ccgcctttct cccttcggga 8280 agcgtggcgc tttctcatag ctcacgctgt aggtatctca gttcggtgta ggtcgttcgc 8340 tccaagctgg gctgtgtgca cgaacccccc gttcagcccg accgctgcgc cttatccggt 8400 aactatcgtc ttgagtccaa cccggtaaga cacgacttat cgccactggc agcagccact 8460 ggtaacagga ttagcagagc gaggtatgta ggcggtgcta cagagttctt gaagtggtgg 8520 cctaactacg gctacactag aaggacagta tttggtatct gcgctctgct gaagccagtt 8580 accttcggaa aaagagttgg tagctcttga tccggcaaac aaaccaccgc tggtagcggt 8640 ggtttttttg tttgcaagca gcagattacg cgcagaaaaa aaggatctca agaagatcct 8700 ttgatctttt ctacggggtc tgacgctcag tggaacgaaa actcacgtta agggattttg 8760 gtcatgagat tatcaaaaag gatcttcacc tagatccttt taaattaaaa atgaagtttt 8820 aaatcaatct aaagtatata tgagtaaact tggtctgaca gttaccaatg cttaatcagt 8880 gaggcaccta tctcagcgat ctgtctattt cgttcatcca tagttgcctg actccccgtc 8940 gtgtagataa ctacgatacg ggagggctta ccatctggcc ccagtgctgc aatgataccg 9000 cgagacccac gctcaccggc tccagattta tcagcaataa accagccagc cggaagggcc 9060 gagcgcagaa gtggtcctgc aactttatcc gcctccatcc agtctattaa ttgttgccgg 9120 gaagctagag taagtagttc gccagttaat agtttgcgca acgttgttgc cattgctgca 9180 gccatgagat tatcaaaaag gatcttcacc tagatccttt tcacgtagaa agccagtccg 9240 cagaaacggt gctgaccccg gatgaatgtc agctactggg ctatctggac aagggaaaac 9300 gcaagcgcaa agagaaagca ggtagcttgc agtgggctta catggcgata gctagactgg 9360 gcggttttat ggacagcaag cgaaccggaa ttgccagctg gggcgccctc tggtaaggtt 9420 gggaagccct gcaaagtaaa ctggatggct ttctcgccgc caaggatctg atggcgcagg 9480 ggatcaagct ctgatcaaga gacaggatga ggatcgtttc gcatgattga acaagatgga 9540 ttgcacgcag gttctccggc cgcttgggtg gagaggctat tcggctatga ctgggcacaa 9600 cagacaatcg gctgctctga tgccgccgtg ttccggctgt cagcgcaggg gcgcccggtt 9660 ctttttgtca agaccgacct gtccggtgcc ctgaatgaac tgcaagacga ggcagcgcgg 9720 ctatcgtggc tggccacgac gggcgttcct tgcgcagctg tgctcgacgt tgtcactgaa 9780 gcgggaaggg actggctgct attgggcgaa gtgccggggc aggatctcct gtcatctcac 9840 cttgctcctg ccgagaaagt atccatcatg gctgatgcaa tgcggcggct gcatacgctt 9900 gatccggcta cctgcccatt cgaccaccaa gcgaaacatc gcatcgagcg agcacgtact 9960 cggatggaag ccggtcttgt cgatcaggat gatctggacg aagagcatca ggggctcgcg 10020 ccagccgaac tgttcgccag gctcaaggcg agcatgcccg acggcgagga tctcgtcgtg 10080 acccatggcg atgcctgctt gccgaatatc atggtggaaa atggccgctt ttctggattc 10140 atcgactgtg gccggctggg tgtggcggac cgctatcagg acatagcgtt ggctacccgt 10200 gatattgctg aagagcttgg cggcgaatgg gctgaccgct tcctcgtgct ttacggtatc 10260 gccgctcccg attcgcagcg catcgccttc tatcgccttc ttgacgagtt cttctgaatt 10320 ttgttaaaat ttttgttaaa tcagctcatt ttttaaccaa taggccgaaa tcggcaacat 10380 cccttataaa tcaaaagaat agaccgcgat agggttgagt gttgttccag tttggaacaa 10440 gagtccacta ttaaagaacg tggactccaa cgtcaaaggg cgaaaaaccg tctatcaggg 10500 cgatggccca ctacgtgaac catcacccaa atcaagtttt ttgcggtcga ggtgccgtaa 10560 agctctaaat cggaacccta aagggagccc ccgatttaga gcttgacggg gaaagccggc 10620 gaacgtggcg agaaaggaag ggaagaaagc gaaaggagcg ggcgctaggg cgctggcaag 10680 tgtagcggtc acgctgcgcg taaccaccac acccgcgcgc ttaatgcgcc gctacagggc 10740 gcgtccattc gccattcagg atcgaattaa ttcttaat 10778 <210> 37 <211> 13816 <212> DNA <213> Artificial Sequence <220> <223> pAVQ PEPCK SD/SA Ribozyme HSV-TK <400> 37 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 ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag tggcgcgccg tcgacgagct 540 ctttggggag tcctaagagg gcagctggca atggacacct agcagtccct ttgagactta 600 tttcagatgg agctgtagaa agatgccatg gctcacagtg cctccctggg aagggggcag 660 agggctgccc agtgaggcct cttgcgagca ggaaatcacc agagacaagg aaagaccaga 720 ccccaggatg acctcagtta ggccttgccc gactgtcctc agagtcccat tctctgtgtc 780 ctggttcttt tagaagatca tggacctcca ggtcatttcg taaccggaat ctgcctgcgg 840 ggggttttga caagctatgg tatagtgtat gtgggggtac tgacgaattg gaagatcatg 900 gagacccctt ctcctcctcc atcattggtc tgccacatcc ctcccaggcg actcacagca 960 gagagacctt ggatgtatgt agggtgcttt aaaactccag ctgagttaca gtctctcctt 1020 tctgttttca ccttaacctt ccagggatgc aaacccacga caggtttagc agcagagtgg 1080 aggctggcca tgaatctcag agaaagtgct cactggaaag gctggtttag cccaggcctg 1140 atgtggaggc actgagctgg acgttctagc ggggttgaca cccaacagtt tacatagggg 1200 gaggccaccc ctcctgagca gtctcggtga cttgaagagg aagccgcttc ttctgtacca 1260 acacagaagc tccagcgaac ccccagaatg ctggcagtgt gggtgctatg taaaagtatt 1320 tacatagctt tgtagagtga gccaagccca gtctgtttgg gatgactctt cacagtgcct 1380 cgaatctgtc acacgtctta gtaagcagag tcacagagtt tctgtcacat catcctcctg 1440 cctacaggga agtaggccat gtccctgccc cctactctga gcccagctgt gggagccagc 1500 cctgcccaat gggctctctc tgattggctt ctcactcact tctaaactcc agtgagcaac 1560 ttctctcggc tcgttcaatt ggcgtgaagg tctgtgtctt gcagagaagg ttcttcacaa 1620 ctgggataaa ggtctcgctg ctcaagtgta gcccagtaga actgccaagc cccttcccct 1680 cctctcccta gactcttgga tgcaagaaga atccaggcag ctccaagggt gattgtgtcc 1740 aacctagaat gtcttgaaaa agacattaag gggactagag aagacagggg atccaacggt 1800 tctctgcagc ccagcctgac tgacatgtaa ctcttctggt tctcaccagc cagctggacc 1860 tgcttagtat tctttctgcc tcagtttccc agcctgtacc cagggctgtc atagttccat 1920 ttcaggcagt agtaatgaat gagctgacat aaaacattta gagcaggggt cagtatgtat 1980 atagagtgat tattctatat caggcattgc ctcctcggaa tgaagcttac aatcacccct 2040 ccctctgcag ttcatcttgg ggtggccaga ggatccagca gacacctagt ggggtaacac 2100 accccagcca actcggctgt tgcagacttt gtctagaagt ttcacgtctc agagctgaat 2160 tcccttctca tgacctttgg ccgtgggagt gacacctcac agctgtggtg ttttgacaac 2220 cagcagccac tggcacacaa aatgtgcagc cagcagcata tgaagtccaa gaggcgtccc 2280 ggccagccct gtccttgacc cccacctgac aattaaggca agagcctata gtttgcatca 2340 gcaacagtca cggtcaaagt ttagtcaatc aaacgttgtg taaggactca actatggctg 2400 acacgggggc ctgaggcctc ccaacattca ttaacaacag caagttcaat cattatctcc 2460 ccaaagttta ttgtgttagg tcagttccaa accgtgctga ccatggctat gatccaaagg 2520 ccggcccctt acgtcagagg cgagcctcca ggtccagctg aggggcaggg ctgtcctccc 2580 ttctgtatac tatttaaagc gaggagggct agctaccaag cacggttggc cttccctctg 2640 ggaacacacc cttggccaac aggggaaatc cggcgagacg ctctgagatc ctgcgagaag 2700 gaggtgcgtc ctgctgcctg ccccggcact ctggctcccc agctcaaggt tcaggccttg 2760 ccccaggccg ggcctctggg tacctgaggt cttctcccgc tctgtgccct tctcctcacc 2820 tggctgcaat gagtggggga gcacggggct tctgcatgct gaaggcaccc cactcagcca 2880 ggcccttctt ctcctccagg tcccccacgg cccttcagat ctgaactgaa aaaccagaaa 2940 gttaactggt aagtttagtc tttttgtctt ttatttcagg tcccggatcc ggtggtggtg 3000 caaatcaaag aactgctcct cagtggatgt tgcctttact tctaggcctg tacggaagtg 3060 ttacttctgc tctaaaagct gcggaattgt acccaggcct aggcttttgc aaaaagcttc 3120 gaatcgcgaa aggccagcac gttcttcgcg ccgcgctcgc acagcctctg cagcactcgg 3180 gccaccagct ccttcaggca ggacacctgg cggaaggagg gggcggcggg gggcggccgt 3240 gcgtcccagg gcacgcacac caggcactgg gccaccagcg cgcggaaagc cgccgggtcc 3300 ccgcgctgca ccagccgcca gccctggggc cccaggcgcc gcacgaacgt ggccagcggc 3360 agcacctcgc ggtagtggct gcgcagcagg gagcgcacgg ctaggcagcg gggagcgcgc 3420 ggcatcgcgg gggtggccgg ggccagggct tcccaagctt cgttttgcgg caggaaaagt 3480 tatcaggcat gcacctggta gctagtcttt aaaccaatag attgcatcgg tttaaaaggc 3540 aagaccgtca aattgcggga aaggggtcaa cagccgttca gtaccaagtc tcaggggaaa 3600 ctttgagatg gccttgcaaa gggtatggta ataagctgac ggacatggtc ctaaccacgc 3660 agccaagtcc taagtcaaca gatcttctgt tgatatggat gcagttcaca gactaaatgt 3720 cggtcgggga agatgtattc ttctcataag atatagtcgg acctctcctt aatgggagct 3780 agcggatgaa gtgatgcaac actggagccg ctgggaacta atttgtatgc gaaagtatat 3840 tgattagttt tggagtactc gcgaaaacgc ccaccatggc ttcgtacccc tgccatcaac 3900 acgcgtctgc gttcgaccag gctgcgcgtt ctcgcggcca tagcaaccga cgtacggcgt 3960 tgcgccctcg ccggcagcaa gaagccacgg aagtccgcct ggagcagaaa atgcccacgc 4020 tactgcgggt ttatatagac ggtcctcacg ggatggggaa aaccaccacc acgcaactgc 4080 tggtggccct gggttcgcgc gacgatatcg tctacgtacc cgagccgatg acttactggc 4140 aggtgctggg ggcttccgag acaatcgcga acatctacac cacacaacac cgcctcgacc 4200 agggtgagat atcggccggg gacgcggcgg tggtaatgac aagcgcccag ataacaatgg 4260 gcatgcctta tgccgtgacc gacgccgttc tggctcctca tatcgggggg gaggctggga 4320 gctcacatgc cccgcccccg gccctcaccc tcatcttcga ccgccatccc atcgccgccc 4380 tcctgtgcta cccggccgcg cgatacctta tgggcagcat gaccccccag gccgtgctgg 4440 cgttcgtggc cctcatcccg ccgaccttgc ccggcacaaa catcgtgttg ggggcccttc 4500 cggaggacag acacatcgac cgcctggcca aacgccagcg ccccggcgag cggcttgacc 4560 tggctatgct ggccgcgatt cgccgcgttt acgggctgct tgccaatacg gtgcggtatc 4620 tgcagggcgg cgggtcgtgg tgggaggatt ggggacagct ttcggggacg gccgtgccgc 4680 cccagggtgc cgagccccag agcaacgcgg gcccacgacc ccatatcggg gacacgttat 4740 ttaccctgtt tcgggccccc gagttgctgg cccccaacgg cgacctgtat aacgtgtttg 4800 cctgggcctt ggacgtcttg gccaaacgcc tccgtcccat gcacgtcttt atcctggatt 4860 acgaccaatc gcccgccggc tgccgggacg ccctgctgca acttacctcc gggatggtcc 4920 agacccacgt caccacccca ggctccatac cgacgatctg cgacctggcg cgcacgtttg 4980 cccgggagat gggggaggct aactgaagcg gccgcgggtg gcatccctgt gacccctccc 5040 cagtgcctct cctggccctg gaagttgcca ctccagtgcc caccagcctt gtcctaataa 5100 aattaagttg catcattttg tctgactagg tgtccttcta taatattatg gggtggaggg 5160 gggtggtatg gagcaagggg caagttggga agacaacctg tagggcctgc ggggtctatt 5220 gggaaccaag ctggagtgca gtggcacaat cttggctcac tgcaatctcc gcctcctggg 5280 ttcaagcgat tctcctgcct cagcctcccg agttgttggg attccaggca tgcatgacca 5340 ggctcagcta atttttgttt ttttggtaga gacggggttt caccatattg gccaggctgg 5400 tctccaactc ctaatctcag gtgatctacc caccttggcc tcccaaattg ctgggattac 5460 aggcgtgaac cactgctccc ttccctgtcc ttctgatttt aaaataacta taccagcagg 5520 aggacgtcca gacacagcat aggctacctg gccatgccca accggtggga catttgagtt 5580 gcttgcttgg cactgtcctc tcatgcgttg ggtccactca gtagatgcct gcaggctcag 5640 aggcacacag gagtttctgg gctcaccctg cccccttcca acccctcagt tcccatcctc 5700 cagcagctgt ttgtgtgctg cctctgaagt ccacactgaa caaacttcag cctactcatg 5760 tccctaaaat gggcaaacat tgcaagcagc aaacagcaaa cacacagccc tccctgcctg 5820 ctgaccttgg agctggggca gaggtcagag acctctctgg gcccatgcca cctccaacat 5880 ccactcgacc ccttggaatt tcggtggaga ggagcagagg ttgtcctggc gtggtttagg 5940 tagtgtgaga gggtccgggt tcaaaaccac ttgctgggtg gggagtcgtc agtaagtggc 6000 tatgccccga ccccgaagcc tgtttcccca tctgtacaat ggaaatgata aagacgccca 6060 tctgataggg tttttgtggc aaataaacat ttggtttttt tgttttgttt tgttttgttt 6120 tttgagatgg aggtttgctc tgtcgcccag gctggagtgc agtgacacaa tctcatctca 6180 ccacaacctt cccctgcctc agcctcccaa gtagctggga ttacaagcat gtgccaccac 6240 acctggctaa ttttctattt ttagtagaga cgggtttctc catgttggtc agcctcagcc 6300 tcccaagtaa ctgggattac aggcctgtgc caccacaccc ggctaatttt ttctattttt 6360 gacagggacg gggtttcacc atgttggtca ggctggtcta gaactcctga cctcaaatga 6420 tccacccacc taggcctccc aaagtgcaca gattacaggc gtgggccacc gcacctggcc 6480 aaatttttaa tttttttcta gagatagggt cttactgtgt tgcccaggct ggtgtcaaac 6540 tcctgggctc aagcagatcc tcctgcctca gcttcccaaa gtggtgggat tataggtgtg 6600 agccactgcg cccagtcagt agccccctct ttgcccctca ctgagcccta ctggatgttc 6660 ttggttgtgt gacagtttcc ccatctatta aacagaaacc cctatagcag aggggaggat 6720 gaggttggaa aatcaggagc attgttattc tattcttgtg ggatcgggga agcagacatc 6780 tgggtggatg tttggggaat gctgggctca gttgaggaag taggggggcc cctggggctt 6840 acagggactg gaagctctga gctggccaga gggatgttgc aatcctgcca gggtcttgtc 6900 tatgctgtcc ctttcacaac catcccccta ccgccaggct gacacgtggt tgtgggggca 6960 caaggccagc cgaactagag tctgaggctg ggctgaggac accctcccca tcagctgcca 7020 gggtcactgg cggtcaaagg cagctggtgg ggaaggaatt ggactccagc cctgggggac 7080 ggatgtggtg atggtgggaa gcaggcttgg tgccaggagg ggcatcagag ggtgaataag 7140 agcagataga gtgtttgggg gaggtagcca gccaaagggg gtgaggcccg gtggaaggga 7200 agaaggggca tacactcaga gctttgcagc tgaaggtttt aattttttga gatggggtct 7260 cactctgtct caccaggctg gagtgcagtg gcgcaatcac agctcactgc agacgcgtga 7320 attcctcgag tctagaggag catgcgcgtc ggcgcgcctt cgaaggcgaa agatcccaac 7380 gaaaagagag accacatggt ccttcttgag tttgtaacag ctgctgggat tacacatggc 7440 atggatgaac tgtacaactg aggatccccc gacctcgacc tctggctaat aaaggaaatt 7500 tattttcatt gcaatagtgt gttggaattt tttgtgtctc tcactcggaa ggacatatgg 7560 gagggcaaat catttggtcg agatccctcg gagatcggat ctgggcgtgg ttaagggtgg 7620 gaaagaatat ataaggtggg ggtcttatgt agttttgtat ctgttttgca gcagccgccg 7680 ccgccatgag caccaactcg tttgatggaa gcattgtgag ctcatatttg acaacgcgca 7740 tgcccccatg ggccggggtg cgtcagaatg tgatgggctc cagcattgat ggtcgccccg 7800 tcctgcccgc aaactctact accttgacct acgagaccgt gtctggaacg ccgttggaga 7860 ctgcagcctc cgccgccgct tcagccgctg cagccaccgc ccgcgggatt gtgactgact 7920 ttgctttcct gagcccgctt gcaagcagtg cagcttcccg ttcatccgcc cgcgatgaca 7980 agttgacggc tcttttggca caattggatt ctttgacccg ggaacttaat gtcgtttctc 8040 agcagctgtt ggatctgcgc cagcaggttt ctgccctgaa ggcttcctcc cctcccaatg 8100 cggtttaaaa cataaataaa aaaccagact ctgtttggat ttggatcaag caagtgtctt 8160 gctgtcttta tttaggggtt ttgcgcgcgc ggtaggcccg ggaccagcgg tctcggtcgt 8220 tgagggtcct gtgtattttt tccaggacgt ggtaaaggtg actctggatg ttcagataca 8280 tgggcataag cccgtctctg gggtggaggt agcaccactg cagagcttca tgctgcgggg 8340 tggtgttgta gatgatccag tcgtagcagg agcgctgggc gtggtgccta aaaatgtctt 8400 tcagtagcaa gctgattgcc aggggcaggc ccttggtgta agtgtttaca aagcggttaa 8460 gctgggatgg gtgcatacgt ggggatatga gatgcatctt ggactgtatt tttaggttgg 8520 ctatgttccc agccatatcc ctccggggat tcatgttgtg cagaaccacc agcacagtgt 8580 atccggtgca cttgggaaat ttgtcatgta gcttagaagg aaatgcgtgg aagaacttgg 8640 agacgccctt gtgacctcca agattttcca tgcattcgtc cataatgatg gcaatgggcc 8700 cacgggcggc ggcctgggcg aagatatttc tgggatcact aacgtcatag ttgtgttcca 8760 ggatgagatc gtcataggcc atttttacaa agcgcgggcg gagggtgcca gactgcggta 8820 taatggttcc atccggccca ggggcgtagt taccctcaca gatttgcatt tcccacgctt 8880 tgagttcaga tggggggatc atgtctacct gcggggcgat gaagaaaacg gtttccgggg 8940 taggggagat cagctgggaa gaaagcaggt tcctgagcag ctgcgactta ccgcagccgg 9000 tgggcccgta aatcacacct attaccgggt gcaactggta gttaagagag ctgcagctgc 9060 cgtcatccct gagcaggggg gccacttcgt taagcatgtc cctgactcgc atgttttccc 9120 tgaccaaatc cgccagaagg cgctcgccgc ccagcgatag cagttcttgc aaggaagcaa 9180 agtttttcaa cggtttgaga ccgtccgccg taggcatgct tttgagcgtt tgaccaagca 9240 gttccaggcg gtcccacagc tcggtcacct gctctacggc atctcgatcc agcatatctc 9300 ctcgtttcgc gggttggggc ggctttcgct gtacggcagt agtcggtgct cgtccagacg 9360 ggccagggtc atgtctttcc acgggcgcag ggtcctcgtc agcgtagtct gggtcacggt 9420 gaaggggtgc gctccgggct gcgcgctggc cagggtgcgc ttgaggctgg tcctgctggt 9480 gctgaagcgc tgccggtctt cgccctgcgc gtcggccagg tagcatttga ccatggtgtc 9540 atagtccagc ccctccgcgg cgtggccctt ggcgcgcagc ttgcccttgg aggaggcgcc 9600 gcacgagggg cagtgcagac ttttgagggc gtagagcttg ggcgcgagaa ataccgattc 9660 cggggagtag gcatccgcgc cgcaggcccc gcagacggtc tcgcattcca cgagccaggt 9720 gagctctggc cgttcggggt caaaaaccag gtttccccca tgctttttga tgcgtttctt 9780 acctctggtt tccatgagcc ggtgtccacg ctcggtgacg aaaaggctgt ccgtgtcccc 9840 gtatacagac ttgagaggga gtttaaacga attcaatagc ttgttgcatg ggcggcgata 9900 taaaatgcaa ggtgctgctc aaaaaatcag gcaaagcctc gcgcaaaaaa gaaagcacat 9960 cgtagtcatg ctcatgcaga taaaggcagg taagctccgg aaccaccaca gaaaaagaca 10020 ccatttttct ctcaaacatg tctgcgggtt tctgcataaa cacaaaataa aataacaaaa 10080 aaacatttaa acattagaag cctgtcttac aacaggaaaa acaaccctta taagcataag 10140 acggactacg gccatgccgg cgtgaccgta aaaaaactgg tcaccgtgat taaaaagcac 10200 caccgacagc tcctcggtca tgtccggagt cataatgtaa gactcggtaa acacatcagg 10260 ttgattcatc ggtcagtgct aaaaagcgac cgaaatagcc cgggggaata catacccgca 10320 ggcgtagaga caacattaca gcccccatag gaggtataac aaaattaata ggagagaaaa 10380 acacataaac acctgaaaaa ccctcctgcc taggcaaaat agcaccctcc cgctccagaa 10440 caacatacag cgcttcacag cggcagccta acagtcagcc ttaccagtaa aaaagaaaac 10500 ctattaaaaa aacaccactc gacacggcac cagctcaatc agtcacagtg taaaaaaggg 10560 ccaagtgcag agcgagtata tataggacta aaaaatgacg taacggttaa agtccacaaa 10620 aaacacccag aaaaccgcac gcgaacctac gcccagaaac gaaagccaaa aaacccacaa 10680 cttcctcaaa tcgtcacttc cgttttccca cgttacgtaa cttcccattt taagaaaact 10740 acaattccca acacatacaa gttactccgc cctaaaacct acgtcacccg ccccgttccc 10800 acgccccgcg ccacgtcaca aactccaccc cctcattatc atattggctt caatccaaaa 10860 taaggtatat tattgatgat gttaattaac atgcatggat ccatatgcgg tgtgaaatac 10920 cgcacagatg cgtaaggaga aaataccgca tcaggcgctc ttccgcttcc tcgctcactg 10980 actcgctgcg ctcggtcgtt cggctgcggc gagcggtatc agctcactca aaggcggtaa 11040 tacggttatc cacagaatca ggggataacg caggaaagaa catgtgagca aaaggccagc 11100 aaaaggccag gaaccgtaaa aaggccgcgt tgctggcgtt tttccatagg ctccgccccc 11160 ctgacgagca tcacaaaaat cgacgctcaa gtcagaggtg gcgaaacccg acaggactat 11220 aaagatacca ggcgtttccc cctggaagct ccctcgtgcg ctctcctgtt ccgaccctgc 11280 cgcttaccgg atacctgtcc gcctttctcc cttcgggaag cgtggcgctt tctcatagct 11340 cacgctgtag gtatctcagt tcggtgtagg tcgttcgctc caagctgggc tgtgtgcacg 11400 aaccccccgt tcagcccgac cgctgcgcct tatccggtaa ctatcgtctt gagtccaacc 11460 cggtaagaca cgacttatcg ccactggcag cagccactgg taacaggatt agcagagcga 11520 ggtatgtagg cggtgctaca gagttcttga agtggtggcc taactacggc tacactagaa 11580 ggacagtatt tggtatctgc gctctgctga agccagttac cttcggaaaa agagttggta 11640 gctcttgatc cggcaaacaa accaccgctg gtagcggtgg tttttttgtt tgcaagcagc 11700 agattacgcg cagaaaaaaa ggatctcaag aagatccttt gatcttttct acggggtctg 11760 acgctcagtg gaacgaaaac tcacgttaag ggattttggt catgagatta tcaaaaagga 11820 tcttcaccta gatcctttta aattaaaaat gaagttttaa atcaatctaa agtatatatg 11880 agtaaacttg gtctgacagt taccaatgct taatcagtga ggcacctatc tcagcgatct 11940 gtctatttcg ttcatccata gttgcctgac tccccgtcgt gtagataact acgatacggg 12000 agggcttacc atctggcccc agtgctgcaa tgataccgcg agacccacgc tcaccggctc 12060 cagatttatc agcaataaac cagccagccg gaagggccga gcgcagaagt ggtcctgcaa 12120 ctttatccgc ctccatccag tctattaatt gttgccggga agctagagta agtagttcgc 12180 cagttaatag tttgcgcaac gttgttgcca ttgctgcagc catgagatta tcaaaaagga 12240 tcttcaccta gatccttttc acgtagaaag ccagtccgca gaaacggtgc tgaccccgga 12300 tgaatgtcag ctactgggct atctggacaa gggaaaacgc aagcgcaaag agaaagcagg 12360 tagcttgcag tgggcttaca tggcgatagc tagactgggc ggttttatgg acagcaagcg 12420 aaccggaatt gccagctggg gcgccctctg gtaaggttgg gaagccctgc aaagtaaact 12480 ggatggcttt ctcgccgcca aggatctgat ggcgcagggg atcaagctct gatcaagaga 12540 caggatgagg atcgtttcgc atgattgaac aagatggatt gcacgcaggt tctccggccg 12600 cttgggtgga gaggctattc ggctatgact gggcacaaca gacaatcggc tgctctgatg 12660 ccgccgtgtt ccggctgtca gcgcaggggc gcccggttct ttttgtcaag accgacctgt 12720 ccggtgccct gaatgaactg caagacgagg cagcgcggct atcgtggctg gccacgacgg 12780 gcgttccttg cgcagctgtg ctcgacgttg tcactgaagc gggaagggac tggctgctat 12840 tgggcgaagt gccggggcag gatctcctgt catctcacct tgctcctgcc gagaaagtat 12900 ccatcatggc tgatgcaatg cggcggctgc atacgcttga tccggctacc tgcccattcg 12960 accaccaagc gaaacatcgc atcgagcgag cacgtactcg gatggaagcc ggtcttgtcg 13020 atcaggatga tctggacgaa gagcatcagg ggctcgcgcc agccgaactg ttcgccaggc 13080 tcaaggcgag catgcccgac ggcgaggatc tcgtcgtgac ccatggcgat gcctgcttgc 13140 cgaatatcat ggtggaaaat ggccgctttt ctggattcat cgactgtggc cggctgggtg 13200 tggcggaccg ctatcaggac atagcgttgg ctacccgtga tattgctgaa gagcttggcg 13260 gcgaatgggc tgaccgcttc ctcgtgcttt acggtatcgc cgctcccgat tcgcagcgca 13320 tcgccttcta tcgccttctt gacgagttct tctgaatttt gttaaaattt ttgttaaatc 13380 agctcatttt ttaaccaata ggccgaaatc ggcaacatcc cttataaatc aaaagaatag 13440 accgcgatag ggttgagtgt tgttccagtt tggaacaaga gtccactatt aaagaacgtg 13500 gactccaacg tcaaagggcg aaaaaccgtc tatcagggcg atggcccact acgtgaacca 13560 tcacccaaat caagtttttt gcggtcgagg tgccgtaaag ctctaaatcg gaaccctaaa 13620 gggagccccc gatttagagc ttgacgggga aagccggcga acgtggcgag aaaggaaggg 13680 aagaaagcga aaggagcggg cgctagggcg ctggcaagtg tagcggtcac gctgcgcgta 13740 accaccacac ccgcgcgctt aatgcgccgc tacagggcgc gtccattcgc cattcaggat 13800 cgaattaatt cttaat 13816 <210> 38 <211> 13765 <212> DNA <213> Artificial Sequence <220> <223> pAVQ PEPCK SD/SA(del 61mer) Ribozyme HSV-TK <400> 38 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 ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag tggcgcgccg tcgacgagct 540 ctttggggag tcctaagagg gcagctggca atggacacct agcagtccct ttgagactta 600 tttcagatgg agctgtagaa agatgccatg gctcacagtg cctccctggg aagggggcag 660 agggctgccc agtgaggcct cttgcgagca ggaaatcacc agagacaagg aaagaccaga 720 ccccaggatg acctcagtta ggccttgccc gactgtcctc agagtcccat tctctgtgtc 780 ctggttcttt tagaagatca tggacctcca ggtcatttcg taaccggaat ctgcctgcgg 840 ggggttttga caagctatgg tatagtgtat gtgggggtac tgacgaattg gaagatcatg 900 gagacccctt ctcctcctcc atcattggtc tgccacatcc ctcccaggcg actcacagca 960 gagagacctt ggatgtatgt agggtgcttt aaaactccag ctgagttaca gtctctcctt 1020 tctgttttca ccttaacctt ccagggatgc aaacccacga caggtttagc agcagagtgg 1080 aggctggcca tgaatctcag agaaagtgct cactggaaag gctggtttag cccaggcctg 1140 atgtggaggc actgagctgg acgttctagc ggggttgaca cccaacagtt tacatagggg 1200 gaggccaccc ctcctgagca gtctcggtga cttgaagagg aagccgcttc ttctgtacca 1260 acacagaagc tccagcgaac ccccagaatg ctggcagtgt gggtgctatg taaaagtatt 1320 tacatagctt tgtagagtga gccaagccca gtctgtttgg gatgactctt cacagtgcct 1380 cgaatctgtc acacgtctta gtaagcagag tcacagagtt tctgtcacat catcctcctg 1440 cctacaggga agtaggccat gtccctgccc cctactctga gcccagctgt gggagccagc 1500 cctgcccaat gggctctctc tgattggctt ctcactcact tctaaactcc agtgagcaac 1560 ttctctcggc tcgttcaatt ggcgtgaagg tctgtgtctt gcagagaagg ttcttcacaa 1620 ctgggataaa ggtctcgctg ctcaagtgta gcccagtaga actgccaagc cccttcccct 1680 cctctcccta gactcttgga tgcaagaaga atccaggcag ctccaagggt gattgtgtcc 1740 aacctagaat gtcttgaaaa agacattaag gggactagag aagacagggg atccaacggt 1800 tctctgcagc ccagcctgac tgacatgtaa ctcttctggt tctcaccagc cagctggacc 1860 tgcttagtat tctttctgcc tcagtttccc agcctgtacc cagggctgtc atagttccat 1920 ttcaggcagt agtaatgaat gagctgacat aaaacattta gagcaggggt cagtatgtat 1980 atagagtgat tattctatat caggcattgc ctcctcggaa tgaagcttac aatcacccct 2040 ccctctgcag ttcatcttgg ggtggccaga ggatccagca gacacctagt ggggtaacac 2100 accccagcca actcggctgt tgcagacttt gtctagaagt ttcacgtctc agagctgaat 2160 tcccttctca tgacctttgg ccgtgggagt gacacctcac agctgtggtg ttttgacaac 2220 cagcagccac tggcacacaa aatgtgcagc cagcagcata tgaagtccaa gaggcgtccc 2280 ggccagccct gtccttgacc cccacctgac aattaaggca agagcctata gtttgcatca 2340 gcaacagtca cggtcaaagt ttagtcaatc aaacgttgtg taaggactca actatggctg 2400 acacgggggc ctgaggcctc ccaacattca ttaacaacag caagttcaat cattatctcc 2460 ccaaagttta ttgtgttagg tcagttccaa accgtgctga ccatggctat gatccaaagg 2520 ccggcccctt acgtcagagg cgagcctcca ggtccagctg aggggcaggg ctgtcctccc 2580 ttctgtatac tatttaaagc gaggagggct agctaccaag cacggttggc cttccctctg 2640 ggaacacacc cttggccaac aggggaaatc cggcgagacg ctctgagatc ctgcgagaag 2700 gaggtgcgtc ctgctgcctg ccccggcact ctggctcccc agctcaaggt tcaggccttg 2760 ccccaggccg ggcctctggg tacctgaggt cttctcccgc tctgtgccct tctcctcacc 2820 tggctgcaat gagtggggga gcacggggct tctgcatgct gaaggcaccc cactcagcca 2880 ggcccttctt ctcctccagg tcccccacgg cccttcagat ctgaactgaa aaaccagaaa 2940 gttaactggt aagtttagtc tttttgtctt ttatttcagg tcccggatcc ggtggtggtg 3000 caaatcaaag aactgctcct cagtggatgt tgcctttact tctaggccta ggcttttgca 3060 aaaagcttcg aatcgcgaaa ggccagcacg ttcttcgcgc cgcgctcgca cagcctctgc 3120 agcactcggg ccaccagctc cttcaggcag gacacctggc ggaaggaggg ggcggcgggg 3180 ggcggccgtg cgtcccaggg cacgcacacc aggcactggg ccaccagcgc gcggaaagcc 3240 gccgggtccc cgcgctgcac cagccgccag ccctggggcc ccaggcgccg cacgaacgtg 3300 gccagcggca gcacctcgcg gtagtggctg cgcagcaggg agcgcacggc taggcagcgg 3360 ggagcgcgcg gcatcgcggg ggtggccggg gccagggctt cccaagcttc gttttgcggc 3420 aggaaaagtt atcaggcatg cacctggtag ctagtcttta aaccaataga ttgcatcggt 3480 ttaaaaggca agaccgtcaa attgcgggaa aggggtcaac agccgttcag taccaagtct 3540 caggggaaac tttgagatgg ccttgcaaag ggtatggtaa taagctgacg gacatggtcc 3600 taaccacgca gccaagtcct aagtcaacag atcttctgtt gatatggatg cagttcacag 3660 actaaatgtc ggtcggggaa gatgtattct tctcataaga tatagtcgga cctctcctta 3720 atgggagcta gcggatgaag tgatgcaaca ctggagccgc tgggaactaa tttgtatgcg 3780 aaagtatatt gattagtttt ggagtactcg cgaaaacgcc caccatggct tcgtacccct 3840 gccatcaaca cgcgtctgcg ttcgaccagg ctgcgcgttc tcgcggccat agcaaccgac 3900 gtacggcgtt gcgccctcgc cggcagcaag aagccacgga agtccgcctg gagcagaaaa 3960 tgcccacgct actgcgggtt tatatagacg gtcctcacgg gatggggaaa accaccacca 4020 cgcaactgct ggtggccctg ggttcgcgcg acgatatcgt ctacgtaccc gagccgatga 4080 cttactggca ggtgctgggg gcttccgaga caatcgcgaa catctacacc acacaacacc 4140 gcctcgacca gggtgagata tcggccgggg acgcggcggt ggtaatgaca agcgcccaga 4200 taacaatggg catgccttat gccgtgaccg acgccgttct ggctcctcat atcggggggg 4260 aggctgggag ctcacatgcc ccgcccccgg ccctcaccct catcttcgac cgccatccca 4320 tcgccgccct cctgtgctac ccggccgcgc gataccttat gggcagcatg accccccagg 4380 ccgtgctggc gttcgtggcc ctcatcccgc cgaccttgcc cggcacaaac atcgtgttgg 4440 gggcccttcc ggaggacaga cacatcgacc gcctggccaa acgccagcgc cccggcgagc 4500 ggcttgacct ggctatgctg gccgcgattc gccgcgttta cgggctgctt gccaatacgg 4560 tgcggtatct gcagggcggc gggtcgtggt gggaggattg gggacagctt tcggggacgg 4620 ccgtgccgcc ccagggtgcc gagccccaga gcaacgcggg cccacgaccc catatcgggg 4680 acacgttatt taccctgttt cgggcccccg agttgctggc ccccaacggc gacctgtata 4740 acgtgtttgc ctgggccttg gacgtcttgg ccaaacgcct ccgtcccatg cacgtcttta 4800 tcctggatta cgaccaatcg cccgccggct gccgggacgc cctgctgcaa cttacctccg 4860 ggatggtcca gacccacgtc accaccccag gctccatacc gacgatctgc gacctggcgc 4920 gcacgtttgc ccgggagatg ggggaggcta actgaagcgg ccgcgggtgg catccctgtg 4980 acccctcccc agtgcctctc ctggccctgg aagttgccac tccagtgccc accagccttg 5040 tcctaataaa attaagttgc atcattttgt ctgactaggt gtccttctat aatattatgg 5100 ggtggagggg ggtggtatgg agcaaggggc aagttgggaa gacaacctgt agggcctgcg 5160 gggtctattg ggaaccaagc tggagtgcag tggcacaatc ttggctcact gcaatctccg 5220 cctcctgggt tcaagcgatt ctcctgcctc agcctcccga gttgttggga ttccaggcat 5280 gcatgaccag gctcagctaa tttttgtttt tttggtagag acggggtttc accatattgg 5340 ccaggctggt ctccaactcc taatctcagg tgatctaccc accttggcct cccaaattgc 5400 tgggattaca ggcgtgaacc actgctccct tccctgtcct tctgatttta aaataactat 5460 accagcagga ggacgtccag acacagcata ggctacctgg ccatgcccaa ccggtgggac 5520 atttgagttg cttgcttggc actgtcctct catgcgttgg gtccactcag tagatgcctg 5580 caggctcaga ggcacacagg agtttctggg ctcaccctgc ccccttccaa cccctcagtt 5640 cccatcctcc agcagctgtt tgtgtgctgc ctctgaagtc cacactgaac aaacttcagc 5700 ctactcatgt ccctaaaatg ggcaaacatt gcaagcagca aacagcaaac acacagccct 5760 ccctgcctgc tgaccttgga gctggggcag aggtcagaga cctctctggg cccatgccac 5820 ctccaacatc cactcgaccc cttggaattt cggtggagag gagcagaggt tgtcctggcg 5880 tggtttaggt agtgtgagag ggtccgggtt caaaaccact tgctgggtgg ggagtcgtca 5940 gtaagtggct atgccccgac cccgaagcct gtttccccat ctgtacaatg gaaatgataa 6000 agacgcccat ctgatagggt ttttgtggca aataaacatt tggttttttt gttttgtttt 6060 gttttgtttt ttgagatgga ggtttgctct gtcgcccagg ctggagtgca gtgacacaat 6120 ctcatctcac cacaaccttc ccctgcctca gcctcccaag tagctgggat tacaagcatg 6180 tgccaccaca cctggctaat tttctatttt tagtagagac gggtttctcc atgttggtca 6240 gcctcagcct cccaagtaac tgggattaca ggcctgtgcc accacacccg gctaattttt 6300 tctatttttg acagggacgg ggtttcacca tgttggtcag gctggtctag aactcctgac 6360 ctcaaatgat ccacccacct aggcctccca aagtgcacag attacaggcg tgggccaccg 6420 cacctggcca aatttttaat ttttttctag agatagggtc ttactgtgtt gcccaggctg 6480 gtgtcaaact cctgggctca agcagatcct cctgcctcag cttcccaaag tggtgggatt 6540 ataggtgtga gccactgcgc ccagtcagta gccccctctt tgcccctcac tgagccctac 6600 tggatgttct tggttgtgtg acagtttccc catctattaa acagaaaccc ctatagcaga 6660 ggggaggatg aggttggaaa atcaggagca ttgttattct attcttgtgg gatcggggaa 6720 gcagacatct gggtggatgt ttggggaatg ctgggctcag ttgaggaagt aggggggccc 6780 ctggggctta cagggactgg aagctctgag ctggccagag ggatgttgca atcctgccag 6840 ggtcttgtct atgctgtccc tttcacaacc atccccctac cgccaggctg acacgtggtt 6900 gtgggggcac aaggccagcc gaactagagt ctgaggctgg gctgaggaca ccctccccat 6960 cagctgccag ggtcactggc ggtcaaaggc agctggtggg gaaggaattg gactccagcc 7020 ctgggggacg gatgtggtga tggtgggaag caggcttggt gccaggaggg gcatcagagg 7080 gtgaataaga gcagatagag tgtttggggg aggtagccag ccaaaggggg tgaggcccgg 7140 tggaagggaa gaaggggcat acactcagag ctttgcagct gaaggtttta attttttgag 7200 atggggtctc actctgtctc accaggctgg agtgcagtgg cgcaatcaca gctcactgca 7260 gacgcgtgaa ttcctcgagt ctagaggagc atgcgcgtcg gcgcgccttc gaaggcgaaa 7320 gatcccaacg aaaagagaga ccacatggtc cttcttgagt ttgtaacagc tgctgggatt 7380 acacatggca tggatgaact gtacaactga ggatcccccg acctcgacct ctggctaata 7440 aaggaaattt attttcattg caatagtgtg ttggaatttt ttgtgtctct cactcggaag 7500 gacatatggg agggcaaatc atttggtcga gatccctcgg agatcggatc tgggcgtggt 7560 taagggtggg aaagaatata taaggtgggg gtcttatgta gttttgtatc tgttttgcag 7620 cagccgccgc cgccatgagc accaactcgt ttgatggaag cattgtgagc tcatatttga 7680 caacgcgcat gcccccatgg gccggggtgc gtcagaatgt gatgggctcc agcattgatg 7740 gtcgccccgt cctgcccgca aactctacta ccttgaccta cgagaccgtg tctggaacgc 7800 cgttggagac tgcagcctcc gccgccgctt cagccgctgc agccaccgcc cgcgggattg 7860 tgactgactt tgctttcctg agcccgcttg caagcagtgc agcttcccgt tcatccgccc 7920 gcgatgacaa gttgacggct cttttggcac aattggattc tttgacccgg gaacttaatg 7980 tcgtttctca gcagctgttg gatctgcgcc agcaggtttc tgccctgaag gcttcctccc 8040 ctcccaatgc ggtttaaaac ataaataaaa aaccagactc tgtttggatt tggatcaagc 8100 aagtgtcttg ctgtctttat ttaggggttt tgcgcgcgcg gtaggcccgg gaccagcggt 8160 ctcggtcgtt gagggtcctg tgtatttttt ccaggacgtg gtaaaggtga ctctggatgt 8220 tcagatacat gggcataagc ccgtctctgg ggtggaggta gcaccactgc agagcttcat 8280 gctgcggggt ggtgttgtag atgatccagt cgtagcagga gcgctgggcg tggtgcctaa 8340 aaatgtcttt cagtagcaag ctgattgcca ggggcaggcc cttggtgtaa gtgtttacaa 8400 agcggttaag ctgggatggg tgcatacgtg gggatatgag atgcatcttg gactgtattt 8460 ttaggttggc tatgttccca gccatatccc tccggggatt catgttgtgc agaaccacca 8520 gcacagtgta tccggtgcac ttgggaaatt tgtcatgtag cttagaagga aatgcgtgga 8580 agaacttgga gacgcccttg tgacctccaa gattttccat gcattcgtcc ataatgatgg 8640 caatgggccc acgggcggcg gcctgggcga agatatttct gggatcacta acgtcatagt 8700 tgtgttccag gatgagatcg tcataggcca tttttacaaa gcgcgggcgg agggtgccag 8760 actgcggtat aatggttcca tccggcccag gggcgtagtt accctcacag atttgcattt 8820 cccacgcttt gagttcagat ggggggatca tgtctacctg cggggcgatg aagaaaacgg 8880 tttccggggt aggggagatc agctgggaag aaagcaggtt cctgagcagc tgcgacttac 8940 cgcagccggt gggcccgtaa atcacaccta ttaccgggtg caactggtag ttaagagagc 9000 tgcagctgcc gtcatccctg agcagggggg ccacttcgtt aagcatgtcc ctgactcgca 9060 tgttttccct gaccaaatcc gccagaaggc gctcgccgcc cagcgatagc agttcttgca 9120 aggaagcaaa gtttttcaac ggtttgagac cgtccgccgt aggcatgctt ttgagcgttt 9180 gaccaagcag ttccaggcgg tcccacagct cggtcacctg ctctacggca tctcgatcca 9240 gcatatctcc tcgtttcgcg ggttggggcg gctttcgctg tacggcagta gtcggtgctc 9300 gtccagacgg gccagggtca tgtctttcca cgggcgcagg gtcctcgtca gcgtagtctg 9360 ggtcacggtg aaggggtgcg ctccgggctg cgcgctggcc agggtgcgct tgaggctggt 9420 cctgctggtg ctgaagcgct gccggtcttc gccctgcgcg tcggccaggt agcatttgac 9480 catggtgtca tagtccagcc cctccgcggc gtggcccttg gcgcgcagct tgcccttgga 9540 ggaggcgccg cacgaggggc agtgcagact tttgagggcg tagagcttgg gcgcgagaaa 9600 taccgattcc ggggagtagg catccgcgcc gcaggccccg cagacggtct cgcattccac 9660 gagccaggtg agctctggcc gttcggggtc aaaaaccagg tttcccccat gctttttgat 9720 gcgtttctta cctctggttt ccatgagccg gtgtccacgc tcggtgacga aaaggctgtc 9780 cgtgtccccg tatacagact tgagagggag tttaaacgaa ttcaatagct tgttgcatgg 9840 gcggcgatat aaaatgcaag gtgctgctca aaaaatcagg caaagcctcg cgcaaaaaag 9900 aaagcacatc gtagtcatgc tcatgcagat aaaggcaggt aagctccgga accaccacag 9960 aaaaagacac catttttctc tcaaacatgt ctgcgggttt ctgcataaac acaaaataaa 10020 ataacaaaaa aacatttaaa cattagaagc ctgtcttaca acaggaaaaa caacccttat 10080 aagcataaga cggactacgg ccatgccggc gtgaccgtaa aaaaactggt caccgtgatt 10140 aaaaagcacc accgacagct cctcggtcat gtccggagtc ataatgtaag actcggtaaa 10200 cacatcaggt tgattcatcg gtcagtgcta aaaagcgacc gaaatagccc gggggaatac 10260 atacccgcag gcgtagagac aacattacag cccccatagg aggtataaca aaattaatag 10320 gagagaaaaa cacataaaca cctgaaaaac cctcctgcct aggcaaaata gcaccctccc 10380 gctccagaac aacatacagc gcttcacagc ggcagcctaa cagtcagcct taccagtaaa 10440 aaagaaaacc tattaaaaaa acaccactcg acacggcacc agctcaatca gtcacagtgt 10500 aaaaaagggc caagtgcaga gcgagtatat ataggactaa aaaatgacgt aacggttaaa 10560 gtccacaaaa aacacccaga aaaccgcacg cgaacctacg cccagaaacg aaagccaaaa 10620 aacccacaac ttcctcaaat cgtcacttcc gttttcccac gttacgtaac ttcccatttt 10680 aagaaaacta caattcccaa cacatacaag ttactccgcc ctaaaaccta cgtcacccgc 10740 cccgttccca cgccccgcgc cacgtcacaa actccacccc ctcattatca tattggcttc 10800 aatccaaaat aaggtatatt attgatgatg ttaattaaca tgcatggatc catatgcggt 10860 gtgaaatacc gcacagatgc gtaaggagaa aataccgcat caggcgctct tccgcttcct 10920 cgctcactga ctcgctgcgc tcggtcgttc ggctgcggcg agcggtatca gctcactcaa 10980 aggcggtaat acggttatcc acagaatcag gggataacgc aggaaagaac atgtgagcaa 11040 aaggccagca aaaggccagg aaccgtaaaa aggccgcgtt gctggcgttt ttccataggc 11100 tccgcccccc tgacgagcat cacaaaaatc gacgctcaag tcagaggtgg cgaaacccga 11160 caggactata aagataccag gcgtttcccc ctggaagctc cctcgtgcgc tctcctgttc 11220 cgaccctgcc gcttaccgga tacctgtccg cctttctccc ttcgggaagc gtggcgcttt 11280 ctcatagctc acgctgtagg tatctcagtt cggtgtaggt cgttcgctcc aagctgggct 11340 gtgtgcacga accccccgtt cagcccgacc gctgcgcctt atccggtaac tatcgtcttg 11400 agtccaaccc ggtaagacac gacttatcgc cactggcagc agccactggt aacaggatta 11460 gcagagcgag gtatgtaggc ggtgctacag agttcttgaa gtggtggcct aactacggct 11520 acactagaag gacagtattt ggtatctgcg ctctgctgaa gccagttacc ttcggaaaaa 11580 gagttggtag ctcttgatcc ggcaaacaaa ccaccgctgg tagcggtggt ttttttgttt 11640 gcaagcagca gattacgcgc agaaaaaaag gatctcaaga agatcctttg atcttttcta 11700 cggggtctga cgctcagtgg aacgaaaact cacgttaagg gattttggtc atgagattat 11760 caaaaaggat cttcacctag atccttttaa attaaaaatg aagttttaaa tcaatctaaa 11820 gtatatatga gtaaacttgg tctgacagtt accaatgctt aatcagtgag gcacctatct 11880 cagcgatctg tctatttcgt tcatccatag ttgcctgact ccccgtcgtg tagataacta 11940 cgatacggga gggcttacca tctggcccca gtgctgcaat gataccgcga gacccacgct 12000 caccggctcc agatttatca gcaataaacc agccagccgg aagggccgag cgcagaagtg 12060 gtcctgcaac tttatccgcc tccatccagt ctattaattg ttgccgggaa gctagagtaa 12120 gtagttcgcc agttaatagt ttgcgcaacg ttgttgccat tgctgcagcc atgagattat 12180 caaaaaggat cttcacctag atccttttca cgtagaaagc cagtccgcag aaacggtgct 12240 gaccccggat gaatgtcagc tactgggcta tctggacaag ggaaaacgca agcgcaaaga 12300 gaaagcaggt agcttgcagt gggcttacat ggcgatagct agactgggcg gttttatgga 12360 cagcaagcga accggaattg ccagctgggg cgccctctgg taaggttggg aagccctgca 12420 aagtaaactg gatggctttc tcgccgccaa ggatctgatg gcgcagggga tcaagctctg 12480 atcaagagac aggatgagga tcgtttcgca tgattgaaca agatggattg cacgcaggtt 12540 ctccggccgc ttgggtggag aggctattcg gctatgactg ggcacaacag acaatcggct 12600 gctctgatgc cgccgtgttc cggctgtcag cgcaggggcg cccggttctt tttgtcaaga 12660 ccgacctgtc cggtgccctg aatgaactgc aagacgaggc agcgcggcta tcgtggctgg 12720 ccacgacggg cgttccttgc gcagctgtgc tcgacgttgt cactgaagcg ggaagggact 12780 ggctgctatt gggcgaagtg ccggggcagg atctcctgtc atctcacctt gctcctgccg 12840 agaaagtatc catcatggct gatgcaatgc ggcggctgca tacgcttgat ccggctacct 12900 gcccattcga ccaccaagcg aaacatcgca tcgagcgagc acgtactcgg atggaagccg 12960 gtcttgtcga tcaggatgat ctggacgaag agcatcaggg gctcgcgcca gccgaactgt 13020 tcgccaggct caaggcgagc atgcccgacg gcgaggatct cgtcgtgacc catggcgatg 13080 cctgcttgcc gaatatcatg gtggaaaatg gccgcttttc tggattcatc gactgtggcc 13140 ggctgggtgt ggcggaccgc tatcaggaca tagcgttggc tacccgtgat attgctgaag 13200 agcttggcgg cgaatgggct gaccgcttcc tcgtgcttta cggtatcgcc gctcccgatt 13260 cgcagcgcat cgccttctat cgccttcttg acgagttctt ctgaattttg ttaaaatttt 13320 tgttaaatca gctcattttt taaccaatag gccgaaatcg gcaacatccc ttataaatca 13380 aaagaataga ccgcgatagg gttgagtgtt gttccagttt ggaacaagag tccactatta 13440 aagaacgtgg actccaacgt caaagggcga aaaaccgtct atcagggcga tggcccacta 13500 cgtgaaccat cacccaaatc aagttttttg cggtcgaggt gccgtaaagc tctaaatcgg 13560 aaccctaaag ggagcccccg atttagagct tgacggggaa agccggcgaa cgtggcgaga 13620 aaggaaggga agaaagcgaa aggagcgggc gctagggcgc tggcaagtgt agcggtcacg 13680 ctgcgcgtaa ccaccacacc cgcgcgctta atgcgccgct acagggcgcg tccattcgcc 13740 attcaggatc gaattaattc ttaat 13765 <210> 39 <211> 14210 <212> DNA <213> Artificial Sequence <220> <223> pAVQ PEPCK Ribozyme HSV-TK WPRE(forward) <400> 39 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 ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag tggcgcgccg tcgacgagct 540 ctttggggag tcctaagagg gcagctggca atggacacct agcagtccct ttgagactta 600 tttcagatgg agctgtagaa agatgccatg gctcacagtg cctccctggg aagggggcag 660 agggctgccc agtgaggcct cttgcgagca ggaaatcacc agagacaagg aaagaccaga 720 ccccaggatg acctcagtta ggccttgccc gactgtcctc agagtcccat tctctgtgtc 780 ctggttcttt tagaagatca tggacctcca ggtcatttcg taaccggaat ctgcctgcgg 840 ggggttttga caagctatgg tatagtgtat gtgggggtac tgacgaattg gaagatcatg 900 gagacccctt ctcctcctcc atcattggtc tgccacatcc ctcccaggcg actcacagca 960 gagagacctt ggatgtatgt agggtgcttt aaaactccag ctgagttaca gtctctcctt 1020 tctgttttca ccttaacctt ccagggatgc aaacccacga caggtttagc agcagagtgg 1080 aggctggcca tgaatctcag agaaagtgct cactggaaag gctggtttag cccaggcctg 1140 atgtggaggc actgagctgg acgttctagc ggggttgaca cccaacagtt tacatagggg 1200 gaggccaccc ctcctgagca gtctcggtga cttgaagagg aagccgcttc ttctgtacca 1260 acacagaagc tccagcgaac ccccagaatg ctggcagtgt gggtgctatg taaaagtatt 1320 tacatagctt tgtagagtga gccaagccca gtctgtttgg gatgactctt cacagtgcct 1380 cgaatctgtc acacgtctta gtaagcagag tcacagagtt tctgtcacat catcctcctg 1440 cctacaggga agtaggccat gtccctgccc cctactctga gcccagctgt gggagccagc 1500 cctgcccaat gggctctctc tgattggctt ctcactcact tctaaactcc agtgagcaac 1560 ttctctcggc tcgttcaatt ggcgtgaagg tctgtgtctt gcagagaagg ttcttcacaa 1620 ctgggataaa ggtctcgctg ctcaagtgta gcccagtaga actgccaagc cccttcccct 1680 cctctcccta gactcttgga tgcaagaaga atccaggcag ctccaagggt gattgtgtcc 1740 aacctagaat gtcttgaaaa agacattaag gggactagag aagacagggg atccaacggt 1800 tctctgcagc ccagcctgac tgacatgtaa ctcttctggt tctcaccagc cagctggacc 1860 tgcttagtat tctttctgcc tcagtttccc agcctgtacc cagggctgtc atagttccat 1920 ttcaggcagt agtaatgaat gagctgacat aaaacattta gagcaggggt cagtatgtat 1980 atagagtgat tattctatat caggcattgc ctcctcggaa tgaagcttac aatcacccct 2040 ccctctgcag ttcatcttgg ggtggccaga ggatccagca gacacctagt ggggtaacac 2100 accccagcca actcggctgt tgcagacttt gtctagaagt ttcacgtctc agagctgaat 2160 tcccttctca tgacctttgg ccgtgggagt gacacctcac agctgtggtg ttttgacaac 2220 cagcagccac tggcacacaa aatgtgcagc cagcagcata tgaagtccaa gaggcgtccc 2280 ggccagccct gtccttgacc cccacctgac aattaaggca agagcctata gtttgcatca 2340 gcaacagtca cggtcaaagt ttagtcaatc aaacgttgtg taaggactca actatggctg 2400 acacgggggc ctgaggcctc ccaacattca ttaacaacag caagttcaat cattatctcc 2460 ccaaagttta ttgtgttagg tcagttccaa accgtgctga ccatggctat gatccaaagg 2520 ccggcccctt acgtcagagg cgagcctcca ggtccagctg aggggcaggg ctgtcctccc 2580 ttctgtatac tatttaaagc gaggagggct agctaccaag cacggttggc cttccctctg 2640 ggaacacacc cttggccaac aggggaaatc cggcgagacg ctctgagatc ctgcgagaag 2700 gaggtgcgtc ctgctgcctg ccccggcact ctggctcccc agctcaaggt tcaggccttg 2760 ccccaggccg ggcctctggg tacctgaggt cttctcccgc tctgtgccct tctcctcacc 2820 tggctgcaat gagtggggga gcacggggct tctgcatgct gaaggcaccc cactcagcca 2880 ggcccttctt ctcctccagg tcccccacgg cccttcagat ccaaggccag cacgttcttc 2940 gcgccgcgct cgcacagcct ctgcagcact cgggccacca gctccttcag gcaggacacc 3000 tggcggaagg agggggcggc ggggggcggc cgtgcgtccc agggcacgca caccaggcac 3060 tgggccacca gcgcgcggaa agccgccggg tccccgcgct gcaccagccg ccagccctgg 3120 ggccccaggc gccgcacgaa cgtggccagc ggcagcacct cgcggtagtg gctgcgcagc 3180 agggagcgca cggctaggca gcggggagcg cgcggcatcg cgggggtggc cggggccagg 3240 gcttcccaag cttcgttttg cggcaggaaa agttatcagg catgcacctg gtagctagtc 3300 tttaaaccaa tagattgcat cggtttaaaa ggcaagaccg tcaaattgcg ggaaaggggt 3360 caacagccgt tcagtaccaa gtctcagggg aaactttgag atggccttgc aaagggtatg 3420 gtaataagct gacggacatg gtcctaacca cgcagccaag tcctaagtca acagatcttc 3480 tgttgatatg gatgcagttc acagactaaa tgtcggtcgg ggaagatgta ttcttctcat 3540 aagatatagt cggacctctc cttaatggga gctagcggat gaagtgatgc aacactggag 3600 ccgctgggaa ctaatttgta tgcgaaagta tattgattag ttttggagta ctcgcgaaaa 3660 cgcccaccat ggcttcgtac ccctgccatc aacacgcgtc tgcgttcgac caggctgcgc 3720 gttctcgcgg ccatagcaac cgacgtacgg cgttgcgccc tcgccggcag caagaagcca 3780 cggaagtccg cctggagcag aaaatgccca cgctactgcg ggtttatata gacggtcctc 3840 acgggatggg gaaaaccacc accacgcaac tgctggtggc cctgggttcg cgcgacgata 3900 tcgtctacgt acccgagccg atgacttact ggcaggtgct gggggcttcc gagacaatcg 3960 cgaacatcta caccacacaa caccgcctcg accagggtga gatatcggcc ggggacgcgg 4020 cggtggtaat gacaagcgcc cagataacaa tgggcatgcc ttatgccgtg accgacgccg 4080 ttctggctcc tcatatcggg ggggaggctg ggagctcaca tgccccgccc ccggccctca 4140 ccctcatctt cgaccgccat cccatcgccg ccctcctgtg ctacccggcc gcgcgatacc 4200 ttatgggcag catgaccccc caggccgtgc tggcgttcgt ggccctcatc ccgccgacct 4260 tgcccggcac aaacatcgtg ttgggggccc ttccggagga cagacacatc gaccgcctgg 4320 ccaaacgcca gcgccccggc gagcggcttg acctggctat gctggccgcg attcgccgcg 4380 tttacgggct gcttgccaat acggtgcggt atctgcaggg cggcgggtcg tggtgggagg 4440 attggggaca gctttcgggg acggccgtgc cgccccaggg tgccgagccc cagagcaacg 4500 cgggcccacg accccatatc ggggacacgt tatttaccct gtttcgggcc cccgagttgc 4560 tggcccccaa cggcgacctg tataacgtgt ttgcctgggc cttggacgtc ttggccaaac 4620 gcctccgtcc catgcacgtc tttatcctgg attacgacca atcgcccgcc ggctgccggg 4680 acgccctgct gcaacttacc tccgggatgg tccagaccca cgtcaccacc ccaggctcca 4740 taccgacgat ctgcgacctg gcgcgcacgt ttgcccggga gatgggggag gctaactgaa 4800 gcttgcggcc gcaatcaacc tctggattac aaaatttgtg aaagattgac tggtattctt 4860 aactatgttg ctccttttac gctatgtgga tacgctgctt taatgccttt gtatcatgct 4920 attgcttccc gtatggcttt cattttctcc tccttgtata aatcctggtt gctgtctctt 4980 tatgaggagt tgtggcccgt tgtcaggcaa cgtggcgtgg tgtgcactgt gtttgctgac 5040 gcaaccccca ctggttgggg cattgccacc acctgtcagc tcctttccgg gactttcgct 5100 ttccccctcc ctattgccac ggcggaactc atcgccgcct gccttgcccg ctgctggaca 5160 ggggctcggc tgttgggcac tgacaattcc gtggtgttgt cggggaaatc atcgtccttt 5220 ccttggctgc tcgcctgtgt tgccacctgg attctgcgcg ggacgtcctt ctgctacgtc 5280 ccttcggccc tcaatccagc ggaccttcct tcccgcggcc tgctgccggc tctgcggcct 5340 cttccgcgtc ttcgccttcg ccctcagacg agtcggatct ccctttgggc cgcctccccg 5400 cgcggccgcg ggtggcatcc ctgtgacccc tccccagtgc ctctcctggc cctggaagtt 5460 gccactccag tgcccaccag ccttgtccta ataaaattaa gttgcatcat tttgtctgac 5520 taggtgtcct tctataatat tatggggtgg aggggggtgg tatggagcaa ggggcaagtt 5580 gggaagacaa cctgtagggc ctgcggggtc tattgggaac caagctggag tgcagtggca 5640 caatcttggc tcactgcaat ctccgcctcc tgggttcaag cgattctcct gcctcagcct 5700 cccgagttgt tgggattcca ggcatgcatg accaggctca gctaattttt gtttttttgg 5760 tagagacggg gtttcaccat attggccagg ctggtctcca actcctaatc tcaggtgatc 5820 tacccacctt ggcctcccaa attgctggga ttacaggcgt gaaccactgc tcccttccct 5880 gtccttctga ttttaaaata actataccag caggaggacg tccagacaca gcataggcta 5940 cctggccatg cccaaccggt gggacatttg agttgcttgc ttggcactgt cctctcatgc 6000 gttgggtcca ctcagtagat gcctgcaggc tcagaggcac acaggagttt ctgggctcac 6060 cctgccccct tccaacccct cagttcccat cctccagcag ctgtttgtgt gctgcctctg 6120 aagtccacac tgaacaaact tcagcctact catgtcccta aaatgggcaa acattgcaag 6180 cagcaaacag caaacacaca gccctccctg cctgctgacc ttggagctgg ggcagaggtc 6240 agagacctct ctgggcccat gccacctcca acatccactc gaccccttgg aatttcggtg 6300 gagaggagca gaggttgtcc tggcgtggtt taggtagtgt gagagggtcc gggttcaaaa 6360 ccacttgctg ggtggggagt cgtcagtaag tggctatgcc ccgaccccga agcctgtttc 6420 cccatctgta caatggaaat gataaagacg cccatctgat agggtttttg tggcaaataa 6480 acatttggtt tttttgtttt gttttgtttt gttttttgag atggaggttt gctctgtcgc 6540 ccaggctgga gtgcagtgac acaatctcat ctcaccacaa ccttcccctg cctcagcctc 6600 ccaagtagct gggattacaa gcatgtgcca ccacacctgg ctaattttct atttttagta 6660 gagacgggtt tctccatgtt ggtcagcctc agcctcccaa gtaactggga ttacaggcct 6720 gtgccaccac acccggctaa ttttttctat ttttgacagg gacggggttt caccatgttg 6780 gtcaggctgg tctagaactc ctgacctcaa atgatccacc cacctaggcc tcccaaagtg 6840 cacagattac aggcgtgggc caccgcacct ggccaaattt ttaatttttt tctagagata 6900 gggtcttact gtgttgccca ggctggtgtc aaactcctgg gctcaagcag atcctcctgc 6960 ctcagcttcc caaagtggtg ggattatagg tgtgagccac tgcgcccagt cagtagcccc 7020 ctctttgccc ctcactgagc cctactggat gttcttggtt gtgtgacagt ttccccatct 7080 attaaacaga aacccctata gcagagggga ggatgaggtt ggaaaatcag gagcattgtt 7140 attctattct tgtgggatcg gggaagcaga catctgggtg gatgtttggg gaatgctggg 7200 ctcagttgag gaagtagggg ggcccctggg gcttacaggg actggaagct ctgagctggc 7260 cagagggatg ttgcaatcct gccagggtct tgtctatgct gtccctttca caaccatccc 7320 cctaccgcca ggctgacacg tggttgtggg ggcacaaggc cagccgaact agagtctgag 7380 gctgggctga ggacaccctc cccatcagct gccagggtca ctggcggtca aaggcagctg 7440 gtggggaagg aattggactc cagccctggg ggacggatgt ggtgatggtg ggaagcaggc 7500 ttggtgccag gaggggcatc agagggtgaa taagagcaga tagagtgttt gggggaggta 7560 gccagccaaa gggggtgagg cccggtggaa gggaagaagg ggcatacact cagagctttg 7620 cagctgaagg ttttaatttt ttgagatggg gtctcactct gtctcaccag gctggagtgc 7680 agtggcgcaa tcacagctca ctgcagacgc gtgaattcct cgagtctaga ggagcatgcg 7740 cgtcggcgcg ccttcgaagg cgaaagatcc caacgaaaag agagaccaca tggtccttct 7800 tgagtttgta acagctgctg ggattacaca tggcatggat gaactgtaca actgaggatc 7860 ccccgacctc gacctctggc taataaagga aatttatttt cattgcaata gtgtgttgga 7920 attttttgtg tctctcactc ggaaggacat atgggagggc aaatcatttg gtcgagatcc 7980 ctcggagatc ggatctgggc gtggttaagg gtgggaaaga atatataagg tgggggtctt 8040 atgtagtttt gtatctgttt tgcagcagcc gccgccgcca tgagcaccaa ctcgtttgat 8100 ggaagcattg tgagctcata tttgacaacg cgcatgcccc catgggccgg ggtgcgtcag 8160 aatgtgatgg gctccagcat tgatggtcgc cccgtcctgc ccgcaaactc tactaccttg 8220 acctacgaga ccgtgtctgg aacgccgttg gagactgcag cctccgccgc cgcttcagcc 8280 gctgcagcca ccgcccgcgg gattgtgact gactttgctt tcctgagccc gcttgcaagc 8340 agtgcagctt cccgttcatc cgcccgcgat gacaagttga cggctctttt ggcacaattg 8400 gattctttga cccgggaact taatgtcgtt tctcagcagc tgttggatct gcgccagcag 8460 gtttctgccc tgaaggcttc ctcccctccc aatgcggttt aaaacataaa taaaaaacca 8520 gactctgttt ggatttggat caagcaagtg tcttgctgtc tttatttagg ggttttgcgc 8580 gcgcggtagg cccgggacca gcggtctcgg tcgttgaggg tcctgtgtat tttttccagg 8640 acgtggtaaa ggtgactctg gatgttcaga tacatgggca taagcccgtc tctggggtgg 8700 aggtagcacc actgcagagc ttcatgctgc ggggtggtgt tgtagatgat ccagtcgtag 8760 caggagcgct gggcgtggtg cctaaaaatg tctttcagta gcaagctgat tgccaggggc 8820 aggcccttgg tgtaagtgtt tacaaagcgg ttaagctggg atgggtgcat acgtggggat 8880 atgagatgca tcttggactg tatttttagg ttggctatgt tcccagccat atccctccgg 8940 ggattcatgt tgtgcagaac caccagcaca gtgtatccgg tgcacttggg aaatttgtca 9000 tgtagcttag aaggaaatgc gtggaagaac ttggagacgc ccttgtgacc tccaagattt 9060 tccatgcatt cgtccataat gatggcaatg ggcccacggg cggcggcctg ggcgaagata 9120 tttctgggat cactaacgtc atagttgtgt tccaggatga gatcgtcata ggccattttt 9180 acaaagcgcg ggcggagggt gccagactgc ggtataatgg ttccatccgg cccaggggcg 9240 tagttaccct cacagatttg catttcccac gctttgagtt cagatggggg gatcatgtct 9300 acctgcgggg cgatgaagaa aacggtttcc ggggtagggg agatcagctg ggaagaaagc 9360 aggttcctga gcagctgcga cttaccgcag ccggtgggcc cgtaaatcac acctattacc 9420 gggtgcaact ggtagttaag agagctgcag ctgccgtcat ccctgagcag gggggccact 9480 tcgttaagca tgtccctgac tcgcatgttt tccctgacca aatccgccag aaggcgctcg 9540 ccgcccagcg atagcagttc ttgcaaggaa gcaaagtttt tcaacggttt gagaccgtcc 9600 gccgtaggca tgcttttgag cgtttgacca agcagttcca ggcggtccca cagctcggtc 9660 acctgctcta cggcatctcg atccagcata tctcctcgtt tcgcgggttg gggcggcttt 9720 cgctgtacgg cagtagtcgg tgctcgtcca gacgggccag ggtcatgtct ttccacgggc 9780 gcagggtcct cgtcagcgta gtctgggtca cggtgaaggg gtgcgctccg ggctgcgcgc 9840 tggccagggt gcgcttgagg ctggtcctgc tggtgctgaa gcgctgccgg tcttcgccct 9900 gcgcgtcggc caggtagcat ttgaccatgg tgtcatagtc cagcccctcc gcggcgtggc 9960 ccttggcgcg cagcttgccc ttggaggagg cgccgcacga ggggcagtgc agacttttga 10020 gggcgtagag cttgggcgcg agaaataccg attccgggga gtaggcatcc gcgccgcagg 10080 ccccgcagac ggtctcgcat tccacgagcc aggtgagctc tggccgttcg gggtcaaaaa 10140 ccaggtttcc cccatgcttt ttgatgcgtt tcttacctct ggtttccatg agccggtgtc 10200 cacgctcggt gacgaaaagg ctgtccgtgt ccccgtatac agacttgaga gggagtttaa 10260 acgaattcaa tagcttgttg catgggcggc gatataaaat gcaaggtgct gctcaaaaaa 10320 tcaggcaaag cctcgcgcaa aaaagaaagc acatcgtagt catgctcatg cagataaagg 10380 caggtaagct ccggaaccac cacagaaaaa gacaccattt ttctctcaaa catgtctgcg 10440 ggtttctgca taaacacaaa ataaaataac aaaaaaacat ttaaacatta gaagcctgtc 10500 ttacaacagg aaaaacaacc cttataagca taagacggac tacggccatg ccggcgtgac 10560 cgtaaaaaaa ctggtcaccg tgattaaaaa gcaccaccga cagctcctcg gtcatgtccg 10620 gagtcataat gtaagactcg gtaaacacat caggttgatt catcggtcag tgctaaaaag 10680 cgaccgaaat agcccggggg aatacatacc cgcaggcgta gagacaacat tacagccccc 10740 ataggaggta taacaaaatt aataggagag aaaaacacat aaacacctga aaaaccctcc 10800 tgcctaggca aaatagcacc ctcccgctcc agaacaacat acagcgcttc acagcggcag 10860 cctaacagtc agccttacca gtaaaaaaga aaacctatta aaaaaacacc actcgacacg 10920 gcaccagctc aatcagtcac agtgtaaaaa agggccaagt gcagagcgag tatatatagg 10980 actaaaaaat gacgtaacgg ttaaagtcca caaaaaacac ccagaaaacc gcacgcgaac 11040 ctacgcccag aaacgaaagc caaaaaaccc acaacttcct caaatcgtca cttccgtttt 11100 cccacgttac gtaacttccc attttaagaa aactacaatt cccaacacat acaagttact 11160 ccgccctaaa acctacgtca cccgccccgt tcccacgccc cgcgccacgt cacaaactcc 11220 accccctcat tatcatattg gcttcaatcc aaaataaggt atattattga tgatgttaat 11280 taacatgcat ggatccatat gcggtgtgaa ataccgcaca gatgcgtaag gagaaaatac 11340 cgcatcaggc gctcttccgc ttcctcgctc actgactcgc tgcgctcggt cgttcggctg 11400 cggcgagcgg tatcagctca ctcaaaggcg gtaatacggt tatccacaga atcaggggat 11460 aacgcaggaa agaacatgtg agcaaaaggc cagcaaaagg ccaggaaccg taaaaaggcc 11520 gcgttgctgg cgtttttcca taggctccgc ccccctgacg agcatcacaa aaatcgacgc 11580 tcaagtcaga ggtggcgaaa cccgacagga ctataaagat accaggcgtt tccccctgga 11640 agctccctcg tgcgctctcc tgttccgacc ctgccgctta ccggatacct gtccgccttt 11700 ctcccttcgg gaagcgtggc gctttctcat agctcacgct gtaggtatct cagttcggtg 11760 taggtcgttc gctccaagct gggctgtgtg cacgaacccc ccgttcagcc cgaccgctgc 11820 gccttatccg gtaactatcg tcttgagtcc aacccggtaa gacacgactt atcgccactg 11880 gcagcagcca ctggtaacag gattagcaga gcgaggtatg taggcggtgc tacagagttc 11940 ttgaagtggt ggcctaacta cggctacact agaaggacag tatttggtat ctgcgctctg 12000 ctgaagccag ttaccttcgg aaaaagagtt ggtagctctt gatccggcaa acaaaccacc 12060 gctggtagcg gtggtttttt tgtttgcaag cagcagatta cgcgcagaaa aaaaggatct 12120 caagaagatc ctttgatctt ttctacgggg tctgacgctc agtggaacga aaactcacgt 12180 taagggattt tggtcatgag attatcaaaa aggatcttca cctagatcct tttaaattaa 12240 aaatgaagtt ttaaatcaat ctaaagtata tatgagtaaa cttggtctga cagttaccaa 12300 tgcttaatca gtgaggcacc tatctcagcg atctgtctat ttcgttcatc catagttgcc 12360 tgactccccg tcgtgtagat aactacgata cgggagggct taccatctgg ccccagtgct 12420 gcaatgatac cgcgagaccc acgctcaccg gctccagatt tatcagcaat aaaccagcca 12480 gccggaaggg ccgagcgcag aagtggtcct gcaactttat ccgcctccat ccagtctatt 12540 aattgttgcc gggaagctag agtaagtagt tcgccagtta atagtttgcg caacgttgtt 12600 gccattgctg cagccatgag attatcaaaa aggatcttca cctagatcct tttcacgtag 12660 aaagccagtc cgcagaaacg gtgctgaccc cggatgaatg tcagctactg ggctatctgg 12720 acaagggaaa acgcaagcgc aaagagaaag caggtagctt gcagtgggct tacatggcga 12780 tagctagact gggcggtttt atggacagca agcgaaccgg aattgccagc tggggcgccc 12840 tctggtaagg ttgggaagcc ctgcaaagta aactggatgg ctttctcgcc gccaaggatc 12900 tgatggcgca ggggatcaag ctctgatcaa gagacaggat gaggatcgtt tcgcatgatt 12960 gaacaagatg gattgcacgc aggttctccg gccgcttggg tggagaggct attcggctat 13020 gactgggcac aacagacaat cggctgctct gatgccgccg tgttccggct gtcagcgcag 13080 gggcgcccgg ttctttttgt caagaccgac ctgtccggtg ccctgaatga actgcaagac 13140 gaggcagcgc ggctatcgtg gctggccacg acgggcgttc cttgcgcagc tgtgctcgac 13200 gttgtcactg aagcgggaag ggactggctg ctattgggcg aagtgccggg gcaggatctc 13260 ctgtcatctc accttgctcc tgccgagaaa gtatccatca tggctgatgc aatgcggcgg 13320 ctgcatacgc ttgatccggc tacctgccca ttcgaccacc aagcgaaaca tcgcatcgag 13380 cgagcacgta ctcggatgga agccggtctt gtcgatcagg atgatctgga cgaagagcat 13440 caggggctcg cgccagccga actgttcgcc aggctcaagg cgagcatgcc cgacggcgag 13500 gatctcgtcg tgacccatgg cgatgcctgc ttgccgaata tcatggtgga aaatggccgc 13560 ttttctggat tcatcgactg tggccggctg ggtgtggcgg accgctatca ggacatagcg 13620 ttggctaccc gtgatattgc tgaagagctt ggcggcgaat gggctgaccg cttcctcgtg 13680 ctttacggta tcgccgctcc cgattcgcag cgcatcgcct tctatcgcct tcttgacgag 13740 ttcttctgaa ttttgttaaa atttttgtta aatcagctca ttttttaacc aataggccga 13800 aatcggcaac atcccttata aatcaaaaga atagaccgcg atagggttga gtgttgttcc 13860 agtttggaac aagagtccac tattaaagaa cgtggactcc aacgtcaaag ggcgaaaaac 13920 cgtctatcag ggcgatggcc cactacgtga accatcaccc aaatcaagtt ttttgcggtc 13980 gaggtgccgt aaagctctaa atcggaaccc taaagggagc ccccgattta gagcttgacg 14040 gggaaagccg gcgaacgtgg cgagaaagga agggaagaaa gcgaaaggag cgggcgctag 14100 ggcgctggca agtgtagcgg tcacgctgcg cgtaaccacc acacccgcgc gcttaatgcg 14160 ccgctacagg gcgcgtccat tcgccattca ggatcgaatt aattcttaat 14210 <210> 40 <211> 14210 <212> DNA <213> Artificial Sequence <220> <223> pAVQ PEPCK Ribozyme HSV-TK WPRE(reverse) <400> 40 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 ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag tggcgcgccg tcgacgagct 540 ctttggggag tcctaagagg gcagctggca atggacacct agcagtccct ttgagactta 600 tttcagatgg agctgtagaa agatgccatg gctcacagtg cctccctggg aagggggcag 660 agggctgccc agtgaggcct cttgcgagca ggaaatcacc agagacaagg aaagaccaga 720 ccccaggatg acctcagtta ggccttgccc gactgtcctc agagtcccat tctctgtgtc 780 ctggttcttt tagaagatca tggacctcca ggtcatttcg taaccggaat ctgcctgcgg 840 ggggttttga caagctatgg tatagtgtat gtgggggtac tgacgaattg gaagatcatg 900 gagacccctt ctcctcctcc atcattggtc tgccacatcc ctcccaggcg actcacagca 960 gagagacctt ggatgtatgt agggtgcttt aaaactccag ctgagttaca gtctctcctt 1020 tctgttttca ccttaacctt ccagggatgc aaacccacga caggtttagc agcagagtgg 1080 aggctggcca tgaatctcag agaaagtgct cactggaaag gctggtttag cccaggcctg 1140 atgtggaggc actgagctgg acgttctagc ggggttgaca cccaacagtt tacatagggg 1200 gaggccaccc ctcctgagca gtctcggtga cttgaagagg aagccgcttc ttctgtacca 1260 acacagaagc tccagcgaac ccccagaatg ctggcagtgt gggtgctatg taaaagtatt 1320 tacatagctt tgtagagtga gccaagccca gtctgtttgg gatgactctt cacagtgcct 1380 cgaatctgtc acacgtctta gtaagcagag tcacagagtt tctgtcacat catcctcctg 1440 cctacaggga agtaggccat gtccctgccc cctactctga gcccagctgt gggagccagc 1500 cctgcccaat gggctctctc tgattggctt ctcactcact tctaaactcc agtgagcaac 1560 ttctctcggc tcgttcaatt ggcgtgaagg tctgtgtctt gcagagaagg ttcttcacaa 1620 ctgggataaa ggtctcgctg ctcaagtgta gcccagtaga actgccaagc cccttcccct 1680 cctctcccta gactcttgga tgcaagaaga atccaggcag ctccaagggt gattgtgtcc 1740 aacctagaat gtcttgaaaa agacattaag gggactagag aagacagggg atccaacggt 1800 tctctgcagc ccagcctgac tgacatgtaa ctcttctggt tctcaccagc cagctggacc 1860 tgcttagtat tctttctgcc tcagtttccc agcctgtacc cagggctgtc atagttccat 1920 ttcaggcagt agtaatgaat gagctgacat aaaacattta gagcaggggt cagtatgtat 1980 atagagtgat tattctatat caggcattgc ctcctcggaa tgaagcttac aatcacccct 2040 ccctctgcag ttcatcttgg ggtggccaga ggatccagca gacacctagt ggggtaacac 2100 accccagcca actcggctgt tgcagacttt gtctagaagt ttcacgtctc agagctgaat 2160 tcccttctca tgacctttgg ccgtgggagt gacacctcac agctgtggtg ttttgacaac 2220 cagcagccac tggcacacaa aatgtgcagc cagcagcata tgaagtccaa gaggcgtccc 2280 ggccagccct gtccttgacc cccacctgac aattaaggca agagcctata gtttgcatca 2340 gcaacagtca cggtcaaagt ttagtcaatc aaacgttgtg taaggactca actatggctg 2400 acacgggggc ctgaggcctc ccaacattca ttaacaacag caagttcaat cattatctcc 2460 ccaaagttta ttgtgttagg tcagttccaa accgtgctga ccatggctat gatccaaagg 2520 ccggcccctt acgtcagagg cgagcctcca ggtccagctg aggggcaggg ctgtcctccc 2580 ttctgtatac tatttaaagc gaggagggct agctaccaag cacggttggc cttccctctg 2640 ggaacacacc cttggccaac aggggaaatc cggcgagacg ctctgagatc ctgcgagaag 2700 gaggtgcgtc ctgctgcctg ccccggcact ctggctcccc agctcaaggt tcaggccttg 2760 ccccaggccg ggcctctggg tacctgaggt cttctcccgc tctgtgccct tctcctcacc 2820 tggctgcaat gagtggggga gcacggggct tctgcatgct gaaggcaccc cactcagcca 2880 ggcccttctt ctcctccagg tcccccacgg cccttcagat ccaaggccag cacgttcttc 2940 gcgccgcgct cgcacagcct ctgcagcact cgggccacca gctccttcag gcaggacacc 3000 tggcggaagg agggggcggc ggggggcggc cgtgcgtccc agggcacgca caccaggcac 3060 tgggccacca gcgcgcggaa agccgccggg tccccgcgct gcaccagccg ccagccctgg 3120 ggccccaggc gccgcacgaa cgtggccagc ggcagcacct cgcggtagtg gctgcgcagc 3180 agggagcgca cggctaggca gcggggagcg cgcggcatcg cgggggtggc cggggccagg 3240 gcttcccaag cttcgttttg cggcaggaaa agttatcagg catgcacctg gtagctagtc 3300 tttaaaccaa tagattgcat cggtttaaaa ggcaagaccg tcaaattgcg ggaaaggggt 3360 caacagccgt tcagtaccaa gtctcagggg aaactttgag atggccttgc aaagggtatg 3420 gtaataagct gacggacatg gtcctaacca cgcagccaag tcctaagtca acagatcttc 3480 tgttgatatg gatgcagttc acagactaaa tgtcggtcgg ggaagatgta ttcttctcat 3540 aagatatagt cggacctctc cttaatggga gctagcggat gaagtgatgc aacactggag 3600 ccgctgggaa ctaatttgta tgcgaaagta tattgattag ttttggagta ctcgcgaaaa 3660 cgcccaccat ggcttcgtac ccctgccatc aacacgcgtc tgcgttcgac caggctgcgc 3720 gttctcgcgg ccatagcaac cgacgtacgg cgttgcgccc tcgccggcag caagaagcca 3780 cggaagtccg cctggagcag aaaatgccca cgctactgcg ggtttatata gacggtcctc 3840 acgggatggg gaaaaccacc accacgcaac tgctggtggc cctgggttcg cgcgacgata 3900 tcgtctacgt acccgagccg atgacttact ggcaggtgct gggggcttcc gagacaatcg 3960 cgaacatcta caccacacaa caccgcctcg accagggtga gatatcggcc ggggacgcgg 4020 cggtggtaat gacaagcgcc cagataacaa tgggcatgcc ttatgccgtg accgacgccg 4080 ttctggctcc tcatatcggg ggggaggctg ggagctcaca tgccccgccc ccggccctca 4140 ccctcatctt cgaccgccat cccatcgccg ccctcctgtg ctacccggcc gcgcgatacc 4200 ttatgggcag catgaccccc caggccgtgc tggcgttcgt ggccctcatc ccgccgacct 4260 tgcccggcac aaacatcgtg ttgggggccc ttccggagga cagacacatc gaccgcctgg 4320 ccaaacgcca gcgccccggc gagcggcttg acctggctat gctggccgcg attcgccgcg 4380 tttacgggct gcttgccaat acggtgcggt atctgcaggg cggcgggtcg tggtgggagg 4440 attggggaca gctttcgggg acggccgtgc cgccccaggg tgccgagccc cagagcaacg 4500 cgggcccacg accccatatc ggggacacgt tatttaccct gtttcgggcc cccgagttgc 4560 tggcccccaa cggcgacctg tataacgtgt ttgcctgggc cttggacgtc ttggccaaac 4620 gcctccgtcc catgcacgtc tttatcctgg attacgacca atcgcccgcc ggctgccggg 4680 acgccctgct gcaacttacc tccgggatgg tccagaccca cgtcaccacc ccaggctcca 4740 taccgacgat ctgcgacctg gcgcgcacgt ttgcccggga gatgggggag gctaactgaa 4800 gcttgcggcc gcgcggggag gcggcccaaa gggagatccg actcgtctga gggcgaaggc 4860 gaagacgcgg aagaggccgc agagccggca gcaggccgcg ggaaggaagg tccgctggat 4920 tgagggccga agggacgtag cagaaggacg tcccgcgcag aatccaggtg gcaacacagg 4980 cgagcagcca aggaaaggac gatgatttcc ccgacaacac cacggaattg tcagtgccca 5040 acagccgagc ccctgtccag cagcgggcaa ggcaggcggc gatgagttcc gccgtggcaa 5100 tagggagggg gaaagcgaaa gtcccggaaa ggagctgaca ggtggtggca atgccccaac 5160 cagtgggggt tgcgtcagca aacacagtgc acaccacgcc acgttgcctg acaacgggcc 5220 acaactcctc ataaagagac agcaaccagg atttatacaa ggaggagaaa atgaaagcca 5280 tacgggaagc aatagcatga tacaaaggca ttaaagcagc gtatccacat agcgtaaaag 5340 gagcaacata gttaagaata ccagtcaatc tttcacaaat tttgtaatcc agaggttgat 5400 tgcggccgcg ggtggcatcc ctgtgacccc tccccagtgc ctctcctggc cctggaagtt 5460 gccactccag tgcccaccag ccttgtccta ataaaattaa gttgcatcat tttgtctgac 5520 taggtgtcct tctataatat tatggggtgg aggggggtgg tatggagcaa ggggcaagtt 5580 gggaagacaa cctgtagggc ctgcggggtc tattgggaac caagctggag tgcagtggca 5640 caatcttggc tcactgcaat ctccgcctcc tgggttcaag cgattctcct gcctcagcct 5700 cccgagttgt tgggattcca ggcatgcatg accaggctca gctaattttt gtttttttgg 5760 tagagacggg gtttcaccat attggccagg ctggtctcca actcctaatc tcaggtgatc 5820 tacccacctt ggcctcccaa attgctggga ttacaggcgt gaaccactgc tcccttccct 5880 gtccttctga ttttaaaata actataccag caggaggacg tccagacaca gcataggcta 5940 cctggccatg cccaaccggt gggacatttg agttgcttgc ttggcactgt cctctcatgc 6000 gttgggtcca ctcagtagat gcctgcaggc tcagaggcac acaggagttt ctgggctcac 6060 cctgccccct tccaacccct cagttcccat cctccagcag ctgtttgtgt gctgcctctg 6120 aagtccacac tgaacaaact tcagcctact catgtcccta aaatgggcaa acattgcaag 6180 cagcaaacag caaacacaca gccctccctg cctgctgacc ttggagctgg ggcagaggtc 6240 agagacctct ctgggcccat gccacctcca acatccactc gaccccttgg aatttcggtg 6300 gagaggagca gaggttgtcc tggcgtggtt taggtagtgt gagagggtcc gggttcaaaa 6360 ccacttgctg ggtggggagt cgtcagtaag tggctatgcc ccgaccccga agcctgtttc 6420 cccatctgta caatggaaat gataaagacg cccatctgat agggtttttg tggcaaataa 6480 acatttggtt tttttgtttt gttttgtttt gttttttgag atggaggttt gctctgtcgc 6540 ccaggctgga gtgcagtgac acaatctcat ctcaccacaa ccttcccctg cctcagcctc 6600 ccaagtagct gggattacaa gcatgtgcca ccacacctgg ctaattttct atttttagta 6660 gagacgggtt tctccatgtt ggtcagcctc agcctcccaa gtaactggga ttacaggcct 6720 gtgccaccac acccggctaa ttttttctat ttttgacagg gacggggttt caccatgttg 6780 gtcaggctgg tctagaactc ctgacctcaa atgatccacc cacctaggcc tcccaaagtg 6840 cacagattac aggcgtgggc caccgcacct ggccaaattt ttaatttttt tctagagata 6900 gggtcttact gtgttgccca ggctggtgtc aaactcctgg gctcaagcag atcctcctgc 6960 ctcagcttcc caaagtggtg ggattatagg tgtgagccac tgcgcccagt cagtagcccc 7020 ctctttgccc ctcactgagc cctactggat gttcttggtt gtgtgacagt ttccccatct 7080 attaaacaga aacccctata gcagagggga ggatgaggtt ggaaaatcag gagcattgtt 7140 attctattct tgtgggatcg gggaagcaga catctgggtg gatgtttggg gaatgctggg 7200 ctcagttgag gaagtagggg ggcccctggg gcttacaggg actggaagct ctgagctggc 7260 cagagggatg ttgcaatcct gccagggtct tgtctatgct gtccctttca caaccatccc 7320 cctaccgcca ggctgacacg tggttgtggg ggcacaaggc cagccgaact agagtctgag 7380 gctgggctga ggacaccctc cccatcagct gccagggtca ctggcggtca aaggcagctg 7440 gtggggaagg aattggactc cagccctggg ggacggatgt ggtgatggtg ggaagcaggc 7500 ttggtgccag gaggggcatc agagggtgaa taagagcaga tagagtgttt gggggaggta 7560 gccagccaaa gggggtgagg cccggtggaa gggaagaagg ggcatacact cagagctttg 7620 cagctgaagg ttttaatttt ttgagatggg gtctcactct gtctcaccag gctggagtgc 7680 agtggcgcaa tcacagctca ctgcagacgc gtgaattcct cgagtctaga ggagcatgcg 7740 cgtcggcgcg ccttcgaagg cgaaagatcc caacgaaaag agagaccaca tggtccttct 7800 tgagtttgta acagctgctg ggattacaca tggcatggat gaactgtaca actgaggatc 7860 ccccgacctc gacctctggc taataaagga aatttatttt cattgcaata gtgtgttgga 7920 attttttgtg tctctcactc ggaaggacat atgggagggc aaatcatttg gtcgagatcc 7980 ctcggagatc ggatctgggc gtggttaagg gtgggaaaga atatataagg tgggggtctt 8040 atgtagtttt gtatctgttt tgcagcagcc gccgccgcca tgagcaccaa ctcgtttgat 8100 ggaagcattg tgagctcata tttgacaacg cgcatgcccc catgggccgg ggtgcgtcag 8160 aatgtgatgg gctccagcat tgatggtcgc cccgtcctgc ccgcaaactc tactaccttg 8220 acctacgaga ccgtgtctgg aacgccgttg gagactgcag cctccgccgc cgcttcagcc 8280 gctgcagcca ccgcccgcgg gattgtgact gactttgctt tcctgagccc gcttgcaagc 8340 agtgcagctt cccgttcatc cgcccgcgat gacaagttga cggctctttt ggcacaattg 8400 gattctttga cccgggaact taatgtcgtt tctcagcagc tgttggatct gcgccagcag 8460 gtttctgccc tgaaggcttc ctcccctccc aatgcggttt aaaacataaa taaaaaacca 8520 gactctgttt ggatttggat caagcaagtg tcttgctgtc tttatttagg ggttttgcgc 8580 gcgcggtagg cccgggacca gcggtctcgg tcgttgaggg tcctgtgtat tttttccagg 8640 acgtggtaaa ggtgactctg gatgttcaga tacatgggca taagcccgtc tctggggtgg 8700 aggtagcacc actgcagagc ttcatgctgc ggggtggtgt tgtagatgat ccagtcgtag 8760 caggagcgct gggcgtggtg cctaaaaatg tctttcagta gcaagctgat tgccaggggc 8820 aggcccttgg tgtaagtgtt tacaaagcgg ttaagctggg atgggtgcat acgtggggat 8880 atgagatgca tcttggactg tatttttagg ttggctatgt tcccagccat atccctccgg 8940 ggattcatgt tgtgcagaac caccagcaca gtgtatccgg tgcacttggg aaatttgtca 9000 tgtagcttag aaggaaatgc gtggaagaac ttggagacgc ccttgtgacc tccaagattt 9060 tccatgcatt cgtccataat gatggcaatg ggcccacggg cggcggcctg ggcgaagata 9120 tttctgggat cactaacgtc atagttgtgt tccaggatga gatcgtcata ggccattttt 9180 acaaagcgcg ggcggagggt gccagactgc ggtataatgg ttccatccgg cccaggggcg 9240 tagttaccct cacagatttg catttcccac gctttgagtt cagatggggg gatcatgtct 9300 acctgcgggg cgatgaagaa aacggtttcc ggggtagggg agatcagctg ggaagaaagc 9360 aggttcctga gcagctgcga cttaccgcag ccggtgggcc cgtaaatcac acctattacc 9420 gggtgcaact ggtagttaag agagctgcag ctgccgtcat ccctgagcag gggggccact 9480 tcgttaagca tgtccctgac tcgcatgttt tccctgacca aatccgccag aaggcgctcg 9540 ccgcccagcg atagcagttc ttgcaaggaa gcaaagtttt tcaacggttt gagaccgtcc 9600 gccgtaggca tgcttttgag cgtttgacca agcagttcca ggcggtccca cagctcggtc 9660 acctgctcta cggcatctcg atccagcata tctcctcgtt tcgcgggttg gggcggcttt 9720 cgctgtacgg cagtagtcgg tgctcgtcca gacgggccag ggtcatgtct ttccacgggc 9780 gcagggtcct cgtcagcgta gtctgggtca cggtgaaggg gtgcgctccg ggctgcgcgc 9840 tggccagggt gcgcttgagg ctggtcctgc tggtgctgaa gcgctgccgg tcttcgccct 9900 gcgcgtcggc caggtagcat ttgaccatgg tgtcatagtc cagcccctcc gcggcgtggc 9960 ccttggcgcg cagcttgccc ttggaggagg cgccgcacga ggggcagtgc agacttttga 10020 gggcgtagag cttgggcgcg agaaataccg attccgggga gtaggcatcc gcgccgcagg 10080 ccccgcagac ggtctcgcat tccacgagcc aggtgagctc tggccgttcg gggtcaaaaa 10140 ccaggtttcc cccatgcttt ttgatgcgtt tcttacctct ggtttccatg agccggtgtc 10200 cacgctcggt gacgaaaagg ctgtccgtgt ccccgtatac agacttgaga gggagtttaa 10260 acgaattcaa tagcttgttg catgggcggc gatataaaat gcaaggtgct gctcaaaaaa 10320 tcaggcaaag cctcgcgcaa aaaagaaagc acatcgtagt catgctcatg cagataaagg 10380 caggtaagct ccggaaccac cacagaaaaa gacaccattt ttctctcaaa catgtctgcg 10440 ggtttctgca taaacacaaa ataaaataac aaaaaaacat ttaaacatta gaagcctgtc 10500 ttacaacagg aaaaacaacc cttataagca taagacggac tacggccatg ccggcgtgac 10560 cgtaaaaaaa ctggtcaccg tgattaaaaa gcaccaccga cagctcctcg gtcatgtccg 10620 gagtcataat gtaagactcg gtaaacacat caggttgatt catcggtcag tgctaaaaag 10680 cgaccgaaat agcccggggg aatacatacc cgcaggcgta gagacaacat tacagccccc 10740 ataggaggta taacaaaatt aataggagag aaaaacacat aaacacctga aaaaccctcc 10800 tgcctaggca aaatagcacc ctcccgctcc agaacaacat acagcgcttc acagcggcag 10860 cctaacagtc agccttacca gtaaaaaaga aaacctatta aaaaaacacc actcgacacg 10920 gcaccagctc aatcagtcac agtgtaaaaa agggccaagt gcagagcgag tatatatagg 10980 actaaaaaat gacgtaacgg ttaaagtcca caaaaaacac ccagaaaacc gcacgcgaac 11040 ctacgcccag aaacgaaagc caaaaaaccc acaacttcct caaatcgtca cttccgtttt 11100 cccacgttac gtaacttccc attttaagaa aactacaatt cccaacacat acaagttact 11160 ccgccctaaa acctacgtca cccgccccgt tcccacgccc cgcgccacgt cacaaactcc 11220 accccctcat tatcatattg gcttcaatcc aaaataaggt atattattga tgatgttaat 11280 taacatgcat ggatccatat gcggtgtgaa ataccgcaca gatgcgtaag gagaaaatac 11340 cgcatcaggc gctcttccgc ttcctcgctc actgactcgc tgcgctcggt cgttcggctg 11400 cggcgagcgg tatcagctca ctcaaaggcg gtaatacggt tatccacaga atcaggggat 11460 aacgcaggaa agaacatgtg agcaaaaggc cagcaaaagg ccaggaaccg taaaaaggcc 11520 gcgttgctgg cgtttttcca taggctccgc ccccctgacg agcatcacaa aaatcgacgc 11580 tcaagtcaga ggtggcgaaa cccgacagga ctataaagat accaggcgtt tccccctgga 11640 agctccctcg tgcgctctcc tgttccgacc ctgccgctta ccggatacct gtccgccttt 11700 ctcccttcgg gaagcgtggc gctttctcat agctcacgct gtaggtatct cagttcggtg 11760 taggtcgttc gctccaagct gggctgtgtg cacgaacccc ccgttcagcc cgaccgctgc 11820 gccttatccg gtaactatcg tcttgagtcc aacccggtaa gacacgactt atcgccactg 11880 gcagcagcca ctggtaacag gattagcaga gcgaggtatg taggcggtgc tacagagttc 11940 ttgaagtggt ggcctaacta cggctacact agaaggacag tatttggtat ctgcgctctg 12000 ctgaagccag ttaccttcgg aaaaagagtt ggtagctctt gatccggcaa acaaaccacc 12060 gctggtagcg gtggtttttt tgtttgcaag cagcagatta cgcgcagaaa aaaaggatct 12120 caagaagatc ctttgatctt ttctacgggg tctgacgctc agtggaacga aaactcacgt 12180 taagggattt tggtcatgag attatcaaaa aggatcttca cctagatcct tttaaattaa 12240 aaatgaagtt ttaaatcaat ctaaagtata tatgagtaaa cttggtctga cagttaccaa 12300 tgcttaatca gtgaggcacc tatctcagcg atctgtctat ttcgttcatc catagttgcc 12360 tgactccccg tcgtgtagat aactacgata cgggagggct taccatctgg ccccagtgct 12420 gcaatgatac cgcgagaccc acgctcaccg gctccagatt tatcagcaat aaaccagcca 12480 gccggaaggg ccgagcgcag aagtggtcct gcaactttat ccgcctccat ccagtctatt 12540 aattgttgcc gggaagctag agtaagtagt tcgccagtta atagtttgcg caacgttgtt 12600 gccattgctg cagccatgag attatcaaaa aggatcttca cctagatcct tttcacgtag 12660 aaagccagtc cgcagaaacg gtgctgaccc cggatgaatg tcagctactg ggctatctgg 12720 acaagggaaa acgcaagcgc aaagagaaag caggtagctt gcagtgggct tacatggcga 12780 tagctagact gggcggtttt atggacagca agcgaaccgg aattgccagc tggggcgccc 12840 tctggtaagg ttgggaagcc ctgcaaagta aactggatgg ctttctcgcc gccaaggatc 12900 tgatggcgca ggggatcaag ctctgatcaa gagacaggat gaggatcgtt tcgcatgatt 12960 gaacaagatg gattgcacgc aggttctccg gccgcttggg tggagaggct attcggctat 13020 gactgggcac aacagacaat cggctgctct gatgccgccg tgttccggct gtcagcgcag 13080 gggcgcccgg ttctttttgt caagaccgac ctgtccggtg ccctgaatga actgcaagac 13140 gaggcagcgc ggctatcgtg gctggccacg acgggcgttc cttgcgcagc tgtgctcgac 13200 gttgtcactg aagcgggaag ggactggctg ctattgggcg aagtgccggg gcaggatctc 13260 ctgtcatctc accttgctcc tgccgagaaa gtatccatca tggctgatgc aatgcggcgg 13320 ctgcatacgc ttgatccggc tacctgccca ttcgaccacc aagcgaaaca tcgcatcgag 13380 cgagcacgta ctcggatgga agccggtctt gtcgatcagg atgatctgga cgaagagcat 13440 caggggctcg cgccagccga actgttcgcc aggctcaagg cgagcatgcc cgacggcgag 13500 gatctcgtcg tgacccatgg cgatgcctgc ttgccgaata tcatggtgga aaatggccgc 13560 ttttctggat tcatcgactg tggccggctg ggtgtggcgg accgctatca ggacatagcg 13620 ttggctaccc gtgatattgc tgaagagctt ggcggcgaat gggctgaccg cttcctcgtg 13680 ctttacggta tcgccgctcc cgattcgcag cgcatcgcct tctatcgcct tcttgacgag 13740 ttcttctgaa ttttgttaaa atttttgtta aatcagctca ttttttaacc aataggccga 13800 aatcggcaac atcccttata aatcaaaaga atagaccgcg atagggttga gtgttgttcc 13860 agtttggaac aagagtccac tattaaagaa cgtggactcc aacgtcaaag ggcgaaaaac 13920 cgtctatcag ggcgatggcc cactacgtga accatcaccc aaatcaagtt ttttgcggtc 13980 gaggtgccgt aaagctctaa atcggaaccc taaagggagc ccccgattta gagcttgacg 14040 gggaaagccg gcgaacgtgg cgagaaagga agggaagaaa gcgaaaggag cgggcgctag 14100 ggcgctggca agtgtagcgg tcacgctgcg cgtaaccacc acacccgcgc gcttaatgcg 14160 ccgctacagg gcgcgtccat tcgccattca ggatcgaatt aattcttaat 14210 <210> 41 <211> 14413 <212> DNA <213> Artificial Sequence <220> <223> pAVQ PEPCK SD/SA Ribozyme HSV-TK WPRE <400> 41 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 ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag tggcgcgccg tcgacgagct 540 ctttggggag tcctaagagg gcagctggca atggacacct agcagtccct ttgagactta 600 tttcagatgg agctgtagaa agatgccatg gctcacagtg cctccctggg aagggggcag 660 agggctgccc agtgaggcct cttgcgagca ggaaatcacc agagacaagg aaagaccaga 720 ccccaggatg acctcagtta ggccttgccc gactgtcctc agagtcccat tctctgtgtc 780 ctggttcttt tagaagatca tggacctcca ggtcatttcg taaccggaat ctgcctgcgg 840 ggggttttga caagctatgg tatagtgtat gtgggggtac tgacgaattg gaagatcatg 900 gagacccctt ctcctcctcc atcattggtc tgccacatcc ctcccaggcg actcacagca 960 gagagacctt ggatgtatgt agggtgcttt aaaactccag ctgagttaca gtctctcctt 1020 tctgttttca ccttaacctt ccagggatgc aaacccacga caggtttagc agcagagtgg 1080 aggctggcca tgaatctcag agaaagtgct cactggaaag gctggtttag cccaggcctg 1140 atgtggaggc actgagctgg acgttctagc ggggttgaca cccaacagtt tacatagggg 1200 gaggccaccc ctcctgagca gtctcggtga cttgaagagg aagccgcttc ttctgtacca 1260 acacagaagc tccagcgaac ccccagaatg ctggcagtgt gggtgctatg taaaagtatt 1320 tacatagctt tgtagagtga gccaagccca gtctgtttgg gatgactctt cacagtgcct 1380 cgaatctgtc acacgtctta gtaagcagag tcacagagtt tctgtcacat catcctcctg 1440 cctacaggga agtaggccat gtccctgccc cctactctga gcccagctgt gggagccagc 1500 cctgcccaat gggctctctc tgattggctt ctcactcact tctaaactcc agtgagcaac 1560 ttctctcggc tcgttcaatt ggcgtgaagg tctgtgtctt gcagagaagg ttcttcacaa 1620 ctgggataaa ggtctcgctg ctcaagtgta gcccagtaga actgccaagc cccttcccct 1680 cctctcccta gactcttgga tgcaagaaga atccaggcag ctccaagggt gattgtgtcc 1740 aacctagaat gtcttgaaaa agacattaag gggactagag aagacagggg atccaacggt 1800 tctctgcagc ccagcctgac tgacatgtaa ctcttctggt tctcaccagc cagctggacc 1860 tgcttagtat tctttctgcc tcagtttccc agcctgtacc cagggctgtc atagttccat 1920 ttcaggcagt agtaatgaat gagctgacat aaaacattta gagcaggggt cagtatgtat 1980 atagagtgat tattctatat caggcattgc ctcctcggaa tgaagcttac aatcacccct 2040 ccctctgcag ttcatcttgg ggtggccaga ggatccagca gacacctagt ggggtaacac 2100 accccagcca actcggctgt tgcagacttt gtctagaagt ttcacgtctc agagctgaat 2160 tcccttctca tgacctttgg ccgtgggagt gacacctcac agctgtggtg ttttgacaac 2220 cagcagccac tggcacacaa aatgtgcagc cagcagcata tgaagtccaa gaggcgtccc 2280 ggccagccct gtccttgacc cccacctgac aattaaggca agagcctata gtttgcatca 2340 gcaacagtca cggtcaaagt ttagtcaatc aaacgttgtg taaggactca actatggctg 2400 acacgggggc ctgaggcctc ccaacattca ttaacaacag caagttcaat cattatctcc 2460 ccaaagttta ttgtgttagg tcagttccaa accgtgctga ccatggctat gatccaaagg 2520 ccggcccctt acgtcagagg cgagcctcca ggtccagctg aggggcaggg ctgtcctccc 2580 ttctgtatac tatttaaagc gaggagggct agctaccaag cacggttggc cttccctctg 2640 ggaacacacc cttggccaac aggggaaatc cggcgagacg ctctgagatc ctgcgagaag 2700 gaggtgcgtc ctgctgcctg ccccggcact ctggctcccc agctcaaggt tcaggccttg 2760 ccccaggccg ggcctctggg tacctgaggt cttctcccgc tctgtgccct tctcctcacc 2820 tggctgcaat gagtggggga gcacggggct tctgcatgct gaaggcaccc cactcagcca 2880 ggcccttctt ctcctccagg tcccccacgg cccttcagat ctgaactgaa aaaccagaaa 2940 gttaactggt aagtttagtc tttttgtctt ttatttcagg tcccggatcc ggtggtggtg 3000 caaatcaaag aactgctcct cagtggatgt tgcctttact tctaggcctg tacggaagtg 3060 ttacttctgc tctaaaagct gcggaattgt acccaggcct aggcttttgc aaaaagcttc 3120 gaatcgcgaa aggccagcac gttcttcgcg ccgcgctcgc acagcctctg cagcactcgg 3180 gccaccagct ccttcaggca ggacacctgg cggaaggagg gggcggcggg gggcggccgt 3240 gcgtcccagg gcacgcacac caggcactgg gccaccagcg cgcggaaagc cgccgggtcc 3300 ccgcgctgca ccagccgcca gccctggggc cccaggcgcc gcacgaacgt ggccagcggc 3360 agcacctcgc ggtagtggct gcgcagcagg gagcgcacgg ctaggcagcg gggagcgcgc 3420 ggcatcgcgg gggtggccgg ggccagggct tcccaagctt cgttttgcgg caggaaaagt 3480 tatcaggcat gcacctggta gctagtcttt aaaccaatag attgcatcgg tttaaaaggc 3540 aagaccgtca aattgcggga aaggggtcaa cagccgttca gtaccaagtc tcaggggaaa 3600 ctttgagatg gccttgcaaa gggtatggta ataagctgac ggacatggtc ctaaccacgc 3660 agccaagtcc taagtcaaca gatcttctgt tgatatggat gcagttcaca gactaaatgt 3720 cggtcgggga agatgtattc ttctcataag atatagtcgg acctctcctt aatgggagct 3780 agcggatgaa gtgatgcaac actggagccg ctgggaacta atttgtatgc gaaagtatat 3840 tgattagttt tggagtactc gcgaaaacgc ccaccatggc ttcgtacccc tgccatcaac 3900 acgcgtctgc gttcgaccag gctgcgcgtt ctcgcggcca tagcaaccga cgtacggcgt 3960 tgcgccctcg ccggcagcaa gaagccacgg aagtccgcct ggagcagaaa atgcccacgc 4020 tactgcgggt ttatatagac ggtcctcacg ggatggggaa aaccaccacc acgcaactgc 4080 tggtggccct gggttcgcgc gacgatatcg tctacgtacc cgagccgatg acttactggc 4140 aggtgctggg ggcttccgag acaatcgcga acatctacac cacacaacac cgcctcgacc 4200 agggtgagat atcggccggg gacgcggcgg tggtaatgac aagcgcccag ataacaatgg 4260 gcatgcctta tgccgtgacc gacgccgttc tggctcctca tatcgggggg gaggctggga 4320 gctcacatgc cccgcccccg gccctcaccc tcatcttcga ccgccatccc atcgccgccc 4380 tcctgtgcta cccggccgcg cgatacctta tgggcagcat gaccccccag gccgtgctgg 4440 cgttcgtggc cctcatcccg ccgaccttgc ccggcacaaa catcgtgttg ggggcccttc 4500 cggaggacag acacatcgac cgcctggcca aacgccagcg ccccggcgag cggcttgacc 4560 tggctatgct ggccgcgatt cgccgcgttt acgggctgct tgccaatacg gtgcggtatc 4620 tgcagggcgg cgggtcgtgg tgggaggatt ggggacagct ttcggggacg gccgtgccgc 4680 cccagggtgc cgagccccag agcaacgcgg gcccacgacc ccatatcggg gacacgttat 4740 ttaccctgtt tcgggccccc gagttgctgg cccccaacgg cgacctgtat aacgtgtttg 4800 cctgggcctt ggacgtcttg gccaaacgcc tccgtcccat gcacgtcttt atcctggatt 4860 acgaccaatc gcccgccggc tgccgggacg ccctgctgca acttacctcc gggatggtcc 4920 agacccacgt caccacccca ggctccatac cgacgatctg cgacctggcg cgcacgtttg 4980 cccgggagat gggggaggct aactgaaggc cggccaatca acctctggat tacaaaattt 5040 gtgaaagatt gactggtatt cttaactatg ttgctccttt tacgctatgt ggatacgctg 5100 ctttaatgcc tttgtatcat gctattgctt cccgtatggc tttcattttc tcctccttgt 5160 ataaatcctg gttgctgtct ctttatgagg agttgtggcc cgttgtcagg caacgtggcg 5220 tggtgtgcac tgtgtttgct gacgcaaccc ccactggttg gggcattgcc accacctgtc 5280 agctcctttc cgggactttc gctttccccc tccctattgc cacggcggaa ctcatcgccg 5340 cctgccttgc ccgctgctgg acaggggctc ggctgttggg cactgacaat tccgtggtgt 5400 tgtcggggaa atcatcgtcc tttccttggc tgctcgcctg tgttgccacc tggattctgc 5460 gcgggacgtc cttctgctac gtcccttcgg ccctcaatcc agcggacctt ccttcccgcg 5520 gcctgctgcc ggctctgcgg cctcttccgc gtcttcgcct tcgccctcag acgagtcgga 5580 tctccctttg ggccgcctcc ccgcgggtgg catccctgtg acccctcccc agtgcctctg 5640 cggccgccct ggccctggaa gttgccactc cagtgcccac cagccttgtc ctaataaaat 5700 taagttgcat cattttgtct gactaggtgt ccttctataa tattatgggg tggagggggg 5760 tggtatggag caaggggcaa gttgggaaga caacctgtag ggcctgcggg gtctattggg 5820 aaccaagctg gagtgcagtg gcacaatctt ggctcactgc aatctccgcc tcctgggttc 5880 aagcgattct cctgcctcag cctcccgagt tgttgggatt ccaggcatgc atgaccaggc 5940 tcagctaatt tttgtttttt tggtagagac ggggtttcac catattggcc aggctggtct 6000 ccaactccta atctcaggtg atctacccac cttggcctcc caaattgctg ggattacagg 6060 cgtgaaccac tgctcccttc cctgtccttc tgattttaaa ataactatac cagcaggagg 6120 acgtccagac acagcatagg ctacctggcc atgcccaacc ggtgggacat ttgagttgct 6180 tgcttggcac tgtcctctca tgcgttgggt ccactcagta gatgcctgca ggctcagagg 6240 cacacaggag tttctgggct caccctgccc ccttccaacc cctcagttcc catcctccag 6300 cagctgtttg tgtgctgcct ctgaagtcca cactgaacaa acttcagcct actcatgtcc 6360 ctaaaatggg caaacattgc aagcagcaaa cagcaaacac acagccctcc ctgcctgctg 6420 accttggagc tggggcagag gtcagagacc tctctgggcc catgccacct ccaacatcca 6480 ctcgacccct tggaatttcg gtggagagga gcagaggttg tcctggcgtg gtttaggtag 6540 tgtgagaggg tccgggttca aaaccacttg ctgggtgggg agtcgtcagt aagtggctat 6600 gccccgaccc cgaagcctgt ttccccatct gtacaatgga aatgataaag acgcccatct 6660 gatagggttt ttgtggcaaa taaacatttg gtttttttgt tttgttttgt tttgtttttt 6720 gagatggagg tttgctctgt cgcccaggct ggagtgcagt gacacaatct catctcacca 6780 caaccttccc ctgcctcagc ctcccaagta gctgggatta caagcatgtg ccaccacacc 6840 tggctaattt tctattttta gtagagacgg gtttctccat gttggtcagc ctcagcctcc 6900 caagtaactg ggattacagg cctgtgccac cacacccggc taattttttc tatttttgac 6960 agggacgggg tttcaccatg ttggtcaggc tggtctagaa ctcctgacct caaatgatcc 7020 acccacctag gcctcccaaa gtgcacagat tacaggcgtg ggccaccgca cctggccaaa 7080 tttttaattt ttttctagag atagggtctt actgtgttgc ccaggctggt gtcaaactcc 7140 tgggctcaag cagatcctcc tgcctcagct tcccaaagtg gtgggattat aggtgtgagc 7200 cactgcgccc agtcagtagc cccctctttg cccctcactg agccctactg gatgttcttg 7260 gttgtgtgac agtttcccca tctattaaac agaaacccct atagcagagg ggaggatgag 7320 gttggaaaat caggagcatt gttattctat tcttgtggga tcggggaagc agacatctgg 7380 gtggatgttt ggggaatgct gggctcagtt gaggaagtag gggggcccct ggggcttaca 7440 gggactggaa gctctgagct ggccagaggg atgttgcaat cctgccaggg tcttgtctat 7500 gctgtccctt tcacaaccat ccccctaccg ccaggctgac acgtggttgt gggggcacaa 7560 ggccagccga actagagtct gaggctgggc tgaggacacc ctccccatca gctgccaggg 7620 tcactggcgg tcaaaggcag ctggtgggga aggaattgga ctccagccct gggggacgga 7680 tgtggtgatg gtgggaagca ggcttggtgc caggaggggc atcagagggt gaataagagc 7740 agatagagtg tttgggggag gtagccagcc aaagggggtg aggcccggtg gaagggaaga 7800 aggggcatac actcagagct ttgcagctga aggttttaat tttttgagat ggggtctcac 7860 tctgtctcac caggctggag tgcagtggcg caatcacagc tcactgcaga cgcgtgaatt 7920 cctcgagtct agaggagcat gcgcgtcggc gcgccttcga aggcgaaaga tcccaacgaa 7980 aagagagacc acatggtcct tcttgagttt gtaacagctg ctgggattac acatggcatg 8040 gatgaactgt acaactgagg atcccccgac ctcgacctct ggctaataaa ggaaatttat 8100 tttcattgca atagtgtgtt ggaatttttt gtgtctctca ctcggaagga catatgggag 8160 ggcaaatcat ttggtcgaga tccctcggag atcggatctg ggcgtggtta agggtgggaa 8220 agaatatata aggtgggggt cttatgtagt tttgtatctg ttttgcagca gccgccgccg 8280 ccatgagcac caactcgttt gatggaagca ttgtgagctc atatttgaca acgcgcatgc 8340 ccccatgggc cggggtgcgt cagaatgtga tgggctccag cattgatggt cgccccgtcc 8400 tgcccgcaaa ctctactacc ttgacctacg agaccgtgtc tggaacgccg ttggagactg 8460 cagcctccgc cgccgcttca gccgctgcag ccaccgcccg cgggattgtg actgactttg 8520 ctttcctgag cccgcttgca agcagtgcag cttcccgttc atccgcccgc gatgacaagt 8580 tgacggctct tttggcacaa ttggattctt tgacccggga acttaatgtc gtttctcagc 8640 agctgttgga tctgcgccag caggtttctg ccctgaaggc ttcctcccct cccaatgcgg 8700 tttaaaacat aaataaaaaa ccagactctg tttggatttg gatcaagcaa gtgtcttgct 8760 gtctttattt aggggttttg cgcgcgcggt aggcccggga ccagcggtct cggtcgttga 8820 gggtcctgtg tattttttcc aggacgtggt aaaggtgact ctggatgttc agatacatgg 8880 gcataagccc gtctctgggg tggaggtagc accactgcag agcttcatgc tgcggggtgg 8940 tgttgtagat gatccagtcg tagcaggagc gctgggcgtg gtgcctaaaa atgtctttca 9000 gtagcaagct gattgccagg ggcaggccct tggtgtaagt gtttacaaag cggttaagct 9060 gggatgggtg catacgtggg gatatgagat gcatcttgga ctgtattttt aggttggcta 9120 tgttcccagc catatccctc cggggattca tgttgtgcag aaccaccagc acagtgtatc 9180 cggtgcactt gggaaatttg tcatgtagct tagaaggaaa tgcgtggaag aacttggaga 9240 cgcccttgtg acctccaaga ttttccatgc attcgtccat aatgatggca atgggcccac 9300 gggcggcggc ctgggcgaag atatttctgg gatcactaac gtcatagttg tgttccagga 9360 tgagatcgtc ataggccatt tttacaaagc gcgggcggag ggtgccagac tgcggtataa 9420 tggttccatc cggcccaggg gcgtagttac cctcacagat ttgcatttcc cacgctttga 9480 gttcagatgg ggggatcatg tctacctgcg gggcgatgaa gaaaacggtt tccggggtag 9540 gggagatcag ctgggaagaa agcaggttcc tgagcagctg cgacttaccg cagccggtgg 9600 gcccgtaaat cacacctatt accgggtgca actggtagtt aagagagctg cagctgccgt 9660 catccctgag caggggggcc acttcgttaa gcatgtccct gactcgcatg ttttccctga 9720 ccaaatccgc cagaaggcgc tcgccgccca gcgatagcag ttcttgcaag gaagcaaagt 9780 ttttcaacgg tttgagaccg tccgccgtag gcatgctttt gagcgtttga ccaagcagtt 9840 ccaggcggtc ccacagctcg gtcacctgct ctacggcatc tcgatccagc atatctcctc 9900 gtttcgcggg ttggggcggc tttcgctgta cggcagtagt cggtgctcgt ccagacgggc 9960 cagggtcatg tctttccacg ggcgcagggt cctcgtcagc gtagtctggg tcacggtgaa 10020 ggggtgcgct ccgggctgcg cgctggccag ggtgcgcttg aggctggtcc tgctggtgct 10080 gaagcgctgc cggtcttcgc cctgcgcgtc ggccaggtag catttgacca tggtgtcata 10140 gtccagcccc tccgcggcgt ggcccttggc gcgcagcttg cccttggagg aggcgccgca 10200 cgaggggcag tgcagacttt tgagggcgta gagcttgggc gcgagaaata ccgattccgg 10260 ggagtaggca tccgcgccgc aggccccgca gacggtctcg cattccacga gccaggtgag 10320 ctctggccgt tcggggtcaa aaaccaggtt tcccccatgc tttttgatgc gtttcttacc 10380 tctggtttcc atgagccggt gtccacgctc ggtgacgaaa aggctgtccg tgtccccgta 10440 tacagacttg agagggagtt taaacgaatt caatagcttg ttgcatgggc ggcgatataa 10500 aatgcaaggt gctgctcaaa aaatcaggca aagcctcgcg caaaaaagaa agcacatcgt 10560 agtcatgctc atgcagataa aggcaggtaa gctccggaac caccacagaa aaagacacca 10620 tttttctctc aaacatgtct gcgggtttct gcataaacac aaaataaaat aacaaaaaaa 10680 catttaaaca ttagaagcct gtcttacaac aggaaaaaca acccttataa gcataagacg 10740 gactacggcc atgccggcgt gaccgtaaaa aaactggtca ccgtgattaa aaagcaccac 10800 cgacagctcc tcggtcatgt ccggagtcat aatgtaagac tcggtaaaca catcaggttg 10860 attcatcggt cagtgctaaa aagcgaccga aatagcccgg gggaatacat acccgcaggc 10920 gtagagacaa cattacagcc cccataggag gtataacaaa attaatagga gagaaaaaca 10980 cataaacacc tgaaaaaccc tcctgcctag gcaaaatagc accctcccgc tccagaacaa 11040 catacagcgc ttcacagcgg cagcctaaca gtcagcctta ccagtaaaaa agaaaaccta 11100 ttaaaaaaac accactcgac acggcaccag ctcaatcagt cacagtgtaa aaaagggcca 11160 agtgcagagc gagtatatat aggactaaaa aatgacgtaa cggttaaagt ccacaaaaaa 11220 cacccagaaa accgcacgcg aacctacgcc cagaaacgaa agccaaaaaa cccacaactt 11280 cctcaaatcg tcacttccgt tttcccacgt tacgtaactt cccattttaa gaaaactaca 11340 attcccaaca catacaagtt actccgccct aaaacctacg tcacccgccc cgttcccacg 11400 ccccgcgcca cgtcacaaac tccaccccct cattatcata ttggcttcaa tccaaaataa 11460 ggtatattat tgatgatgtt aattaacatg catggatcca tatgcggtgt gaaataccgc 11520 acagatgcgt aaggagaaaa taccgcatca ggcgctcttc cgcttcctcg ctcactgact 11580 cgctgcgctc ggtcgttcgg ctgcggcgag cggtatcagc tcactcaaag gcggtaatac 11640 ggttatccac agaatcaggg gataacgcag gaaagaacat gtgagcaaaa ggccagcaaa 11700 aggccaggaa ccgtaaaaag gccgcgttgc tggcgttttt ccataggctc cgcccccctg 11760 acgagcatca caaaaatcga cgctcaagtc agaggtggcg aaacccgaca ggactataaa 11820 gataccaggc gtttccccct ggaagctccc tcgtgcgctc tcctgttccg accctgccgc 11880 ttaccggata cctgtccgcc tttctccctt cgggaagcgt ggcgctttct catagctcac 11940 gctgtaggta tctcagttcg gtgtaggtcg ttcgctccaa gctgggctgt gtgcacgaac 12000 cccccgttca gcccgaccgc tgcgccttat ccggtaacta tcgtcttgag tccaacccgg 12060 taagacacga cttatcgcca ctggcagcag ccactggtaa caggattagc agagcgaggt 12120 atgtaggcgg tgctacagag ttcttgaagt ggtggcctaa ctacggctac actagaagga 12180 cagtatttgg tatctgcgct ctgctgaagc cagttacctt cggaaaaaga gttggtagct 12240 cttgatccgg caaacaaacc accgctggta gcggtggttt ttttgtttgc aagcagcaga 12300 ttacgcgcag aaaaaaagga tctcaagaag atcctttgat cttttctacg gggtctgacg 12360 ctcagtggaa cgaaaactca cgttaaggga ttttggtcat gagattatca aaaaggatct 12420 tcacctagat ccttttaaat taaaaatgaa gttttaaatc aatctaaagt atatatgagt 12480 aaacttggtc tgacagttac caatgcttaa tcagtgaggc acctatctca gcgatctgtc 12540 tatttcgttc atccatagtt gcctgactcc ccgtcgtgta gataactacg atacgggagg 12600 gcttaccatc tggccccagt gctgcaatga taccgcgaga cccacgctca ccggctccag 12660 atttatcagc aataaaccag ccagccggaa gggccgagcg cagaagtggt cctgcaactt 12720 tatccgcctc catccagtct attaattgtt gccgggaagc tagagtaagt agttcgccag 12780 ttaatagttt gcgcaacgtt gttgccattg ctgcagccat gagattatca aaaaggatct 12840 tcacctagat ccttttcacg tagaaagcca gtccgcagaa acggtgctga ccccggatga 12900 atgtcagcta ctgggctatc tggacaaggg aaaacgcaag cgcaaagaga aagcaggtag 12960 cttgcagtgg gcttacatgg cgatagctag actgggcggt tttatggaca gcaagcgaac 13020 cggaattgcc agctggggcg ccctctggta aggttgggaa gccctgcaaa gtaaactgga 13080 tggctttctc gccgccaagg atctgatggc gcaggggatc aagctctgat caagagacag 13140 gatgaggatc gtttcgcatg attgaacaag atggattgca cgcaggttct ccggccgctt 13200 gggtggagag gctattcggc tatgactggg cacaacagac aatcggctgc tctgatgccg 13260 ccgtgttccg gctgtcagcg caggggcgcc cggttctttt tgtcaagacc gacctgtccg 13320 gtgccctgaa tgaactgcaa gacgaggcag cgcggctatc gtggctggcc acgacgggcg 13380 ttccttgcgc agctgtgctc gacgttgtca ctgaagcggg aagggactgg ctgctattgg 13440 gcgaagtgcc ggggcaggat ctcctgtcat ctcaccttgc tcctgccgag aaagtatcca 13500 tcatggctga tgcaatgcgg cggctgcata cgcttgatcc ggctacctgc ccattcgacc 13560 accaagcgaa acatcgcatc gagcgagcac gtactcggat ggaagccggt cttgtcgatc 13620 aggatgatct ggacgaagag catcaggggc tcgcgccagc cgaactgttc gccaggctca 13680 aggcgagcat gcccgacggc gaggatctcg tcgtgaccca tggcgatgcc tgcttgccga 13740 atatcatggt ggaaaatggc cgcttttctg gattcatcga ctgtggccgg ctgggtgtgg 13800 cggaccgcta tcaggacata gcgttggcta cccgtgatat tgctgaagag cttggcggcg 13860 aatgggctga ccgcttcctc gtgctttacg gtatcgccgc tcccgattcg cagcgcatcg 13920 ccttctatcg ccttcttgac gagttcttct gaattttgtt aaaatttttg ttaaatcagc 13980 tcatttttta accaataggc cgaaatcggc aacatccctt ataaatcaaa agaatagacc 14040 gcgatagggt tgagtgttgt tccagtttgg aacaagagtc cactattaaa gaacgtggac 14100 tccaacgtca aagggcgaaa aaccgtctat cagggcgatg gcccactacg tgaaccatca 14160 cccaaatcaa gttttttgcg gtcgaggtgc cgtaaagctc taaatcggaa ccctaaaggg 14220 agcccccgat ttagagcttg acggggaaag ccggcgaacg tggcgagaaa ggaagggaag 14280 aaagcgaaag gagcgggcgc tagggcgctg gcaagtgtag cggtcacgct gcgcgtaacc 14340 accacacccg cgcgcttaat gcgccgctac agggcgcgtc cattcgccat tcaggatcga 14400 attaattctt aat 14413 <210> 42 <211> 36641 <212> DNA <213> Artificial Sequence <220> <223> Ad-SD/SA CMV Ribozyme HSV-TK <400> 42 ttaagggtgg gaaagaatat ataaggtggg ggtcttatgt agttttgtat ctgttttgca 60 gcagccgccg ccgccatgag caccaactcg tttgatggaa gcattgtgag ctcatatttg 120 acaacgcgca tgcccccatg ggccggggtg cgtcagaatg tgatgggctc cagcattgat 180 ggtcgccccg tcctgcccgc aaactctact accttgacct acgagaccgt gtctggaacg 240 ccgttggaga ctgcagcctc cgccgccgct tcagccgctg cagccaccgc ccgcgggatt 300 gtgactgact ttgctttcct gagcccgctt gcaagcagtg cagcttcccg ttcatccgcc 360 cgcgatgaca agttgacggc tcttttggca caattggatt ctttgacccg ggaacttaat 420 gtcgtttctc agcagctgtt ggatctgcgc cagcaggttt ctgccctgaa ggcttcctcc 480 cctcccaatg cggtttaaaa cataaataaa aaaccagact ctgtttggat ttggatcaag 540 caagtgtctt gctgtcttta tttaggggtt ttgcgcgcgc ggtaggcccg ggaccagcgg 600 tctcggtcgt tgagggtcct gtgtattttt tccaggacgt ggtaaaggtg actctggatg 660 ttcagataca tgggcataag cccgtctctg gggtggaggt agcaccactg cagagcttca 720 tgctgcgggg tggtgttgta gatgatccag tcgtagcagg agcgctgggc gtggtgccta 780 aaaatgtctt tcagtagcaa gctgattgcc aggggcaggc ccttggtgta agtgtttaca 840 aagcggttaa gctgggatgg gtgcatacgt ggggatatga gatgcatctt ggactgtatt 900 tttaggttgg ctatgttccc agccatatcc ctccggggat tcatgttgtg cagaaccacc 960 agcacagtgt atccggtgca cttgggaaat ttgtcatgta gcttagaagg aaatgcgtgg 1020 aagaacttgg agacgccctt gtgacctcca agattttcca tgcattcgtc cataatgatg 1080 gcaatgggcc cacgggcggc ggcctgggcg aagatatttc tgggatcact aacgtcatag 1140 ttgtgttcca ggatgagatc gtcataggcc atttttacaa agcgcgggcg gagggtgcca 1200 gactgcggta taatggttcc atccggccca ggggcgtagt taccctcaca gatttgcatt 1260 tcccacgctt tgagttcaga tggggggatc atgtctacct gcggggcgat gaagaaaacg 1320 gtttccgggg taggggagat cagctgggaa gaaagcaggt tcctgagcag ctgcgactta 1380 ccgcagccgg tgggcccgta aatcacacct attaccgggt gcaactggta gttaagagag 1440 ctgcagctgc cgtcatccct gagcaggggg gccacttcgt taagcatgtc cctgactcgc 1500 atgttttccc tgaccaaatc cgccagaagg cgctcgccgc ccagcgatag cagttcttgc 1560 aaggaagcaa agtttttcaa cggtttgaga ccgtccgccg taggcatgct tttgagcgtt 1620 tgaccaagca gttccaggcg gtcccacagc tcggtcacct gctctacggc atctcgatcc 1680 agcatatctc ctcgtttcgc gggttggggc ggctttcgct gtacggcagt agtcggtgct 1740 cgtccagacg ggccagggtc atgtctttcc acgggcgcag ggtcctcgtc agcgtagtct 1800 gggtcacggt gaaggggtgc gctccgggct gcgcgctggc cagggtgcgc ttgaggctgg 1860 tcctgctggt gctgaagcgc tgccggtctt cgccctgcgc gtcggccagg tagcatttga 1920 ccatggtgtc atagtccagc ccctccgcgg cgtggccctt ggcgcgcagc ttgcccttgg 1980 aggaggcgcc gcacgagggg cagtgcagac ttttgagggc gtagagcttg ggcgcgagaa 2040 ataccgattc cggggagtag gcatccgcgc cgcaggcccc gcagacggtc tcgcattcca 2100 cgagccaggt gagctctggc cgttcggggt caaaaaccag gtttccccca tgctttttga 2160 tgcgtttctt acctctggtt tccatgagcc ggtgtccacg ctcggtgacg aaaaggctgt 2220 ccgtgtcccc gtatacagac ttgagaggcc tgtcctcgag cggtgttccg cggtcctcct 2280 cgtatagaaa ctcggaccac tctgagacaa aggctcgcgt ccaggccagc acgaaggagg 2340 ctaagtggga ggggtagcgg tcgttgtcca ctagggggtc cactcgctcc agggtgtgaa 2400 gacacatgtc gccctcttcg gcatcaagga aggtgattgg tttgtaggtg taggccacgt 2460 gaccgggtgt tcctgaaggg gggctataaa agggggtggg ggcgcgttcg tcctcactct 2520 cttccgcatc gctgtctgcg agggccagct gttggggtga gtactccctc tgaaaagcgg 2580 gcatgacttc tgcgctaaga ttgtcagttt ccaaaaacga ggaggatttg atattcacct 2640 ggcccgcggt gatgcctttg agggtggccg catccatctg gtcagaaaag acaatctttt 2700 tgttgtcaag cttggtggca aacgacccgt agagggcgtt ggacagcaac ttggcgatgg 2760 agcgcagggt ttggtttttg tcgcgatcgg cgcgctcctt ggccgcgatg tttagctgca 2820 cgtattcgcg cgcaacgcac cgccattcgg gaaagacggt ggtgcgctcg tcgggcacca 2880 ggtgcacgcg ccaaccgcgg ttgtgcaggg tgacaaggtc aacgctggtg gctacctctc 2940 cgcgtaggcg ctcgttggtc cagcagaggc ggccgccctt gcgcgagcag aatggcggta 3000 gggggtctag ctgcgtctcg tccggggggt ctgcgtccac ggtaaagacc ccgggcagca 3060 ggcgcgcgtc gaagtagtct atcttgcatc cttgcaagtc tagcgcctgc tgccatgcgc 3120 gggcggcaag cgcgcgctcg tatgggttga gtgggggacc ccatggcatg gggtgggtga 3180 gcgcggaggc gtacatgccg caaatgtcgt aaacgtagag gggctctctg agtattccaa 3240 gatatgtagg gtagcatctt ccaccgcgga tgctggcgcg cacgtaatcg tatagttcgt 3300 gcgagggagc gaggaggtcg ggaccgaggt tgctacgggc gggctgctct gctcggaaga 3360 ctatctgcct gaagatggca tgtgagttgg atgatatggt tggacgctgg aagacgttga 3420 agctggcgtc tgtgagacct accgcgtcac gcacgaagga ggcgtaggag tcgcgcagct 3480 tgttgaccag ctcggcggtg acctgcacgt ctagggcgca gtagtccagg gtttccttga 3540 tgatgtcata cttatcctgt cccttttttt tccacagctc gcggttgagg acaaactctt 3600 cgcggtcttt ccagtactct tggatcggaa acccgtcggc ctccgaacgg taagagccta 3660 gcatgtagaa ctggttgacg gcctggtagg cgcagcatcc cttttctacg ggtagcgcgt 3720 atgcctgcgc ggccttccgg agcgaggtgt gggtgagcgc aaaggtgtcc ctgaccatga 3780 ctttgaggta ctggtatttg aagtcagtgt cgtcgcatcc gccctgctcc cagagcaaaa 3840 agtccgtgcg ctttttggaa cgcggatttg gcagggcgaa ggtgacatcg ttgaagagta 3900 tctttcccgc gcgaggcata aagttgcgtg tgatgcggaa gggtcccggc acctcggaac 3960 ggttgttaat tacctgggcg gcgagcacga tctcgtcaaa gccgttgatg ttgtggccca 4020 caatgtaaag ttccaagaag cgcgggatgc ccttgatgga aggcaatttt ttaagttcct 4080 cgtaggtgag ctcttcaggg gagctgagcc cgtgctctga aagggcccag tctgcaagat 4140 gagggttgga agcgacgaat gagctccaca ggtcacgggc cattagcatt tgcaggtggt 4200 cgcgaaaggt cctaaactgg cgacctatgg ccattttttc tggggtgatg cagtagaagg 4260 taagcgggtc ttgttcccag cggtcccatc caaggttcgc ggctaggtct cgcgcggcag 4320 tcactagagg ctcatctccg ccgaacttca tgaccagcat gaagggcacg agctgcttcc 4380 caaaggcccc catccaagta taggtctcta catcgtaggt gacaaagaga cgctcggtgc 4440 gaggatgcga gccgatcggg aagaactgga tctcccgcca ccaattggag gagtggctat 4500 tgatgtggtg aaagtagaag tccctgcgac gggccgaaca ctcgtgctgg cttttgtaaa 4560 aacgtgcgca gtactggcag cggtgcacgg gctgtacatc ctgcacgagg ttgacctgac 4620 gaccgcgcac aaggaagcag agtgggaatt tgagcccctc gcctggcggg tttggctggt 4680 ggtcttctac ttcggctgct tgtccttgac cgtctggctg ctcgagggga gttacggtgg 4740 atcggaccac cacgccgcgc gagcccaaag tccagatgtc cgcgcgcggc ggtcggagct 4800 tgatgacaac atcgcgcaga tgggagctgt ccatggtctg gagctcccgc ggcgtcaggt 4860 caggcgggag ctcctgcagg tttacctcgc atagacgggt cagggcgcgg gctagatcca 4920 ggtgatacct aatttccagg ggctggttgg tggcggcgtc gatggcttgc aagaggccgc 4980 atccccgcgg cgcgactacg gtaccgcgcg gcgggcggtg ggccgcgggg gtgtccttgg 5040 atgatgcatc taaaagcggt gacgcgggcg agcccccgga ggtagggggg gctccggacc 5100 cgccgggaga gggggcaggg gcacgtcggc gccgcgcgcg ggcaggagct ggtgctgcgc 5160 gcgtaggttg ctggcgaacg cgacgacgcg gcggttgatc tcctgaatct ggcgcctctg 5220 cgtgaagacg acgggcccgg tgagcttgag cctgaaagag agttcgacag aatcaatttc 5280 ggtgtcgttg acggcggcct ggcgcaaaat ctcctgcacg tctcctgagt tgtcttgata 5340 ggcgatctcg gccatgaact gctcgatctc ttcctcctgg agatctccgc gtccggctcg 5400 ctccacggtg gcggcgaggt cgttggaaat gcgggccatg agctgcgaga aggcgttgag 5460 gcctccctcg ttccagacgc ggctgtagac cacgccccct tcggcatcgc gggcgcgcat 5520 gaccacctgc gcgagattga gctccacgtg ccgggcgaag acggcgtagt ttcgcaggcg 5580 ctgaaagagg tagttgaggg tggtggcggt gtgttctgcc acgaagaagt acataaccca 5640 gcgtcgcaac gtggattcgt tgatatcccc caaggcctca aggcgctcca tggcctcgta 5700 gaagtccacg gcgaagttga aaaactggga gttgcgcgcc gacacggtta actcctcctc 5760 cagaagacgg atgagctcgg cgacagtgtc gcgcacctcg cgctcaaagg ctacaggggc 5820 ctcttcttct tcttcaatct cctcttccat aagggcctcc ccttcttctt cttctggcgg 5880 cggtggggga ggggggacac ggcggcgacg acggcgcacc gggaggcggt cgacaaagcg 5940 ctcgatcatc tccccgcggc gacggcgcat ggtctcggtg acggcgcggc cgttctcgcg 6000 ggggcgcagt tggaagacgc cgcccgtcat gtcccggtta tgggttggcg gggggctgcc 6060 atgcggcagg gatacggcgc taacgatgca tctcaacaat tgttgtgtag gtactccgcc 6120 gccgagggac ctgagcgagt ccgcatcgac cggatcggaa aacctctcga gaaaggcgtc 6180 taaccagtca cagtcgcaag gtaggctgag caccgtggcg ggcggcagcg ggcggcggtc 6240 ggggttgttt ctggcggagg tgctgctgat gatgtaatta aagtaggcgg tcttgagacg 6300 gcggatggtc gacagaagca ccatgtcctt gggtccggcc tgctgaatgc gcaggcggtc 6360 ggccatgccc caggcttcgt tttgacatcg gcgcaggtct ttgtagtagt cttgcatgag 6420 cctttctacc ggcacttctt cttctccttc ctcttgtcct gcatctcttg catctatcgc 6480 tgcggcggcg gcggagtttg gccgtaggtg gcgccctctt cctcccatgc gtgtgacccc 6540 gaagcccctc atcggctgaa gcagggctag gtcggcgaca acgcgctcgg ctaatatggc 6600 ctgctgcacc tgcgtgaggg tagactggaa gtcatccatg tccacaaagc ggtggtatgc 6660 gcccgtgttg atggtgtaag tgcagttggc cataacggac cagttaacgg tctggtgacc 6720 cggctgcgag agctcggtgt acctgagacg cgagtaagcc ctcgagtcaa atacgtagtc 6780 gttgcaagtc cgcaccaggt actggtatcc caccaaaaag tgcggcggcg gctggcggta 6840 gaggggccag cgtagggtgg ccggggctcc gggggcgaga tcttccaaca taaggcgatg 6900 atatccgtag atgtacctgg acatccaggt gatgccggcg gcggtggtgg aggcgcgcgg 6960 aaagtcgcgg acgcggttcc agatgttgcg cagcggcaaa aagtgctcca tggtcgggac 7020 gctctggccg gtcaggcgcg cgcaatcgtt gacgctctac cgtgcaaaag gagagcctgt 7080 aagcgggcac tcttccgtgg tctggtggat aaattcgcaa gggtatcatg gcggacgacc 7140 ggggttcgag ccccgtatcc ggccgtccgc cgtgatccat gcggttaccg cccgcgtgtc 7200 gaacccaggt gtgcgacgtc agacaacggg ggagtgctcc ttttggcttc cttccaggcg 7260 cggcggctgc tgcgctagct tttttggcca ctggccgcgc gcagcgtaag cggttaggct 7320 ggaaagcgaa agcattaagt ggctcgctcc ctgtagccgg agggttattt tccaagggtt 7380 gagtcgcggg acccccggtt cgagtctcgg accggccgga ctgcggcgaa cgggggtttg 7440 cctccccgtc atgcaagacc ccgcttgcaa attcctccgg aaacagggac gagccccttt 7500 tttgcttttc ccagatgcat ccggtgctgc ggcagatgcg cccccctcct cagcagcggc 7560 aagagcaaga gcagcggcag acatgcaggg caccctcccc tcctcctacc gcgtcaggag 7620 gggcgacatc cgcggttgac gcggcagcag atggtgatta cgaacccccg cggcgccggg 7680 cccggcacta cctggacttg gaggagggcg agggcctggc gcggctagga gcgccctctc 7740 ctgagcggta cccaagggtg cagctgaagc gtgatacgcg tgaggcgtac gtgccgcggc 7800 agaacctgtt tcgcgaccgc gagggagagg agcccgagga gatgcgggat cgaaagttcc 7860 acgcagggcg cgagctgcgg catggcctga atcgcgagcg gttgctgcgc gaggaggact 7920 ttgagcccga cgcgcgaacc gggattagtc ccgcgcgcgc acacgtggcg gccgccgacc 7980 tggtaaccgc atacgagcag acggtgaacc aggagattaa ctttcaaaaa agctttaaca 8040 accacgtgcg tacgcttgtg gcgcgcgagg aggtggctat aggactgatg catctgtggg 8100 actttgtaag cgcgctggag caaaacccaa atagcaagcc gctcatggcg cagctgttcc 8160 ttatagtgca gcacagcagg gacaacgagg cattcaggga tgcgctgcta aacatagtag 8220 agcccgaggg ccgctggctg ctcgatttga taaacatcct gcagagcata gtggtgcagg 8280 agcgcagctt gagcctggct gacaaggtgg ccgccatcaa ctattccatg cttagcctgg 8340 gcaagtttta cgcccgcaag atataccata ccccttacgt tcccatagac aaggaggtaa 8400 agatcgaggg gttctacatg cgcatggcgc tgaaggtgct taccttgagc gacgacctgg 8460 gcgtttatcg caacgagcgc atccacaagg ccgtgagcgt gagccggcgg cgcgagctca 8520 gcgaccgcga gctgatgcac agcctgcaaa gggccctggc tggcacgggc agcggcgata 8580 gagaggccga gtcctacttt gacgcgggcg ctgacctgcg ctgggcccca agccgacgcg 8640 ccctggaggc agctggggcc ggacctgggc tggcggtggc acccgcgcgc gctggcaacg 8700 tcggcggcgt ggaggaatat gacgaggacg atgagtacga gccagaggac ggcgagtact 8760 aagcggtgat gtttctgatc agatgatgca agacgcaacg gacccggcgg tgcgggcggc 8820 gctgcagagc cagccgtccg gccttaactc cacggacgac tggcgccagg tcatggaccg 8880 catcatgtcg ctgactgcgc gcaatcctga cgcgttccgg cagcagccgc aggccaaccg 8940 gctctccgca attctggaag cggtggtccc ggcgcgcgca aaccccacgc acgagaaggt 9000 gctggcgatc gtaaacgcgc tggccgaaaa cagggccatc cggcccgacg aggccggcct 9060 ggtctacgac gcgctgcttc agcgcgtggc tcgttacaac agcggcaacg tgcagaccaa 9120 cctggaccgg ctggtggggg atgtgcgcga ggccgtggcg cagcgtgagc gcgcgcagca 9180 gcagggcaac ctgggctcca tggttgcact aaacgccttc ctgagtacac agcccgccaa 9240 cgtgccgcgg ggacaggagg actacaccaa ctttgtgagc gcactgcggc taatggtgac 9300 tgagacaccg caaagtgagg tgtaccagtc tgggccagac tattttttcc agaccagtag 9360 acaaggcctg cagaccgtaa acctgagcca ggctttcaaa aacttgcagg ggctgtgggg 9420 ggtgcgggct cccacaggcg accgcgcgac cgtgtctagc ttgctgacgc ccaactcgcg 9480 cctgttgctg ctgctaatag cgcccttcac ggacagtggc agcgtgtccc gggacacata 9540 cctaggtcac ttgctgacac tgtaccgcga ggccataggt caggcgcatg tggacgagca 9600 tactttccag gagattacaa gtgtcagccg cgcgctgggg caggaggaca cgggcagcct 9660 ggaggcaacc ctaaactacc tgctgaccaa ccggcggcag aagatcccct cgttgcacag 9720 tttaaacagc gaggaggagc gcattttgcg ctacgtgcag cagagcgtga gccttaacct 9780 gatgcgcgac ggggtaacgc ccagcgtggc gctggacatg accgcgcgca acatggaacc 9840 gggcatgtat gcctcaaacc ggccgtttat caaccgccta atggactact tgcatcgcgc 9900 ggccgccgtg aaccccgagt atttcaccaa tgccatcttg aacccgcact ggctaccgcc 9960 ccctggtttc tacaccgggg gattcgaggt gcccgagggt aacgatggat tcctctggga 10020 cgacatagac gacagcgtgt tttccccgca accgcagacc ctgctagagt tgcaacagcg 10080 cgagcaggca gaggcggcgc tgcgaaagga aagcttccgc aggccaagca gcttgtccga 10140 tctaggcgct gcggccccgc ggtcagatgc tagtagccca tttccaagct tgatagggtc 10200 tcttaccagc actcgcacca cccgcccgcg cctgctgggc gaggaggagt acctaaacaa 10260 ctcgctgctg cagccgcagc gcgaaaaaaa cctgcctccg gcatttccca acaacgggat 10320 agagagccta gtggacaaga tgagtagatg gaagacgtac gcgcaggagc acagggacgt 10380 gccaggcccg cgcccgccca cccgtcgtca aaggcacgac cgtcagcggg gtctggtgtg 10440 ggaggacgat gactcggcag acgacagcag cgtcctggat ttgggaggga gtggcaaccc 10500 gtttgcgcac cttcgcccca ggctggggag aatgttttaa aaaaaaaaaa gcatgatgca 10560 aaataaaaaa ctcaccaagg ccatggcacc gagcgttggt tttcttgtat tccccttagt 10620 atgcggcgcg cggcgatgta tgaggaaggt cctcctccct cctacgagag tgtggtgagc 10680 gcggcgccag tggcggcggc gctgggttct cccttcgatg ctcccctgga cccgccgttt 10740 gtgcctccgc ggtacctgcg gcctaccggg gggagaaaca gcatccgtta ctctgagttg 10800 gcacccctat tcgacaccac ccgtgtgtac ctggtggaca acaagtcaac ggatgtggca 10860 tccctgaact accagaacga ccacagcaac tttctgacca cggtcattca aaacaatgac 10920 tacagcccgg gggaggcaag cacacagacc atcaatcttg acgaccggtc gcactggggc 10980 ggcgacctga aaaccatcct gcataccaac atgccaaatg tgaacgagtt catgtttacc 11040 aataagttta aggcgcgggt gatggtgtcg cgcttgccta ctaaggacaa tcaggtggag 11100 ctgaaatacg agtgggtgga gttcacgctg cccgagggca actactccga gaccatgacc 11160 atagacctta tgaacaacgc gatcgtggag cactacttga aagtgggcag acagaacggg 11220 gttctggaaa gcgacatcgg ggtaaagttt gacacccgca acttcagact ggggtttgac 11280 cccgtcactg gtcttgtcat gcctggggta tatacaaacg aagccttcca tccagacatc 11340 attttgctgc caggatgcgg ggtggacttc acccacagcc gcctgagcaa cttgttgggc 11400 atccgcaagc ggcaaccctt ccaggagggc tttaggatca cctacgatga tctggagggt 11460 ggtaacattc ccgcactgtt ggatgtggac gcctaccagg cgagcttgaa agatgacacc 11520 gaacagggcg ggggtggcgc aggcggcagc aacagcagtg gcagcggcgc ggaagagaac 11580 tccaacgcgg cagccgcggc aatgcagccg gtggaggaca tgaacgatca tgccattcgc 11640 ggcgacacct ttgccacacg ggctgaggag aagcgcgctg aggccgaagc agcggccgaa 11700 gctgccgccc ccgctgcgca acccgaggtc gagaagcctc agaagaaacc ggtgatcaaa 11760 cccctgacag aggacagcaa gaaacgcagt tacaacctaa taagcaatga cagcaccttc 11820 acccagtacc gcagctggta ccttgcatac aactacggcg accctcagac cggaatccgc 11880 tcatggaccc tgctttgcac tcctgacgta acctgcggct cggagcaggt ctactggtcg 11940 ttgccagaca tgatgcaaga ccccgtgacc ttccgctcca cgcgccagat cagcaacttt 12000 ccggtggtgg gcgccgagct gttgcccgtg cactccaaga gcttctacaa cgaccaggcc 12060 gtctactccc aactcatccg ccagtttacc tctctgaccc acgtgttcaa tcgctttccc 12120 gagaaccaga ttttggcgcg cccgccagcc cccaccatca ccaccgtcag tgaaaacgtt 12180 cctgctctca cagatcacgg gacgctaccg ctgcgcaaca gcatcggagg agtccagcga 12240 gtgaccatta ctgacgccag acgccgcacc tgcccctacg tttacaaggc cctgggcata 12300 gtctcgccgc gcgtcctatc gagccgcact ttttgagcaa gcatgtccat ccttatatcg 12360 cccagcaata acacaggctg gggcctgcgc ttcccaagca agatgtttgg cggggccaag 12420 aagcgctccg accaacaccc agtgcgcgtg cgcgggcact accgcgcgcc ctggggcgcg 12480 cacaaacgcg gccgcactgg gcgcaccacc gtcgatgacg ccatcgacgc ggtggtggag 12540 gaggcgcgca actacacgcc cacgccgcca ccagtgtcca cagtggacgc ggccattcag 12600 accgtggtgc gcggagcccg gcgctatgct aaaatgaaga gacggcggag gcgcgtagca 12660 cgtcgccacc gccgccgacc cggcactgcc gcccaacgcg cggcggcggc cctgcttaac 12720 cgcgcacgtc gcaccggccg acgggcggcc atgcgggccg ctcgaaggct ggccgcgggt 12780 attgtcactg tgccccccag gtccaggcga cgagcggccg ccgcagcagc cgcggccatt 12840 agtgctatga ctcagggtcg caggggcaac gtgtattggg tgcgcgactc ggttagcggc 12900 ctgcgcgtgc ccgtgcgcac ccgccccccg cgcaactaga ttgcaagaaa aaactactta 12960 gactcgtact gttgtatgta tccagcggcg gcggcgcgca acgaagctat gtccaagcgc 13020 aaaatcaaag aagagatgct ccaggtcatc gcgccggaga tctatggccc cccgaagaag 13080 gaagagcagg attacaagcc ccgaaagcta aagcgggtca aaaagaaaaa gaaagatgat 13140 gatgatgaac ttgacgacga ggtggaactg ctgcacgcta ccgcgcccag gcgacgggta 13200 cagtggaaag gtcgacgcgt aaaacgtgtt ttgcgacccg gcaccaccgt agtctttacg 13260 cccggtgagc gctccacccg cacctacaag cgcgtgtatg atgaggtgta cggcgacgag 13320 gacctgcttg agcaggccaa cgagcgcctc ggggagtttg cctacggaaa gcggcataag 13380 gacatgctgg cgttgccgct ggacgagggc aacccaacac ctagcctaaa gcccgtaaca 13440 ctgcagcagg tgctgcccgc gcttgcaccg tccgaagaaa agcgcggcct aaagcgcgag 13500 tctggtgact tggcacccac cgtgcagctg atggtaccca agcgccagcg actggaagat 13560 gtcttggaaa aaatgaccgt ggaacctggg ctggagcccg aggtccgcgt gcggccaatc 13620 aagcaggtgg cgccgggact gggcgtgcag accgtggacg ttcagatacc cactaccagt 13680 agcaccagta ttgccaccgc cacagagggc atggagacac aaacgtcccc ggttgcctca 13740 gcggtggcgg atgccgcggt gcaggcggtc gctgcggccg cgtccaagac ctctacggag 13800 gtgcaaacgg acccgtggat gtttcgcgtt tcagcccccc ggcgcccgcg cggttcgagg 13860 aagtacggcg ccgccagcgc gctactgccc gaatatgccc tacatccttc cattgcgcct 13920 acccccggct atcgtggcta cacctaccgc cccagaagac gagcaactac ccgacgccga 13980 accaccactg gaacccgccg ccgccgtcgc cgtcgccagc ccgtgctggc cccgatttcc 14040 gtgcgcaggg tggctcgcga aggaggcagg accctggtgc tgccaacagc gcgctaccac 14100 cccagcatcg tttaaaagcc ggtctttgtg gttcttgcag atatggccct cacctgccgc 14160 ctccgtttcc cggtgccggg attccgagga agaatgcacc gtaggagggg catggccggc 14220 cacggcctga cgggcggcat gcgtcgtgcg caccaccggc ggcggcgcgc gtcgcaccgt 14280 cgcatgcgcg gcggtatcct gcccctcctt attccactga tcgccgcggc gattggcgcc 14340 gtgcccggaa ttgcatccgt ggccttgcag gcgcagagac actgattaaa aacaagttgc 14400 atgtggaaaa atcaaaataa aaagtctgga ctctcacgct cgcttggtcc tgtaactatt 14460 ttgtagaatg gaagacatca actttgcgtc tctggccccg cgacacggct cgcgcccgtt 14520 catgggaaac tggcaagata tcggcaccag caatatgagc ggtggcgcct tcagctgggg 14580 ctcgctgtgg agcggcatta aaaatttcgg ttccaccgtt aagaactatg gcagcaaggc 14640 ctggaacagc agcacaggcc agatgctgag ggataagttg aaagagcaaa atttccaaca 14700 aaaggtggta gatggcctgg cctctggcat tagcggggtg gtggacctgg ccaaccaggc 14760 agtgcaaaat aagattaaca gtaagcttga tccccgccct cccgtagagg agcctccacc 14820 ggccgtggag acagtgtctc cagaggggcg tggcgaaaag cgtccgcgcc ccgacaggga 14880 agaaactctg gtgacgcaaa tagacgagcc tccctcgtac gaggaggcac taaagcaagg 14940 cctgcccacc acccgtccca tcgcgcccat ggctaccgga gtgctgggcc agcacacacc 15000 cgtaacgctg gacctgcctc cccccgccga cacccagcag aaacctgtgc tgccaggccc 15060 gaccgccgtt gttgtaaccc gtcctagccg cgcgtccctg cgccgcgccg ccagcggtcc 15120 gcgatcgttg cggcccgtag ccagtggcaa ctggcaaagc acactgaaca gcatcgtggg 15180 tctgggggtg caatccctga agcgccgacg atgcttctga atagctaacg tgtcgtatgt 15240 gtgtcatgta tgcgtccatg tcgccgccag aggagctgct gagccgccgc gcgcccgctt 15300 tccaagatgg ctaccccttc gatgatgccg cagtggtctt acatgcacat ctcgggccag 15360 gacgcctcgg agtacctgag ccccgggctg gtgcagtttg cccgcgccac cgagacgtac 15420 ttcagcctga ataacaagtt tagaaacccc acggtggcgc ctacgcacga cgtgaccaca 15480 gaccggtccc agcgtttgac gctgcggttc atccctgtgg accgtgagga tactgcgtac 15540 tcgtacaagg cgcggttcac cctagctgtg ggtgataacc gtgtgctgga catggcttcc 15600 acgtactttg acatccgcgg cgtgctggac aggggcccta cttttaagcc ctactctggc 15660 actgcctaca acgccctggc tcccaagggt gccccaaatc cttgcgaatg ggatgaagct 15720 gctactgctc ttgaaataaa cctagaagaa gaggacgatg acaacgaaga cgaagtagac 15780 gagcaagctg agcagcaaaa aactcacgta tttgggcagg cgccttattc tggtataaat 15840 attacaaagg agggtattca aataggtgtc gaaggtcaaa cacctaaata tgccgataaa 15900 acatttcaac ctgaacctca aataggagaa tctcagtggt acgaaactga aattaatcat 15960 gcagctggga gagtccttaa aaagactacc ccaatgaaac catgttacgg ttcatatgca 16020 aaacccacaa atgaaaatgg agggcaaggc attcttgtaa agcaacaaaa tggaaagcta 16080 gaaagtcaag tggaaatgca atttttctca actactgagg cgaccgcagg caatggtgat 16140 aacttgactc ctaaagtggt attgtacagt gaagatgtag atatagaaac cccagacact 16200 catatttctt acatgcccac tattaaggaa ggtaactcac gagaactaat gggccaacaa 16260 tctatgccca acaggcctaa ttacattgct tttagggaca attttattgg tctaatgtat 16320 tacaacagca cgggtaatat gggtgttctg gcgggccaag catcgcagtt gaatgctgtt 16380 gtagatttgc aagacagaaa cacagagctt tcataccagc ttttgcttga ttccattggt 16440 gatagaacca ggtacttttc tatgtggaat caggctgttg acagctatga tccagatgtt 16500 agaattattg aaaatcatgg aactgaagat gaacttccaa attactgctt tccactggga 16560 ggtgtgatta atacagagac tcttaccaag gtaaaaccta aaacaggtca ggaaaatgga 16620 tgggaaaaag atgctacaga attttcagat aaaaatgaaa taagagttgg aaataatttt 16680 gccatggaaa tcaatctaaa tgccaacctg tggagaaatt tcctgtactc caacatagcg 16740 ctgtatttgc ccgacaagct aaagtacagt ccttccaacg taaaaatttc tgataaccca 16800 aacacctacg actacatgaa caagcgagtg gtggctcccg ggttagtgga ctgctacatt 16860 aaccttggag cacgctggtc ccttgactat atggacaacg tcaacccatt taaccaccac 16920 cgcaatgctg gcctgcgcta ccgctcaatg ttgctgggca atggtcgcta tgtgcccttc 16980 cacatccagg tgcctcagaa gttctttgcc attaaaaacc tccttctcct gccgggctca 17040 tacacctacg agtggaactt caggaaggat gttaacatgg ttctgcagag ctccctagga 17100 aatgacctaa gggttgacgg agccagcatt aagtttgata gcatttgcct ttacgccacc 17160 ttcttcccca tggcccacaa caccgcctcc acgcttgagg ccatgcttag aaacgacacc 17220 aacgaccagt cctttaacga ctatctctcc gccgccaaca tgctctaccc tatacccgcc 17280 aacgctacca acgtgcccat atccatcccc tcccgcaact gggcggcttt ccgcggctgg 17340 gccttcacgc gccttaagac taaggaaacc ccatcactgg gctcgggcta cgacccttat 17400 tacacctact ctggctctat accctaccta gatggaacct tttacctcaa ccacaccttt 17460 aagaaggtgg ccattacctt tgactcttct gtcagctggc ctggcaatga ccgcctgctt 17520 acccccaacg agtttgaaat taagcgctca gttgacgggg agggttacaa cgttgcccag 17580 tgtaacatga ccaaagactg gttcctggta caaatgctag ctaactacaa cattggctac 17640 cagggcttct atatcccaga gagctacaag gaccgcatgt actccttctt tagaaacttc 17700 cagcccatga gccgtcaggt ggtggatgat actaaataca aggactacca acaggtgggc 17760 atcctacacc aacacaacaa ctctggattt gttggctacc ttgcccccac catgcgcgaa 17820 ggacaggcct accctgctaa cttcccctat ccgcttatag gcaagaccgc agttgacagc 17880 attacccaga aaaagtttct ttgcgatcgc accctttggc gcatcccatt ctccagtaac 17940 tttatgtcca tgggcgcact cacagacctg ggccaaaacc ttctctacgc caactccgcc 18000 cacgcgctag acatgacttt tgaggtggat cccatggacg agcccaccct tctttatgtt 18060 ttgtttgaag tctttgacgt ggtccgtgtg caccggccgc accgcggcgt catcgaaacc 18120 gtgtacctgc gcacgccctt ctcggccggc aacgccacaa cataaagaag caagcaacat 18180 caacaacagc tgccgccatg ggctccagtg agcaggaact gaaagccatt gtcaaagatc 18240 ttggttgtgg gccatatttt ttgggcacct atgacaagcg ctttccaggc tttgtttctc 18300 cacacaagct cgcctgcgcc atagtcaata cggccggtcg cgagactggg ggcgtacact 18360 ggatggcctt tgcctggaac ccgcactcaa aaacatgcta cctctttgag ccctttggct 18420 tttctgacca gcgactcaag caggtttacc agtttgagta cgagtcactc ctgcgccgta 18480 gcgccattgc ttcttccccc gaccgctgta taacgctgga aaagtccacc caaagcgtac 18540 aggggcccaa ctcggccgcc tgtggactat tctgctgcat gtttctccac gcctttgcca 18600 actggcccca aactcccatg gatcacaacc ccaccatgaa ccttattacc ggggtaccca 18660 actccatgct caacagtccc caggtacagc ccaccctgcg tcgcaaccag gaacagctct 18720 acagcttcct ggagcgccac tcgccctact tccgcagcca cagtgcgcag attaggagcg 18780 ccacttcttt ttgtcacttg aaaaacatgt aaaaataatg tactagagac actttcaata 18840 aaggcaaatg cttttatttg tacactctcg ggtgattatt tacccccacc cttgccgtct 18900 gcgccgttta aaaatcaaag gggttctgcc gcgcatcgct atgcgccact ggcagggaca 18960 cgttgcgata ctggtgttta gtgctccact taaactcagg cacaaccatc cgcggcagct 19020 cggtgaagtt ttcactccac aggctgcgca ccatcaccaa cgcgtttagc aggtcgggcg 19080 ccgatatctt gaagtcgcag ttggggcctc cgccctgcgc gcgcgagttg cgatacacag 19140 ggttgcagca ctggaacact atcagcgccg ggtggtgcac gctggccagc acgctcttgt 19200 cggagatcag atccgcgtcc aggtcctccg cgttgctcag ggcgaacgga gtcaactttg 19260 gtagctgcct tcccaaaaag ggcgcgtgcc caggctttga gttgcactcg caccgtagtg 19320 gcatcaaaag gtgaccgtgc ccggtctggg cgttaggata cagcgcctgc ataaaagcct 19380 tgatctgctt aaaagccacc tgagcctttg cgccttcaga gaagaacatg ccgcaagact 19440 tgccggaaaa ctgattggcc ggacaggccg cgtcgtgcac gcagcacctt gcgtcggtgt 19500 tggagatctg caccacattt cggccccacc ggttcttcac gatcttggcc ttgctagact 19560 gctccttcag cgcgcgctgc ccgttttcgc tcgtcacatc catttcaatc acgtgctcct 19620 tatttatcat aatgcttccg tgtagacact taagctcgcc ttcgatctca gcgcagcggt 19680 gcagccacaa cgcgcagccc gtgggctcgt gatgcttgta ggtcacctct gcaaacgact 19740 gcaggtacgc ctgcaggaat cgccccatca tcgtcacaaa ggtcttgttg ctggtgaagg 19800 tcagctgcaa cccgcggtgc tcctcgttca gccaggtctt gcatacggcc gccagagctt 19860 ccacttggtc aggcagtagt ttgaagttcg cctttagatc gttatccacg tggtacttgt 19920 ccatcagcgc gcgcgcagcc tccatgccct tctcccacgc agacacgatc ggcacactca 19980 gcgggttcat caccgtaatt tcactttccg cttcgctggg ctcttcctct tcctcttgcg 20040 tccgcatacc acgcgccact gggtcgtctt cattcagccg ccgcactgtg cgcttacctc 20100 ctttgccatg cttgattagc accggtgggt tgctgaaacc caccatttgt agcgccacat 20160 cttctctttc ttcctcgctg tccacgatta cctctggtga tggcgggcgc tcgggcttgg 20220 gagaagggcg cttctttttc ttcttgggcg caatggccaa atccgccgcc gaggtcgatg 20280 gccgcgggct gggtgtgcgc ggcaccagcg cgtcttgtga tgagtcttcc tcgtcctcgg 20340 actcgatacg ccgcctcatc cgcttttttg ggggcgcccg gggaggcggc ggcgacgggg 20400 acggggacga cacgtcctcc atggttgggg gacgtcgcgc cgcaccgcgt ccgcgctcgg 20460 gggtggtttc gcgctgctcc tcttcccgac tggccatttc cttctcctat aggcagaaaa 20520 agatcatgga gtcagtcgag aagaaggaca gcctaaccgc cccctctgag ttcgccacca 20580 ccgcctccac cgatgccgcc aacgcgccta ccaccttccc cgtcgaggca cccccgcttg 20640 aggaggagga agtgattatc gagcaggacc caggttttgt aagcgaagac gacgaggacc 20700 gctcagtacc aacagaggat aaaaagcaag accaggacaa cgcagaggca aacgaggaac 20760 aagtcgggcg gggggacgaa aggcatggcg actacctaga tgtgggagac gacgtgctgt 20820 tgaagcatct gcagcgccag tgcgccatta tctgcgacgc gttgcaagag cgcagcgatg 20880 tgcccctcgc catagcggat gtcagccttg cctacgaacg ccacctattc tcaccgcgcg 20940 taccccccaa acgccaagaa aacggcacat gcgagcccaa cccgcgcctc aacttctacc 21000 ccgtatttgc cgtgccagag gtgcttgcca cctatcacat ctttttccaa aactgcaaga 21060 tacccctatc ctgccgtgcc aaccgcagcc gagcggacaa gcagctggcc ttgcggcagg 21120 gcgctgtcat acctgatatc gcctcgctca acgaagtgcc aaaaatcttt gagggtcttg 21180 gacgcgacga gaagcgcgcg gcaaacgctc tgcaacagga aaacagcgaa aatgaaagtc 21240 actctggagt gttggtggaa ctcgagggtg acaacgcgcg cctagccgta ctaaaacgca 21300 gcatcgaggt cacccacttt gcctacccgg cacttaacct accccccaag gtcatgagca 21360 cagtcatgag tgagctgatc gtgcgccgtg cgcagcccct ggagagggat gcaaatttgc 21420 aagaacaaac agaggagggc ctacccgcag ttggcgacga gcagctagcg cgctggcttc 21480 aaacgcgcga gcctgccgac ttggaggagc gacgcaaact aatgatggcc gcagtgctcg 21540 ttaccgtgga gcttgagtgc atgcagcggt tctttgctga cccggagatg cagcgcaagc 21600 tagaggaaac attgcactac acctttcgac agggctacgt acgccaggcc tgcaagatct 21660 ccaacgtgga gctctgcaac ctggtctcct accttggaat tttgcacgaa aaccgccttg 21720 ggcaaaacgt gcttcattcc acgctcaagg gcgaggcgcg ccgcgactac gtccgcgact 21780 gcgtttactt atttctatgc tacacctggc agacggccat gggcgtttgg cagcagtgct 21840 tggaggagtg caacctcaag gagctgcaga aactgctaaa gcaaaacttg aaggacctat 21900 ggacggcctt caacgagcgc tccgtggccg cgcacctggc ggacatcatt ttccccgaac 21960 gcctgcttaa aaccctgcaa cagggtctgc cagacttcac cagtcaaagc atgttgcaga 22020 actttaggaa ctttatccta gagcgctcag gaatcttgcc cgccacctgc tgtgcacttc 22080 ctagcgactt tgtgcccatt aagtaccgcg aatgccctcc gccgctttgg ggccactgct 22140 accttctgca gctagccaac taccttgcct accactctga cataatggaa gacgtgagcg 22200 gtgacggtct actggagtgt cactgtcgct gcaacctatg caccccgcac cgctccctgg 22260 tttgcaattc gcagctgctt aacgaaagtc aaattatcgg tacctttgag ctgcagggtc 22320 cctcgcctga cgaaaagtcc gcggctccgg ggttgaaact cactccgggg ctgtggacgt 22380 cggcttacct tcgcaaattt gtacctgagg actaccacgc ccacgagatt aggttctacg 22440 aagaccaatc ccgcccgcca aatgcggagc ttaccgcctg cgtcattacc cagggccaca 22500 ttcttggcca attgcaagcc atcaacaaag cccgccaaga gtttctgcta cgaaagggac 22560 ggggggttta cttggacccc cagtccggcg aggagctcaa cccaatcccc ccgccgccgc 22620 agccctatca gcagcagccg cgggcccttg cttcccagga tggcacccaa aaagaagctg 22680 cagctgccgc cgccacccac ggacgaggag gaatactggg acagtcaggc agaggaggtt 22740 ttggacgagg aggaggagga catgatggaa gactgggaga gcctagacga ggaagcttcc 22800 gaggtcgaag aggtgtcaga cgaaacaccg tcaccctcgg tcgcattccc ctcgccggcg 22860 ccccagaaat cggcaaccgg ttccagcatg gctacaacct ccgctcctca ggcgccgccg 22920 gcactgcccg ttcgccgacc caaccgtaga tgggacacca ctggaaccag ggccggtaag 22980 tccaagcagc cgccgccgtt agcccaagag caacaacagc gccaaggcta ccgctcatgg 23040 cgcgggcaca agaacgccat agttgcttgc ttgcaagact gtgggggcaa catctccttc 23100 gcccgccgct ttcttctcta ccatcacggc gtggccttcc cccgtaacat cctgcattac 23160 taccgtcatc tctacagccc atactgcacc ggcggcagcg gcagcggcag caacagcagc 23220 ggccacacag aagcaaaggc gaccggatag caagactctg acaaagccca agaaatccac 23280 agcggcggca gcagcaggag gaggagcgct gcgtctggcg cccaacgaac ccgtatcgac 23340 ccgcgagctt agaaacagga tttttcccac tctgtatgct atatttcaac agagcagggg 23400 ccaagaacaa gagctgaaaa taaaaaacag gtctctgcga tccctcaccc gcagctgcct 23460 gtatcacaaa agcgaagatc agcttcggcg cacgctggaa gacgcggagg ctctcttcag 23520 taaatactgc gcgctgactc ttaaggacta gtttcgcgcc ctttctcaaa tttaagcgcg 23580 aaaactacgt catctccagc ggccacaccc ggcgccagca cctgtcgtca gcgccattat 23640 gagcaaggaa attcccacgc cctacatgtg gagttaccag ccacaaatgg gacttgcggc 23700 tggagctgcc caagactact caacccgaat aaactacatg agcgcgggac cccacatgat 23760 atcccgggtc aacggaatcc gcgcccaccg aaaccgaatt ctcttggaac aggcggctat 23820 taccaccaca cctcgtaata accttaatcc ccgtagttgg cccgctgccc tggtgtacca 23880 ggaaagtccc gctcccacca ctgtggtact tcccagagac gcccaggccg aagttcagat 23940 gactaactca ggggcgcagc ttgcgggcgg ctttcgtcac agggtgcggt cgcccgggca 24000 gggtataact cacctgacaa tcagagggcg aggtattcag ctcaacgacg agtcggtgag 24060 ctcctcgctt ggtctccgtc cggacgggac atttcagatc ggcggcgccg gccgtccttc 24120 attcacgcct cgtcaggcaa tcctaactct gcagacctcg tcctctgagc cgcgctctgg 24180 aggcattgga actctgcaat ttattgagga gtttgtgcca tcggtctact ttaacccctt 24240 ctcgggacct cccggccact atccggatca atttattcct aactttgacg cggtaaagga 24300 ctcggcggac ggctacgact gaatgttaag tggagaggca gagcaactgc gcctgaaaca 24360 cctggtccac tgtcgccgcc acaagtgctt tgcccgcgac tccggtgagt tttgctactt 24420 tgaattgccc gaggatcata tcgagggccc ggcgcacggc gtccggctta ccgcccaggg 24480 agagcttgcc cgtagcctga ttcgggagtt tacccagcgc cccctgctag ttgagcggga 24540 caggggaccc tgtgttctca ctgtgatttg caactgtcct aaccttggat tacatcaaga 24600 tcctctagtt ataactagag tacccgggga tcttattccc tttaactaat aaaaaaaaat 24660 aataaagcat cacttactta aaatcagtta gcaaatttct gtccagttta ttcagcagca 24720 cctccttgcc ctcctcccag ctctggtatt gcagcttcct cctggctgca aactttctcc 24780 acaatctaaa tggaatgtca gtttcctcct gttcctgtcc atccgcaccc actatcttca 24840 tgttgttgca gatgaagcgc gcaagaccgt ctgaagatac cttcaacccc gtgtatccat 24900 atgacacgga aaccggtcct ccaactgtgc cttttcttac tcctcccttt gtatccccca 24960 atgggtttca agagagtccc cctggggtac tctctttgcg cctatccgaa cctctagtta 25020 cctccaatgg catgcttgcg ctcaaaatgg gcaacggcct ctctctggac gaggccggca 25080 accttacctc ccaaaatgta accactgtga gcccacctct caaaaaaacc aagtcaaaca 25140 taaacctgga aatatctgca cccctcacag ttacctcaga agccctaact gtggctgccg 25200 ccgcacctct aatggtcgcg ggcaacacac tcaccatgca atcacaggcc ccgctaaccg 25260 tgcacgactc caaacttagc attgccaccc aaggacccct cacagtgtca gaaggaaagc 25320 tagccctgca aacatcaggc cccctcacca ccaccgatag cagtaccctt actatcactg 25380 cctcaccccc tctaactact gccactggta gcttgggcat tgacttgaaa gagcccattt 25440 atacacaaaa tggaaaacta ggactaaagt acggggctcc tttgcatgta acagacgacc 25500 taaacacttt gaccgtagca actggtccag gtgtgactat taataatact tccttgcaaa 25560 ctaaagttac tggagccttg ggttttgatt cacaaggcaa tatgcaactt aatgtagcag 25620 gaggactaag gattgattct caaaacagac gccttatact tgatgttagt tatccgtttg 25680 atgctcaaaa ccaactaaat ctaagactag gacagggccc tctttttata aactcagccc 25740 acaacttgga tattaactac aacaaaggcc tttacttgtt tacagcttca aacaattcca 25800 aaaagcttga ggttaaccta agcactgcca aggggttgat gtttgacgct acagccatag 25860 ccattaatgc aggagatggg cttgaatttg gttcacctaa tgcaccaaac acaaatcccc 25920 tcaaaacaaa aattggccat ggcctagaat ttgattcaaa caaggctatg gttcctaaac 25980 taggaactgg ccttagtttt gacagcacag gtgccattac agtaggaaac aaaaataatg 26040 ataagctaac tttgtggacc acaccagctc catctcctaa ctgtagacta aatgcagaga 26100 aagatgctaa actcactttg gtcttaacaa aatgtggcag tcaaatactt gctacagttt 26160 cagttttggc tgttaaaggc agtttggctc caatatctgg aacagttcaa agtgctcatc 26220 ttattataag atttgacgaa aatggagtgc tactaaacaa ttccttcctg gacccagaat 26280 attggaactt tagaaatgga gatcttactg aaggcacagc ctatacaaac gctgttggat 26340 ttatgcctaa cctatcagct tatccaaaat ctcacggtaa aactgccaaa agtaacattg 26400 tcagtcaagt ttacttaaac ggagacaaaa ctaaacctgt aacactaacc attacactaa 26460 acggtacaca ggaaacagga gacacaactc caagtgcata ctctatgtca ttttcatggg 26520 actggtctgg ccacaactac attaatgaaa tatttgccac atcctcttac actttttcat 26580 acattgccca agaataaaga atcgtttgtg ttatgtttca acgtgtttat ttttcaattg 26640 cagaaaattt caagtcattt ttcattcagt agtatagccc caccaccaca tagcttatac 26700 agatcaccgt accttaatca aactcacaga accctagtat tcaacctgcc acctccctcc 26760 caacacacag agtacacagt cctttctccc cggctggcct taaaaagcat catatcatgg 26820 gtaacagaca tattcttagg tgttatattc cacacggttt cctgtcgagc caaacgctca 26880 tcagtgatat taataaactc cccgggcagc tcacttaagt tcatgtcgct gtccagctgc 26940 tgagccacag gctgctgtcc aacttgcggt tgcttaacgg gcggcgaagg agaagtccac 27000 gcctacatgg gggtagagtc ataatcgtgc atcaggatag ggcggtggtg ctgcagcagc 27060 gcgcgaataa actgctgccg ccgccgctcc gtcctgcagg aatacaacat ggcagtggtc 27120 tcctcagcga tgattcgcac cgcccgcagc ataaggcgcc ttgtcctccg ggcacagcag 27180 cgcaccctga tctcacttaa atcagcacag taactgcagc acagcaccac aatattgttc 27240 aaaatcccac agtgcaaggc gctgtatcca aagctcatgg cggggaccac agaacccacg 27300 tggccatcat accacaagcg caggtagatt aagtggcgac ccctcataaa cacgctggac 27360 ataaacatta cctcttttgg catgttgtaa ttcaccacct cccggtacca tataaacctc 27420 tgattaaaca tggcgccatc caccaccatc ctaaaccagc tggccaaaac ctgcccgccg 27480 gctatacact gcagggaacc gggactggaa caatgacagt ggagagccca ggactcgtaa 27540 ccatggatca tcatgctcgt catgatatca atgttggcac aacacaggca cacgtgcata 27600 cacttcctca ggattacaag ctcctcccgc gttagaacca tatcccaggg aacaacccat 27660 tcctgaatca gcgtaaatcc cacactgcag ggaagacctc gcacgtaact cacgttgtgc 27720 attgtcaaag tgttacattc gggcagcagc ggatgatcct ccagtatggt agcgcgggtt 27780 tctgtctcaa aaggaggtag acgatcccta ctgtacggag tgcgccgaga caaccgagat 27840 cgtgttggtc gtagtgtcat gccaaatgga acgccggacg tagtcatatt tcctgaagca 27900 aaaccaggtg cgggcgtgac aaacagatct gcgtctccgg tctcgccgct tagatcgctc 27960 tgtgtagtag ttgtagtata tccactctct caaagcatcc aggcgccccc tggcttcggg 28020 ttctatgtaa actccttcat gcgccgctgc cctgataaca tccaccaccg cagaataagc 28080 cacacccagc caacctacac attcgttctg cgagtcacac acgggaggag cgggaagagc 28140 tggaagaacc atgttttttt ttttattcca aaagattatc caaaacctca aaatgaagat 28200 ctattaagtg aacgcgctcc cctccggtgg cgtggtcaaa ctctacagcc aaagaacaga 28260 taatggcatt tgtaagatgt tgcacaatgg cttccaaaag gcaaacggcc ctcacgtcca 28320 agtggacgta aaggctaaac ccttcagggt gaatctcctc tataaacatt ccagcacctt 28380 caaccatgcc caaataattc tcatctcgcc accttctcaa tatatctcta agcaaatccc 28440 gaatattaag tccggccatt gtaaaaatct gctccagagc gccctccacc ttcagcctca 28500 agcagcgaat catgattgca aaaattcagg ttcctcacag acctgtataa gattcaaaag 28560 cggaacatta acaaaaatac cgcgatcccg taggtccctt cgcagggcca gctgaacata 28620 atcgtgcagg tctgcacgga ccagcgcggc cacttccccg ccaggaacct tgacaaaaga 28680 acccacactg attatgacac gcatactcgg agctatgcta accagcgtag ccccgatgta 28740 agctttcaat agcttgttgc atgggcggcg atataaaatg caaggtgctg ctcaaaaaat 28800 caggcaaagc ctcgcgcaaa aaagaaagca catcgtagtc atgctcatgc agataaaggc 28860 aggtaagctc cggaaccacc acagaaaaag acaccatttt tctctcaaac atgtctgcgg 28920 gtttctgcat aaacacaaaa taaaataaca aaaaaacatt taaacattag aagcctgtct 28980 tacaacagga aaaacaaccc ttataagcat aagacggact acggccatgc cggcgtgacc 29040 gtaaaaaaac tggtcaccgt gattaaaaag caccaccgac agctcctcgg tcatgtccgg 29100 agtcataatg taagactcgg taaacacatc aggttgattc atcggtcagt gctaaaaagc 29160 gaccgaaata gcccggggga atacataccc gcaggcgtag agacaacatt acagccccca 29220 taggaggtat aacaaaatta ataggagaga aaaacacata aacacctgaa aaaccctcct 29280 gcctaggcaa aatagcaccc tcccgctcca gaacaacata cagcgcttca cagcggcagc 29340 ctaacagtca gccttaccag taaaaaagaa aacctattaa aaaaacacca ctcgacacgg 29400 caccagctca atcagtcaca gtgtaaaaaa gggccaagtg cagagcgagt atatatagga 29460 ctaaaaaatg acgtaacggt taaagtccac aaaaaacacc cagaaaaccg cacgcgaacc 29520 tacgcccaga aacgaaagcc aaaaaaccca caacttcctc aaatcgtcac ttccgttttc 29580 ccacgttacg taacttccca ttttaagaaa actacaattc ccaacacata caagttactc 29640 cgccctaaaa cctacgtcac ccgccccgtt cccacgcccc gcgccacgtc acaaactcca 29700 ccccctcatt atcatattgg cttcaatcca aaataaggta tattattgat gatgttaatt 29760 aacatgcatg gatccatatg cggtgtgaaa taccgcacag atgcgtaagg agaaaatacc 29820 gcatcaggcg ctcttccgct tcctcgctca ctgactcgct gcgctcggtc gttcggctgc 29880 ggcgagcggt atcagctcac tcaaaggcgg taatacggtt atccacagaa tcaggggata 29940 acgcaggaaa gaacatgtga gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg 30000 cgttgctggc gtttttccat aggctccgcc cccctgacga gcatcacaaa aatcgacgct 30060 caagtcagag gtggcgaaac ccgacaggac tataaagata ccaggcgttt ccccctggaa 30120 gctccctcgt gcgctctcct gttccgaccc tgccgcttac cggatacctg tccgcctttc 30180 tcccttcggg aagcgtggcg ctttctcata gctcacgctg taggtatctc agttcggtgt 30240 aggtcgttcg ctccaagctg ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg 30300 ccttatccgg taactatcgt cttgagtcca acccggtaag acacgactta tcgccactgg 30360 cagcagccac tggtaacagg attagcagag cgaggtatgt aggcggtgct acagagttct 30420 tgaagtggtg gcctaactac ggctacacta gaaggacagt atttggtatc tgcgctctgc 30480 tgaagccagt taccttcgga aaaagagttg gtagctcttg atccggcaaa caaaccaccg 30540 ctggtagcgg tggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc 30600 aagaagatcc tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt 30660 aagggatttt ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa 30720 aatgaagttt taaatcaatc taaagtatat atgagtaaac ttggtctgac agttaccaat 30780 gcttaatcag tgaggcacct atctcagcga tctgtctatt tcgttcatcc atagttgcct 30840 gactccccgt cgtgtagata actacgatac gggagggctt accatctggc cccagtgctg 30900 caatgatacc gcgagaccca cgctcaccgg ctccagattt atcagcaata aaccagccag 30960 ccggaagggc cgagcgcaga agtggtcctg caactttatc cgcctccatc cagtctatta 31020 attgttgccg ggaagctaga gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg 31080 ccattgctgc agccatgaga ttatcaaaaa ggatcttcac ctagatcctt ttcacgtaga 31140 aagccagtcc gcagaaacgg tgctgacccc ggatgaatgt cagctactgg gctatctgga 31200 caagggaaaa cgcaagcgca aagagaaagc aggtagcttg cagtgggctt acatggcgat 31260 agctagactg ggcggtttta tggacagcaa gcgaaccgga attgccagct ggggcgccct 31320 ctggtaaggt tgggaagccc tgcaaagtaa actggatggc tttctcgccg ccaaggatct 31380 gatggcgcag gggatcaagc tctgatcaag agacaggatg aggatcgttt cgcatgattg 31440 aacaagatgg attgcacgca ggttctccgg ccgcttgggt ggagaggcta ttcggctatg 31500 actgggcaca acagacaatc ggctgctctg atgccgccgt gttccggctg tcagcgcagg 31560 ggcgcccggt tctttttgtc aagaccgacc tgtccggtgc cctgaatgaa ctgcaagacg 31620 aggcagcgcg gctatcgtgg ctggccacga cgggcgttcc ttgcgcagct gtgctcgacg 31680 ttgtcactga agcgggaagg gactggctgc tattgggcga agtgccgggg caggatctcc 31740 tgtcatctca ccttgctcct gccgagaaag tatccatcat ggctgatgca atgcggcggc 31800 tgcatacgct tgatccggct acctgcccat tcgaccacca agcgaaacat cgcatcgagc 31860 gagcacgtac tcggatggaa gccggtcttg tcgatcagga tgatctggac gaagagcatc 31920 aggggctcgc gccagccgaa ctgttcgcca ggctcaaggc gagcatgccc gacggcgagg 31980 atctcgtcgt gacccatggc gatgcctgct tgccgaatat catggtggaa aatggccgct 32040 tttctggatt catcgactgt ggccggctgg gtgtggcgga ccgctatcag gacatagcgt 32100 tggctacccg tgatattgct gaagagcttg gcggcgaatg ggctgaccgc ttcctcgtgc 32160 tttacggtat cgccgctccc gattcgcagc gcatcgcctt ctatcgcctt cttgacgagt 32220 tcttctgaat tttgttaaaa tttttgttaa atcagctcat tttttaacca ataggccgaa 32280 atcggcaaca tcccttataa atcaaaagaa tagaccgcga tagggttgag tgttgttcca 32340 gtttggaaca agagtccact attaaagaac gtggactcca acgtcaaagg gcgaaaaacc 32400 gtctatcagg gcgatggccc actacgtgaa ccatcaccca aatcaagttt tttgcggtcg 32460 aggtgccgta aagctctaaa tcggaaccct aaagggagcc cccgatttag agcttgacgg 32520 ggaaagccgg cgaacgtggc gagaaaggaa gggaagaaag cgaaaggagc gggcgctagg 32580 gcgctggcaa gtgtagcggt cacgctgcgc gtaaccacca cacccgcgcg cttaatgcgc 32640 cgctacaggg cgcgtccatt cgccattcag gatcgaatta attcttaatt aacatcatca 32700 ataatatacc ttattttgga ttgaagccaa tatgataatg agggggtgga gtttgtgacg 32760 tggcgcgggg cgtgggaacg gggcgggtga cgtagtagtg tggcggaagt gtgatgttgc 32820 aagtgtggcg gaacacatgt aagcgacgga tgtggcaaaa gtgacgtttt tggtgtgcgc 32880 cggtgtacac aggaagtgac aattttcgcg cggttttagg cggatgttgt agtaaatttg 32940 ggcgtaaccg agtaagattt ggccattttc gcgggaaaac tgaataagag gaagtgaaat 33000 ctgaataatt ttgtgttact catagcgcgt aatactgcga tctatacatt gaatcaatat 33060 tggcaattag ccatattagt cattggttat atagcataaa tcaatattgg ctattggcca 33120 ttgcatacgt tgtatctata tcataatatg tacatttata ttggctcatg tccaatatga 33180 ccgccatgtt gacattgatt attgactagt agttcatagc ccatatatgg agttccgcgt 33240 tacataactt acggtaaatg gcccgcctgg ctgaccgccc aacgaccccc gcccattgac 33300 gtcaataatg acgtatgttc ccatagtaac gccaataggg actttccatt gacgtcaatg 33360 ggtggagtat ttacggtaaa ctgcccactt ggcagtacat caagtgtatc atatgccaag 33420 tccgccccct attgacgtca atgacggtaa atggcccgcc tggcattatg cccagtacat 33480 gaccttacgg gactttccta cttggcagta catctacgta ttagtcatcg ctattaccat 33540 ggtgatgcgg ttttggcagt acaccaatgg gcgtggatag cggtttgact cacggggatt 33600 tccaagtctc caccccattg acgtcaatgg gagtttgttt tggcaccaaa atcaacggga 33660 ctttccaaaa tgtcgtaata accccgcccc gttgacgcaa atgggcggta ggcgtgtacg 33720 gtgggaggtc tatataagca gagctcgttt agtgaaccgt cagatcctca ctctcttccg 33780 catcgctgtc tgcgagggcc agctgttggg ctcgcggttg aggacaaact cttcgcggtc 33840 tttccagtac tcttggatcg gaaacccgtc ggcctccgaa cggtactccg ccaccgaggg 33900 acctgagcca gtccgcatcg accggatcgg aaaacctctc gagaaaggcg tctaaccagt 33960 cacagtcgca aggtaggctg agcaccgtgg cgggcggcag cgggtggcgg tcggggttgt 34020 ttctggcgga ggtgctgctg atgatgtaat taaagtaggc ggtcttgagc cggcggatgg 34080 tcgaggtgag gtgtggcagg cttgagatcc agctgttggg gtgagtactc cctctcaaaa 34140 gcgggcatga cttctgcgct aagattgtca gtttccaaaa acgaggagga tttgatattc 34200 acctggcccg atctggccat acacttgagt gacaatgaca tccactttgc ctttctctcc 34260 acaggtgtcc actcccaggt ccaagtttgg aagatctgaa ctgaaaaacc agaaagttaa 34320 ctggtaagtt tagtcttttt gtcttttatt tcaggtcccg gatccggtgg tggtgcaaat 34380 caaagaactg ctcctcagtg gatgttgcct ttacttctag gcctgtacgg aagtgttact 34440 tctgctctaa aagctgcgga attgtaccca ggcctaggct tttgcaaaaa gcttcgaatc 34500 gcgaaaggcc agcacgttct tcgcgccgcg ctcgcacagc ctctgcagca ctcgggccac 34560 cagctccttc aggcaggaca cctggcggaa ggagggggcg gcggggggcg gccgtgcgtc 34620 ccagggcacg cacaccaggc actgggccac cagcgcgcgg aaagccgccg ggtccccgcg 34680 ctgcaccagc cgccagccct ggggccccag gcgccgcacg aacgtggcca gcggcagcac 34740 ctcgcggtag tggctgcgca gcagggagcg cacggctagg cagcggggag cgcgcggcat 34800 cgcgggggtg gccggggcca gggcttccca agcttcgttt tgcggcagga aaagttatca 34860 ggcatgcacc tggtagctag tctttaaacc aatagattgc atcggtttaa aaggcaagac 34920 cgtcaaattg cgggaaaggg gtcaacagcc gttcagtacc aagtctcagg ggaaactttg 34980 agatggcctt gcaaagggta tggtaataag ctgacggaca tggtcctaac cacgcagcca 35040 agtcctaagt caacagatct tctgttgata tggatgcagt tcacagacta aatgtcggtc 35100 ggggaagatg tattcttctc ataagatata gtcggacctc tccttaatgg gagctagcgg 35160 atgaagtgat gcaacactgg agccgctggg aactaatttg tatgcgaaag tatattgatt 35220 agttttggag tactcgaaaa cgcccaccat ggcttcgtac ccctgccatc aacacgcgtc 35280 tgcgttcgac caggctgcgc gttctcgcgg ccatagcaac cgacgtacgg cgttgcgccc 35340 tcgccggcag caagaagcca cggaagtccg cctggagcag aaaatgccca cgctactgcg 35400 ggtttatata gacggtcctc acgggatggg gaaaaccacc accacgcaac tgctggtggc 35460 cctgggttcg cgcgacgata tcgtctacgt acccgagccg atgacttact ggcaggtgct 35520 gggggcttcc gagacaatcg cgaacatcta caccacacaa caccgcctcg accagggtga 35580 gatatcggcc ggggacgcgg cggtggtaat gacaagcgcc cagataacaa tgggcatgcc 35640 ttatgccgtg accgacgccg ttctggctcc tcatgtcggg ggggaggctg ggagttcaca 35700 tgccccgccc ccggccctca ccctcatctt cgaccgccat cccatcgccg ccctcctgtg 35760 ctacccggcc gcgcgatacc ttatgggcag catgaccccc caggccgtgc tggcgttcgt 35820 ggccctcatc ccgccgacct tgcccggcac aaacatcgtg ttgggggccc ttccggagga 35880 cagacacatc gaccgcctgg ccaaacgcca gcgccccggc gagcggcttg acctggctat 35940 gctggccgcg attcgccgcg tttacgggct gcttgccaat acggtgcggt atctgcaggg 36000 cggcgggtcg tggtgggagg attggggaca gctttcgggg acggccgtgc cgccccaggg 36060 tgccgagccc cagagcaacg cgggcccacg accccatatc ggggacacgt tatttaccct 36120 gtttcgggcc cccgagttgc tggcccccaa cggcgacctg tataacgtgt ttgcctgggc 36180 cttggacgtc ttggccaaac gcctccgtcc catgcacgtc tttatcctgg attacgacca 36240 atcgcccgcc ggctgccggg acgccctgct gcaacttacc tccgggatgg tccagaccca 36300 cgtcaccacc ccaggctcca taccgacgat ctgcgacctg gcgcgcacgt ttgcccggga 36360 gatgggggag gctaactgag gccggccgct tcgaaggcga aagatcccaa cgaaaagaga 36420 gaccacatgg tccttcttga gtttgtaaca gctgctggga ttacacatgg catggatgaa 36480 ctgtacaact gaggatcccc cgacctcgac ctctggctaa taaaggaaat ttattttcat 36540 tgcaatagtg tgttggaatt ttttgtgtct ctcactcgga aggacatatg ggagggcaaa 36600 tcatttggtc gagatccctc ggagatcgga tctgggcgtg g 36641 <210> 43 <211> 37031 <212> DNA <213> Artificial Sequence <220> <223> Ad-CMV Ribozyme HSV-TK WPRE(forward) <400> 43 ttaagggtgg gaaagaatat ataaggtggg ggtcttatgt agttttgtat ctgttttgca 60 gcagccgccg ccgccatgag caccaactcg tttgatggaa gcattgtgag ctcatatttg 120 acaacgcgca tgcccccatg ggccggggtg cgtcagaatg tgatgggctc cagcattgat 180 ggtcgccccg tcctgcccgc aaactctact accttgacct acgagaccgt gtctggaacg 240 ccgttggaga ctgcagcctc cgccgccgct tcagccgctg cagccaccgc ccgcgggatt 300 gtgactgact ttgctttcct gagcccgctt gcaagcagtg cagcttcccg ttcatccgcc 360 cgcgatgaca agttgacggc tcttttggca caattggatt ctttgacccg ggaacttaat 420 gtcgtttctc agcagctgtt ggatctgcgc cagcaggttt ctgccctgaa ggcttcctcc 480 cctcccaatg cggtttaaaa cataaataaa aaaccagact ctgtttggat ttggatcaag 540 caagtgtctt gctgtcttta tttaggggtt ttgcgcgcgc ggtaggcccg ggaccagcgg 600 tctcggtcgt tgagggtcct gtgtattttt tccaggacgt ggtaaaggtg actctggatg 660 ttcagataca tgggcataag cccgtctctg gggtggaggt agcaccactg cagagcttca 720 tgctgcgggg tggtgttgta gatgatccag tcgtagcagg agcgctgggc gtggtgccta 780 aaaatgtctt tcagtagcaa gctgattgcc aggggcaggc ccttggtgta agtgtttaca 840 aagcggttaa gctgggatgg gtgcatacgt ggggatatga gatgcatctt ggactgtatt 900 tttaggttgg ctatgttccc agccatatcc ctccggggat tcatgttgtg cagaaccacc 960 agcacagtgt atccggtgca cttgggaaat ttgtcatgta gcttagaagg aaatgcgtgg 1020 aagaacttgg agacgccctt gtgacctcca agattttcca tgcattcgtc cataatgatg 1080 gcaatgggcc cacgggcggc ggcctgggcg aagatatttc tgggatcact aacgtcatag 1140 ttgtgttcca ggatgagatc gtcataggcc atttttacaa agcgcgggcg gagggtgcca 1200 gactgcggta taatggttcc atccggccca ggggcgtagt taccctcaca gatttgcatt 1260 tcccacgctt tgagttcaga tggggggatc atgtctacct gcggggcgat gaagaaaacg 1320 gtttccgggg taggggagat cagctgggaa gaaagcaggt tcctgagcag ctgcgactta 1380 ccgcagccgg tgggcccgta aatcacacct attaccgggt gcaactggta gttaagagag 1440 ctgcagctgc cgtcatccct gagcaggggg gccacttcgt taagcatgtc cctgactcgc 1500 atgttttccc tgaccaaatc cgccagaagg cgctcgccgc ccagcgatag cagttcttgc 1560 aaggaagcaa agtttttcaa cggtttgaga ccgtccgccg taggcatgct tttgagcgtt 1620 tgaccaagca gttccaggcg gtcccacagc tcggtcacct gctctacggc atctcgatcc 1680 agcatatctc ctcgtttcgc gggttggggc ggctttcgct gtacggcagt agtcggtgct 1740 cgtccagacg ggccagggtc atgtctttcc acgggcgcag ggtcctcgtc agcgtagtct 1800 gggtcacggt gaaggggtgc gctccgggct gcgcgctggc cagggtgcgc ttgaggctgg 1860 tcctgctggt gctgaagcgc tgccggtctt cgccctgcgc gtcggccagg tagcatttga 1920 ccatggtgtc atagtccagc ccctccgcgg cgtggccctt ggcgcgcagc ttgcccttgg 1980 aggaggcgcc gcacgagggg cagtgcagac ttttgagggc gtagagcttg ggcgcgagaa 2040 ataccgattc cggggagtag gcatccgcgc cgcaggcccc gcagacggtc tcgcattcca 2100 cgagccaggt gagctctggc cgttcggggt caaaaaccag gtttccccca tgctttttga 2160 tgcgtttctt acctctggtt tccatgagcc ggtgtccacg ctcggtgacg aaaaggctgt 2220 ccgtgtcccc gtatacagac ttgagaggcc tgtcctcgag cggtgttccg cggtcctcct 2280 cgtatagaaa ctcggaccac tctgagacaa aggctcgcgt ccaggccagc acgaaggagg 2340 ctaagtggga ggggtagcgg tcgttgtcca ctagggggtc cactcgctcc agggtgtgaa 2400 gacacatgtc gccctcttcg gcatcaagga aggtgattgg tttgtaggtg taggccacgt 2460 gaccgggtgt tcctgaaggg gggctataaa agggggtggg ggcgcgttcg tcctcactct 2520 cttccgcatc gctgtctgcg agggccagct gttggggtga gtactccctc tgaaaagcgg 2580 gcatgacttc tgcgctaaga ttgtcagttt ccaaaaacga ggaggatttg atattcacct 2640 ggcccgcggt gatgcctttg agggtggccg catccatctg gtcagaaaag acaatctttt 2700 tgttgtcaag cttggtggca aacgacccgt agagggcgtt ggacagcaac ttggcgatgg 2760 agcgcagggt ttggtttttg tcgcgatcgg cgcgctcctt ggccgcgatg tttagctgca 2820 cgtattcgcg cgcaacgcac cgccattcgg gaaagacggt ggtgcgctcg tcgggcacca 2880 ggtgcacgcg ccaaccgcgg ttgtgcaggg tgacaaggtc aacgctggtg gctacctctc 2940 cgcgtaggcg ctcgttggtc cagcagaggc ggccgccctt gcgcgagcag aatggcggta 3000 gggggtctag ctgcgtctcg tccggggggt ctgcgtccac ggtaaagacc ccgggcagca 3060 ggcgcgcgtc gaagtagtct atcttgcatc cttgcaagtc tagcgcctgc tgccatgcgc 3120 gggcggcaag cgcgcgctcg tatgggttga gtgggggacc ccatggcatg gggtgggtga 3180 gcgcggaggc gtacatgccg caaatgtcgt aaacgtagag gggctctctg agtattccaa 3240 gatatgtagg gtagcatctt ccaccgcgga tgctggcgcg cacgtaatcg tatagttcgt 3300 gcgagggagc gaggaggtcg ggaccgaggt tgctacgggc gggctgctct gctcggaaga 3360 ctatctgcct gaagatggca tgtgagttgg atgatatggt tggacgctgg aagacgttga 3420 agctggcgtc tgtgagacct accgcgtcac gcacgaagga ggcgtaggag tcgcgcagct 3480 tgttgaccag ctcggcggtg acctgcacgt ctagggcgca gtagtccagg gtttccttga 3540 tgatgtcata cttatcctgt cccttttttt tccacagctc gcggttgagg acaaactctt 3600 cgcggtcttt ccagtactct tggatcggaa acccgtcggc ctccgaacgg taagagccta 3660 gcatgtagaa ctggttgacg gcctggtagg cgcagcatcc cttttctacg ggtagcgcgt 3720 atgcctgcgc ggccttccgg agcgaggtgt gggtgagcgc aaaggtgtcc ctgaccatga 3780 ctttgaggta ctggtatttg aagtcagtgt cgtcgcatcc gccctgctcc cagagcaaaa 3840 agtccgtgcg ctttttggaa cgcggatttg gcagggcgaa ggtgacatcg ttgaagagta 3900 tctttcccgc gcgaggcata aagttgcgtg tgatgcggaa gggtcccggc acctcggaac 3960 ggttgttaat tacctgggcg gcgagcacga tctcgtcaaa gccgttgatg ttgtggccca 4020 caatgtaaag ttccaagaag cgcgggatgc ccttgatgga aggcaatttt ttaagttcct 4080 cgtaggtgag ctcttcaggg gagctgagcc cgtgctctga aagggcccag tctgcaagat 4140 gagggttgga agcgacgaat gagctccaca ggtcacgggc cattagcatt tgcaggtggt 4200 cgcgaaaggt cctaaactgg cgacctatgg ccattttttc tggggtgatg cagtagaagg 4260 taagcgggtc ttgttcccag cggtcccatc caaggttcgc ggctaggtct cgcgcggcag 4320 tcactagagg ctcatctccg ccgaacttca tgaccagcat gaagggcacg agctgcttcc 4380 caaaggcccc catccaagta taggtctcta catcgtaggt gacaaagaga cgctcggtgc 4440 gaggatgcga gccgatcggg aagaactgga tctcccgcca ccaattggag gagtggctat 4500 tgatgtggtg aaagtagaag tccctgcgac gggccgaaca ctcgtgctgg cttttgtaaa 4560 aacgtgcgca gtactggcag cggtgcacgg gctgtacatc ctgcacgagg ttgacctgac 4620 gaccgcgcac aaggaagcag agtgggaatt tgagcccctc gcctggcggg tttggctggt 4680 ggtcttctac ttcggctgct tgtccttgac cgtctggctg ctcgagggga gttacggtgg 4740 atcggaccac cacgccgcgc gagcccaaag tccagatgtc cgcgcgcggc ggtcggagct 4800 tgatgacaac atcgcgcaga tgggagctgt ccatggtctg gagctcccgc ggcgtcaggt 4860 caggcgggag ctcctgcagg tttacctcgc atagacgggt cagggcgcgg gctagatcca 4920 ggtgatacct aatttccagg ggctggttgg tggcggcgtc gatggcttgc aagaggccgc 4980 atccccgcgg cgcgactacg gtaccgcgcg gcgggcggtg ggccgcgggg gtgtccttgg 5040 atgatgcatc taaaagcggt gacgcgggcg agcccccgga ggtagggggg gctccggacc 5100 cgccgggaga gggggcaggg gcacgtcggc gccgcgcgcg ggcaggagct ggtgctgcgc 5160 gcgtaggttg ctggcgaacg cgacgacgcg gcggttgatc tcctgaatct ggcgcctctg 5220 cgtgaagacg acgggcccgg tgagcttgag cctgaaagag agttcgacag aatcaatttc 5280 ggtgtcgttg acggcggcct ggcgcaaaat ctcctgcacg tctcctgagt tgtcttgata 5340 ggcgatctcg gccatgaact gctcgatctc ttcctcctgg agatctccgc gtccggctcg 5400 ctccacggtg gcggcgaggt cgttggaaat gcgggccatg agctgcgaga aggcgttgag 5460 gcctccctcg ttccagacgc ggctgtagac cacgccccct tcggcatcgc gggcgcgcat 5520 gaccacctgc gcgagattga gctccacgtg ccgggcgaag acggcgtagt ttcgcaggcg 5580 ctgaaagagg tagttgaggg tggtggcggt gtgttctgcc acgaagaagt acataaccca 5640 gcgtcgcaac gtggattcgt tgatatcccc caaggcctca aggcgctcca tggcctcgta 5700 gaagtccacg gcgaagttga aaaactggga gttgcgcgcc gacacggtta actcctcctc 5760 cagaagacgg atgagctcgg cgacagtgtc gcgcacctcg cgctcaaagg ctacaggggc 5820 ctcttcttct tcttcaatct cctcttccat aagggcctcc ccttcttctt cttctggcgg 5880 cggtggggga ggggggacac ggcggcgacg acggcgcacc gggaggcggt cgacaaagcg 5940 ctcgatcatc tccccgcggc gacggcgcat ggtctcggtg acggcgcggc cgttctcgcg 6000 ggggcgcagt tggaagacgc cgcccgtcat gtcccggtta tgggttggcg gggggctgcc 6060 atgcggcagg gatacggcgc taacgatgca tctcaacaat tgttgtgtag gtactccgcc 6120 gccgagggac ctgagcgagt ccgcatcgac cggatcggaa aacctctcga gaaaggcgtc 6180 taaccagtca cagtcgcaag gtaggctgag caccgtggcg ggcggcagcg ggcggcggtc 6240 ggggttgttt ctggcggagg tgctgctgat gatgtaatta aagtaggcgg tcttgagacg 6300 gcggatggtc gacagaagca ccatgtcctt gggtccggcc tgctgaatgc gcaggcggtc 6360 ggccatgccc caggcttcgt tttgacatcg gcgcaggtct ttgtagtagt cttgcatgag 6420 cctttctacc ggcacttctt cttctccttc ctcttgtcct gcatctcttg catctatcgc 6480 tgcggcggcg gcggagtttg gccgtaggtg gcgccctctt cctcccatgc gtgtgacccc 6540 gaagcccctc atcggctgaa gcagggctag gtcggcgaca acgcgctcgg ctaatatggc 6600 ctgctgcacc tgcgtgaggg tagactggaa gtcatccatg tccacaaagc ggtggtatgc 6660 gcccgtgttg atggtgtaag tgcagttggc cataacggac cagttaacgg tctggtgacc 6720 cggctgcgag agctcggtgt acctgagacg cgagtaagcc ctcgagtcaa atacgtagtc 6780 gttgcaagtc cgcaccaggt actggtatcc caccaaaaag tgcggcggcg gctggcggta 6840 gaggggccag cgtagggtgg ccggggctcc gggggcgaga tcttccaaca taaggcgatg 6900 atatccgtag atgtacctgg acatccaggt gatgccggcg gcggtggtgg aggcgcgcgg 6960 aaagtcgcgg acgcggttcc agatgttgcg cagcggcaaa aagtgctcca tggtcgggac 7020 gctctggccg gtcaggcgcg cgcaatcgtt gacgctctac cgtgcaaaag gagagcctgt 7080 aagcgggcac tcttccgtgg tctggtggat aaattcgcaa gggtatcatg gcggacgacc 7140 ggggttcgag ccccgtatcc ggccgtccgc cgtgatccat gcggttaccg cccgcgtgtc 7200 gaacccaggt gtgcgacgtc agacaacggg ggagtgctcc ttttggcttc cttccaggcg 7260 cggcggctgc tgcgctagct tttttggcca ctggccgcgc gcagcgtaag cggttaggct 7320 ggaaagcgaa agcattaagt ggctcgctcc ctgtagccgg agggttattt tccaagggtt 7380 gagtcgcggg acccccggtt cgagtctcgg accggccgga ctgcggcgaa cgggggtttg 7440 cctccccgtc atgcaagacc ccgcttgcaa attcctccgg aaacagggac gagccccttt 7500 tttgcttttc ccagatgcat ccggtgctgc ggcagatgcg cccccctcct cagcagcggc 7560 aagagcaaga gcagcggcag acatgcaggg caccctcccc tcctcctacc gcgtcaggag 7620 gggcgacatc cgcggttgac gcggcagcag atggtgatta cgaacccccg cggcgccggg 7680 cccggcacta cctggacttg gaggagggcg agggcctggc gcggctagga gcgccctctc 7740 ctgagcggta cccaagggtg cagctgaagc gtgatacgcg tgaggcgtac gtgccgcggc 7800 agaacctgtt tcgcgaccgc gagggagagg agcccgagga gatgcgggat cgaaagttcc 7860 acgcagggcg cgagctgcgg catggcctga atcgcgagcg gttgctgcgc gaggaggact 7920 ttgagcccga cgcgcgaacc gggattagtc ccgcgcgcgc acacgtggcg gccgccgacc 7980 tggtaaccgc atacgagcag acggtgaacc aggagattaa ctttcaaaaa agctttaaca 8040 accacgtgcg tacgcttgtg gcgcgcgagg aggtggctat aggactgatg catctgtggg 8100 actttgtaag cgcgctggag caaaacccaa atagcaagcc gctcatggcg cagctgttcc 8160 ttatagtgca gcacagcagg gacaacgagg cattcaggga tgcgctgcta aacatagtag 8220 agcccgaggg ccgctggctg ctcgatttga taaacatcct gcagagcata gtggtgcagg 8280 agcgcagctt gagcctggct gacaaggtgg ccgccatcaa ctattccatg cttagcctgg 8340 gcaagtttta cgcccgcaag atataccata ccccttacgt tcccatagac aaggaggtaa 8400 agatcgaggg gttctacatg cgcatggcgc tgaaggtgct taccttgagc gacgacctgg 8460 gcgtttatcg caacgagcgc atccacaagg ccgtgagcgt gagccggcgg cgcgagctca 8520 gcgaccgcga gctgatgcac agcctgcaaa gggccctggc tggcacgggc agcggcgata 8580 gagaggccga gtcctacttt gacgcgggcg ctgacctgcg ctgggcccca agccgacgcg 8640 ccctggaggc agctggggcc ggacctgggc tggcggtggc acccgcgcgc gctggcaacg 8700 tcggcggcgt ggaggaatat gacgaggacg atgagtacga gccagaggac ggcgagtact 8760 aagcggtgat gtttctgatc agatgatgca agacgcaacg gacccggcgg tgcgggcggc 8820 gctgcagagc cagccgtccg gccttaactc cacggacgac tggcgccagg tcatggaccg 8880 catcatgtcg ctgactgcgc gcaatcctga cgcgttccgg cagcagccgc aggccaaccg 8940 gctctccgca attctggaag cggtggtccc ggcgcgcgca aaccccacgc acgagaaggt 9000 gctggcgatc gtaaacgcgc tggccgaaaa cagggccatc cggcccgacg aggccggcct 9060 ggtctacgac gcgctgcttc agcgcgtggc tcgttacaac agcggcaacg tgcagaccaa 9120 cctggaccgg ctggtggggg atgtgcgcga ggccgtggcg cagcgtgagc gcgcgcagca 9180 gcagggcaac ctgggctcca tggttgcact aaacgccttc ctgagtacac agcccgccaa 9240 cgtgccgcgg ggacaggagg actacaccaa ctttgtgagc gcactgcggc taatggtgac 9300 tgagacaccg caaagtgagg tgtaccagtc tgggccagac tattttttcc agaccagtag 9360 acaaggcctg cagaccgtaa acctgagcca ggctttcaaa aacttgcagg ggctgtgggg 9420 ggtgcgggct cccacaggcg accgcgcgac cgtgtctagc ttgctgacgc ccaactcgcg 9480 cctgttgctg ctgctaatag cgcccttcac ggacagtggc agcgtgtccc gggacacata 9540 cctaggtcac ttgctgacac tgtaccgcga ggccataggt caggcgcatg tggacgagca 9600 tactttccag gagattacaa gtgtcagccg cgcgctgggg caggaggaca cgggcagcct 9660 ggaggcaacc ctaaactacc tgctgaccaa ccggcggcag aagatcccct cgttgcacag 9720 tttaaacagc gaggaggagc gcattttgcg ctacgtgcag cagagcgtga gccttaacct 9780 gatgcgcgac ggggtaacgc ccagcgtggc gctggacatg accgcgcgca acatggaacc 9840 gggcatgtat gcctcaaacc ggccgtttat caaccgccta atggactact tgcatcgcgc 9900 ggccgccgtg aaccccgagt atttcaccaa tgccatcttg aacccgcact ggctaccgcc 9960 ccctggtttc tacaccgggg gattcgaggt gcccgagggt aacgatggat tcctctggga 10020 cgacatagac gacagcgtgt tttccccgca accgcagacc ctgctagagt tgcaacagcg 10080 cgagcaggca gaggcggcgc tgcgaaagga aagcttccgc aggccaagca gcttgtccga 10140 tctaggcgct gcggccccgc ggtcagatgc tagtagccca tttccaagct tgatagggtc 10200 tcttaccagc actcgcacca cccgcccgcg cctgctgggc gaggaggagt acctaaacaa 10260 ctcgctgctg cagccgcagc gcgaaaaaaa cctgcctccg gcatttccca acaacgggat 10320 agagagccta gtggacaaga tgagtagatg gaagacgtac gcgcaggagc acagggacgt 10380 gccaggcccg cgcccgccca cccgtcgtca aaggcacgac cgtcagcggg gtctggtgtg 10440 ggaggacgat gactcggcag acgacagcag cgtcctggat ttgggaggga gtggcaaccc 10500 gtttgcgcac cttcgcccca ggctggggag aatgttttaa aaaaaaaaaa gcatgatgca 10560 aaataaaaaa ctcaccaagg ccatggcacc gagcgttggt tttcttgtat tccccttagt 10620 atgcggcgcg cggcgatgta tgaggaaggt cctcctccct cctacgagag tgtggtgagc 10680 gcggcgccag tggcggcggc gctgggttct cccttcgatg ctcccctgga cccgccgttt 10740 gtgcctccgc ggtacctgcg gcctaccggg gggagaaaca gcatccgtta ctctgagttg 10800 gcacccctat tcgacaccac ccgtgtgtac ctggtggaca acaagtcaac ggatgtggca 10860 tccctgaact accagaacga ccacagcaac tttctgacca cggtcattca aaacaatgac 10920 tacagcccgg gggaggcaag cacacagacc atcaatcttg acgaccggtc gcactggggc 10980 ggcgacctga aaaccatcct gcataccaac atgccaaatg tgaacgagtt catgtttacc 11040 aataagttta aggcgcgggt gatggtgtcg cgcttgccta ctaaggacaa tcaggtggag 11100 ctgaaatacg agtgggtgga gttcacgctg cccgagggca actactccga gaccatgacc 11160 atagacctta tgaacaacgc gatcgtggag cactacttga aagtgggcag acagaacggg 11220 gttctggaaa gcgacatcgg ggtaaagttt gacacccgca acttcagact ggggtttgac 11280 cccgtcactg gtcttgtcat gcctggggta tatacaaacg aagccttcca tccagacatc 11340 attttgctgc caggatgcgg ggtggacttc acccacagcc gcctgagcaa cttgttgggc 11400 atccgcaagc ggcaaccctt ccaggagggc tttaggatca cctacgatga tctggagggt 11460 ggtaacattc ccgcactgtt ggatgtggac gcctaccagg cgagcttgaa agatgacacc 11520 gaacagggcg ggggtggcgc aggcggcagc aacagcagtg gcagcggcgc ggaagagaac 11580 tccaacgcgg cagccgcggc aatgcagccg gtggaggaca tgaacgatca tgccattcgc 11640 ggcgacacct ttgccacacg ggctgaggag aagcgcgctg aggccgaagc agcggccgaa 11700 gctgccgccc ccgctgcgca acccgaggtc gagaagcctc agaagaaacc ggtgatcaaa 11760 cccctgacag aggacagcaa gaaacgcagt tacaacctaa taagcaatga cagcaccttc 11820 acccagtacc gcagctggta ccttgcatac aactacggcg accctcagac cggaatccgc 11880 tcatggaccc tgctttgcac tcctgacgta acctgcggct cggagcaggt ctactggtcg 11940 ttgccagaca tgatgcaaga ccccgtgacc ttccgctcca cgcgccagat cagcaacttt 12000 ccggtggtgg gcgccgagct gttgcccgtg cactccaaga gcttctacaa cgaccaggcc 12060 gtctactccc aactcatccg ccagtttacc tctctgaccc acgtgttcaa tcgctttccc 12120 gagaaccaga ttttggcgcg cccgccagcc cccaccatca ccaccgtcag tgaaaacgtt 12180 cctgctctca cagatcacgg gacgctaccg ctgcgcaaca gcatcggagg agtccagcga 12240 gtgaccatta ctgacgccag acgccgcacc tgcccctacg tttacaaggc cctgggcata 12300 gtctcgccgc gcgtcctatc gagccgcact ttttgagcaa gcatgtccat ccttatatcg 12360 cccagcaata acacaggctg gggcctgcgc ttcccaagca agatgtttgg cggggccaag 12420 aagcgctccg accaacaccc agtgcgcgtg cgcgggcact accgcgcgcc ctggggcgcg 12480 cacaaacgcg gccgcactgg gcgcaccacc gtcgatgacg ccatcgacgc ggtggtggag 12540 gaggcgcgca actacacgcc cacgccgcca ccagtgtcca cagtggacgc ggccattcag 12600 accgtggtgc gcggagcccg gcgctatgct aaaatgaaga gacggcggag gcgcgtagca 12660 cgtcgccacc gccgccgacc cggcactgcc gcccaacgcg cggcggcggc cctgcttaac 12720 cgcgcacgtc gcaccggccg acgggcggcc atgcgggccg ctcgaaggct ggccgcgggt 12780 attgtcactg tgccccccag gtccaggcga cgagcggccg ccgcagcagc cgcggccatt 12840 agtgctatga ctcagggtcg caggggcaac gtgtattggg tgcgcgactc ggttagcggc 12900 ctgcgcgtgc ccgtgcgcac ccgccccccg cgcaactaga ttgcaagaaa aaactactta 12960 gactcgtact gttgtatgta tccagcggcg gcggcgcgca acgaagctat gtccaagcgc 13020 aaaatcaaag aagagatgct ccaggtcatc gcgccggaga tctatggccc cccgaagaag 13080 gaagagcagg attacaagcc ccgaaagcta aagcgggtca aaaagaaaaa gaaagatgat 13140 gatgatgaac ttgacgacga ggtggaactg ctgcacgcta ccgcgcccag gcgacgggta 13200 cagtggaaag gtcgacgcgt aaaacgtgtt ttgcgacccg gcaccaccgt agtctttacg 13260 cccggtgagc gctccacccg cacctacaag cgcgtgtatg atgaggtgta cggcgacgag 13320 gacctgcttg agcaggccaa cgagcgcctc ggggagtttg cctacggaaa gcggcataag 13380 gacatgctgg cgttgccgct ggacgagggc aacccaacac ctagcctaaa gcccgtaaca 13440 ctgcagcagg tgctgcccgc gcttgcaccg tccgaagaaa agcgcggcct aaagcgcgag 13500 tctggtgact tggcacccac cgtgcagctg atggtaccca agcgccagcg actggaagat 13560 gtcttggaaa aaatgaccgt ggaacctggg ctggagcccg aggtccgcgt gcggccaatc 13620 aagcaggtgg cgccgggact gggcgtgcag accgtggacg ttcagatacc cactaccagt 13680 agcaccagta ttgccaccgc cacagagggc atggagacac aaacgtcccc ggttgcctca 13740 gcggtggcgg atgccgcggt gcaggcggtc gctgcggccg cgtccaagac ctctacggag 13800 gtgcaaacgg acccgtggat gtttcgcgtt tcagcccccc ggcgcccgcg cggttcgagg 13860 aagtacggcg ccgccagcgc gctactgccc gaatatgccc tacatccttc cattgcgcct 13920 acccccggct atcgtggcta cacctaccgc cccagaagac gagcaactac ccgacgccga 13980 accaccactg gaacccgccg ccgccgtcgc cgtcgccagc ccgtgctggc cccgatttcc 14040 gtgcgcaggg tggctcgcga aggaggcagg accctggtgc tgccaacagc gcgctaccac 14100 cccagcatcg tttaaaagcc ggtctttgtg gttcttgcag atatggccct cacctgccgc 14160 ctccgtttcc cggtgccggg attccgagga agaatgcacc gtaggagggg catggccggc 14220 cacggcctga cgggcggcat gcgtcgtgcg caccaccggc ggcggcgcgc gtcgcaccgt 14280 cgcatgcgcg gcggtatcct gcccctcctt attccactga tcgccgcggc gattggcgcc 14340 gtgcccggaa ttgcatccgt ggccttgcag gcgcagagac actgattaaa aacaagttgc 14400 atgtggaaaa atcaaaataa aaagtctgga ctctcacgct cgcttggtcc tgtaactatt 14460 ttgtagaatg gaagacatca actttgcgtc tctggccccg cgacacggct cgcgcccgtt 14520 catgggaaac tggcaagata tcggcaccag caatatgagc ggtggcgcct tcagctgggg 14580 ctcgctgtgg agcggcatta aaaatttcgg ttccaccgtt aagaactatg gcagcaaggc 14640 ctggaacagc agcacaggcc agatgctgag ggataagttg aaagagcaaa atttccaaca 14700 aaaggtggta gatggcctgg cctctggcat tagcggggtg gtggacctgg ccaaccaggc 14760 agtgcaaaat aagattaaca gtaagcttga tccccgccct cccgtagagg agcctccacc 14820 ggccgtggag acagtgtctc cagaggggcg tggcgaaaag cgtccgcgcc ccgacaggga 14880 agaaactctg gtgacgcaaa tagacgagcc tccctcgtac gaggaggcac taaagcaagg 14940 cctgcccacc acccgtccca tcgcgcccat ggctaccgga gtgctgggcc agcacacacc 15000 cgtaacgctg gacctgcctc cccccgccga cacccagcag aaacctgtgc tgccaggccc 15060 gaccgccgtt gttgtaaccc gtcctagccg cgcgtccctg cgccgcgccg ccagcggtcc 15120 gcgatcgttg cggcccgtag ccagtggcaa ctggcaaagc acactgaaca gcatcgtggg 15180 tctgggggtg caatccctga agcgccgacg atgcttctga atagctaacg tgtcgtatgt 15240 gtgtcatgta tgcgtccatg tcgccgccag aggagctgct gagccgccgc gcgcccgctt 15300 tccaagatgg ctaccccttc gatgatgccg cagtggtctt acatgcacat ctcgggccag 15360 gacgcctcgg agtacctgag ccccgggctg gtgcagtttg cccgcgccac cgagacgtac 15420 ttcagcctga ataacaagtt tagaaacccc acggtggcgc ctacgcacga cgtgaccaca 15480 gaccggtccc agcgtttgac gctgcggttc atccctgtgg accgtgagga tactgcgtac 15540 tcgtacaagg cgcggttcac cctagctgtg ggtgataacc gtgtgctgga catggcttcc 15600 acgtactttg acatccgcgg cgtgctggac aggggcccta cttttaagcc ctactctggc 15660 actgcctaca acgccctggc tcccaagggt gccccaaatc cttgcgaatg ggatgaagct 15720 gctactgctc ttgaaataaa cctagaagaa gaggacgatg acaacgaaga cgaagtagac 15780 gagcaagctg agcagcaaaa aactcacgta tttgggcagg cgccttattc tggtataaat 15840 attacaaagg agggtattca aataggtgtc gaaggtcaaa cacctaaata tgccgataaa 15900 acatttcaac ctgaacctca aataggagaa tctcagtggt acgaaactga aattaatcat 15960 gcagctggga gagtccttaa aaagactacc ccaatgaaac catgttacgg ttcatatgca 16020 aaacccacaa atgaaaatgg agggcaaggc attcttgtaa agcaacaaaa tggaaagcta 16080 gaaagtcaag tggaaatgca atttttctca actactgagg cgaccgcagg caatggtgat 16140 aacttgactc ctaaagtggt attgtacagt gaagatgtag atatagaaac cccagacact 16200 catatttctt acatgcccac tattaaggaa ggtaactcac gagaactaat gggccaacaa 16260 tctatgccca acaggcctaa ttacattgct tttagggaca attttattgg tctaatgtat 16320 tacaacagca cgggtaatat gggtgttctg gcgggccaag catcgcagtt gaatgctgtt 16380 gtagatttgc aagacagaaa cacagagctt tcataccagc ttttgcttga ttccattggt 16440 gatagaacca ggtacttttc tatgtggaat caggctgttg acagctatga tccagatgtt 16500 agaattattg aaaatcatgg aactgaagat gaacttccaa attactgctt tccactggga 16560 ggtgtgatta atacagagac tcttaccaag gtaaaaccta aaacaggtca ggaaaatgga 16620 tgggaaaaag atgctacaga attttcagat aaaaatgaaa taagagttgg aaataatttt 16680 gccatggaaa tcaatctaaa tgccaacctg tggagaaatt tcctgtactc caacatagcg 16740 ctgtatttgc ccgacaagct aaagtacagt ccttccaacg taaaaatttc tgataaccca 16800 aacacctacg actacatgaa caagcgagtg gtggctcccg ggttagtgga ctgctacatt 16860 aaccttggag cacgctggtc ccttgactat atggacaacg tcaacccatt taaccaccac 16920 cgcaatgctg gcctgcgcta ccgctcaatg ttgctgggca atggtcgcta tgtgcccttc 16980 cacatccagg tgcctcagaa gttctttgcc attaaaaacc tccttctcct gccgggctca 17040 tacacctacg agtggaactt caggaaggat gttaacatgg ttctgcagag ctccctagga 17100 aatgacctaa gggttgacgg agccagcatt aagtttgata gcatttgcct ttacgccacc 17160 ttcttcccca tggcccacaa caccgcctcc acgcttgagg ccatgcttag aaacgacacc 17220 aacgaccagt cctttaacga ctatctctcc gccgccaaca tgctctaccc tatacccgcc 17280 aacgctacca acgtgcccat atccatcccc tcccgcaact gggcggcttt ccgcggctgg 17340 gccttcacgc gccttaagac taaggaaacc ccatcactgg gctcgggcta cgacccttat 17400 tacacctact ctggctctat accctaccta gatggaacct tttacctcaa ccacaccttt 17460 aagaaggtgg ccattacctt tgactcttct gtcagctggc ctggcaatga ccgcctgctt 17520 acccccaacg agtttgaaat taagcgctca gttgacgggg agggttacaa cgttgcccag 17580 tgtaacatga ccaaagactg gttcctggta caaatgctag ctaactacaa cattggctac 17640 cagggcttct atatcccaga gagctacaag gaccgcatgt actccttctt tagaaacttc 17700 cagcccatga gccgtcaggt ggtggatgat actaaataca aggactacca acaggtgggc 17760 atcctacacc aacacaacaa ctctggattt gttggctacc ttgcccccac catgcgcgaa 17820 ggacaggcct accctgctaa cttcccctat ccgcttatag gcaagaccgc agttgacagc 17880 attacccaga aaaagtttct ttgcgatcgc accctttggc gcatcccatt ctccagtaac 17940 tttatgtcca tgggcgcact cacagacctg ggccaaaacc ttctctacgc caactccgcc 18000 cacgcgctag acatgacttt tgaggtggat cccatggacg agcccaccct tctttatgtt 18060 ttgtttgaag tctttgacgt ggtccgtgtg caccggccgc accgcggcgt catcgaaacc 18120 gtgtacctgc gcacgccctt ctcggccggc aacgccacaa cataaagaag caagcaacat 18180 caacaacagc tgccgccatg ggctccagtg agcaggaact gaaagccatt gtcaaagatc 18240 ttggttgtgg gccatatttt ttgggcacct atgacaagcg ctttccaggc tttgtttctc 18300 cacacaagct cgcctgcgcc atagtcaata cggccggtcg cgagactggg ggcgtacact 18360 ggatggcctt tgcctggaac ccgcactcaa aaacatgcta cctctttgag ccctttggct 18420 tttctgacca gcgactcaag caggtttacc agtttgagta cgagtcactc ctgcgccgta 18480 gcgccattgc ttcttccccc gaccgctgta taacgctgga aaagtccacc caaagcgtac 18540 aggggcccaa ctcggccgcc tgtggactat tctgctgcat gtttctccac gcctttgcca 18600 actggcccca aactcccatg gatcacaacc ccaccatgaa ccttattacc ggggtaccca 18660 actccatgct caacagtccc caggtacagc ccaccctgcg tcgcaaccag gaacagctct 18720 acagcttcct ggagcgccac tcgccctact tccgcagcca cagtgcgcag attaggagcg 18780 ccacttcttt ttgtcacttg aaaaacatgt aaaaataatg tactagagac actttcaata 18840 aaggcaaatg cttttatttg tacactctcg ggtgattatt tacccccacc cttgccgtct 18900 gcgccgttta aaaatcaaag gggttctgcc gcgcatcgct atgcgccact ggcagggaca 18960 cgttgcgata ctggtgttta gtgctccact taaactcagg cacaaccatc cgcggcagct 19020 cggtgaagtt ttcactccac aggctgcgca ccatcaccaa cgcgtttagc aggtcgggcg 19080 ccgatatctt gaagtcgcag ttggggcctc cgccctgcgc gcgcgagttg cgatacacag 19140 ggttgcagca ctggaacact atcagcgccg ggtggtgcac gctggccagc acgctcttgt 19200 cggagatcag atccgcgtcc aggtcctccg cgttgctcag ggcgaacgga gtcaactttg 19260 gtagctgcct tcccaaaaag ggcgcgtgcc caggctttga gttgcactcg caccgtagtg 19320 gcatcaaaag gtgaccgtgc ccggtctggg cgttaggata cagcgcctgc ataaaagcct 19380 tgatctgctt aaaagccacc tgagcctttg cgccttcaga gaagaacatg ccgcaagact 19440 tgccggaaaa ctgattggcc ggacaggccg cgtcgtgcac gcagcacctt gcgtcggtgt 19500 tggagatctg caccacattt cggccccacc ggttcttcac gatcttggcc ttgctagact 19560 gctccttcag cgcgcgctgc ccgttttcgc tcgtcacatc catttcaatc acgtgctcct 19620 tatttatcat aatgcttccg tgtagacact taagctcgcc ttcgatctca gcgcagcggt 19680 gcagccacaa cgcgcagccc gtgggctcgt gatgcttgta ggtcacctct gcaaacgact 19740 gcaggtacgc ctgcaggaat cgccccatca tcgtcacaaa ggtcttgttg ctggtgaagg 19800 tcagctgcaa cccgcggtgc tcctcgttca gccaggtctt gcatacggcc gccagagctt 19860 ccacttggtc aggcagtagt ttgaagttcg cctttagatc gttatccacg tggtacttgt 19920 ccatcagcgc gcgcgcagcc tccatgccct tctcccacgc agacacgatc ggcacactca 19980 gcgggttcat caccgtaatt tcactttccg cttcgctggg ctcttcctct tcctcttgcg 20040 tccgcatacc acgcgccact gggtcgtctt cattcagccg ccgcactgtg cgcttacctc 20100 ctttgccatg cttgattagc accggtgggt tgctgaaacc caccatttgt agcgccacat 20160 cttctctttc ttcctcgctg tccacgatta cctctggtga tggcgggcgc tcgggcttgg 20220 gagaagggcg cttctttttc ttcttgggcg caatggccaa atccgccgcc gaggtcgatg 20280 gccgcgggct gggtgtgcgc ggcaccagcg cgtcttgtga tgagtcttcc tcgtcctcgg 20340 actcgatacg ccgcctcatc cgcttttttg ggggcgcccg gggaggcggc ggcgacgggg 20400 acggggacga cacgtcctcc atggttgggg gacgtcgcgc cgcaccgcgt ccgcgctcgg 20460 gggtggtttc gcgctgctcc tcttcccgac tggccatttc cttctcctat aggcagaaaa 20520 agatcatgga gtcagtcgag aagaaggaca gcctaaccgc cccctctgag ttcgccacca 20580 ccgcctccac cgatgccgcc aacgcgccta ccaccttccc cgtcgaggca cccccgcttg 20640 aggaggagga agtgattatc gagcaggacc caggttttgt aagcgaagac gacgaggacc 20700 gctcagtacc aacagaggat aaaaagcaag accaggacaa cgcagaggca aacgaggaac 20760 aagtcgggcg gggggacgaa aggcatggcg actacctaga tgtgggagac gacgtgctgt 20820 tgaagcatct gcagcgccag tgcgccatta tctgcgacgc gttgcaagag cgcagcgatg 20880 tgcccctcgc catagcggat gtcagccttg cctacgaacg ccacctattc tcaccgcgcg 20940 taccccccaa acgccaagaa aacggcacat gcgagcccaa cccgcgcctc aacttctacc 21000 ccgtatttgc cgtgccagag gtgcttgcca cctatcacat ctttttccaa aactgcaaga 21060 tacccctatc ctgccgtgcc aaccgcagcc gagcggacaa gcagctggcc ttgcggcagg 21120 gcgctgtcat acctgatatc gcctcgctca acgaagtgcc aaaaatcttt gagggtcttg 21180 gacgcgacga gaagcgcgcg gcaaacgctc tgcaacagga aaacagcgaa aatgaaagtc 21240 actctggagt gttggtggaa ctcgagggtg acaacgcgcg cctagccgta ctaaaacgca 21300 gcatcgaggt cacccacttt gcctacccgg cacttaacct accccccaag gtcatgagca 21360 cagtcatgag tgagctgatc gtgcgccgtg cgcagcccct ggagagggat gcaaatttgc 21420 aagaacaaac agaggagggc ctacccgcag ttggcgacga gcagctagcg cgctggcttc 21480 aaacgcgcga gcctgccgac ttggaggagc gacgcaaact aatgatggcc gcagtgctcg 21540 ttaccgtgga gcttgagtgc atgcagcggt tctttgctga cccggagatg cagcgcaagc 21600 tagaggaaac attgcactac acctttcgac agggctacgt acgccaggcc tgcaagatct 21660 ccaacgtgga gctctgcaac ctggtctcct accttggaat tttgcacgaa aaccgccttg 21720 ggcaaaacgt gcttcattcc acgctcaagg gcgaggcgcg ccgcgactac gtccgcgact 21780 gcgtttactt atttctatgc tacacctggc agacggccat gggcgtttgg cagcagtgct 21840 tggaggagtg caacctcaag gagctgcaga aactgctaaa gcaaaacttg aaggacctat 21900 ggacggcctt caacgagcgc tccgtggccg cgcacctggc ggacatcatt ttccccgaac 21960 gcctgcttaa aaccctgcaa cagggtctgc cagacttcac cagtcaaagc atgttgcaga 22020 actttaggaa ctttatccta gagcgctcag gaatcttgcc cgccacctgc tgtgcacttc 22080 ctagcgactt tgtgcccatt aagtaccgcg aatgccctcc gccgctttgg ggccactgct 22140 accttctgca gctagccaac taccttgcct accactctga cataatggaa gacgtgagcg 22200 gtgacggtct actggagtgt cactgtcgct gcaacctatg caccccgcac cgctccctgg 22260 tttgcaattc gcagctgctt aacgaaagtc aaattatcgg tacctttgag ctgcagggtc 22320 cctcgcctga cgaaaagtcc gcggctccgg ggttgaaact cactccgggg ctgtggacgt 22380 cggcttacct tcgcaaattt gtacctgagg actaccacgc ccacgagatt aggttctacg 22440 aagaccaatc ccgcccgcca aatgcggagc ttaccgcctg cgtcattacc cagggccaca 22500 ttcttggcca attgcaagcc atcaacaaag cccgccaaga gtttctgcta cgaaagggac 22560 ggggggttta cttggacccc cagtccggcg aggagctcaa cccaatcccc ccgccgccgc 22620 agccctatca gcagcagccg cgggcccttg cttcccagga tggcacccaa aaagaagctg 22680 cagctgccgc cgccacccac ggacgaggag gaatactggg acagtcaggc agaggaggtt 22740 ttggacgagg aggaggagga catgatggaa gactgggaga gcctagacga ggaagcttcc 22800 gaggtcgaag aggtgtcaga cgaaacaccg tcaccctcgg tcgcattccc ctcgccggcg 22860 ccccagaaat cggcaaccgg ttccagcatg gctacaacct ccgctcctca ggcgccgccg 22920 gcactgcccg ttcgccgacc caaccgtaga tgggacacca ctggaaccag ggccggtaag 22980 tccaagcagc cgccgccgtt agcccaagag caacaacagc gccaaggcta ccgctcatgg 23040 cgcgggcaca agaacgccat agttgcttgc ttgcaagact gtgggggcaa catctccttc 23100 gcccgccgct ttcttctcta ccatcacggc gtggccttcc cccgtaacat cctgcattac 23160 taccgtcatc tctacagccc atactgcacc ggcggcagcg gcagcggcag caacagcagc 23220 ggccacacag aagcaaaggc gaccggatag caagactctg acaaagccca agaaatccac 23280 agcggcggca gcagcaggag gaggagcgct gcgtctggcg cccaacgaac ccgtatcgac 23340 ccgcgagctt agaaacagga tttttcccac tctgtatgct atatttcaac agagcagggg 23400 ccaagaacaa gagctgaaaa taaaaaacag gtctctgcga tccctcaccc gcagctgcct 23460 gtatcacaaa agcgaagatc agcttcggcg cacgctggaa gacgcggagg ctctcttcag 23520 taaatactgc gcgctgactc ttaaggacta gtttcgcgcc ctttctcaaa tttaagcgcg 23580 aaaactacgt catctccagc ggccacaccc ggcgccagca cctgtcgtca gcgccattat 23640 gagcaaggaa attcccacgc cctacatgtg gagttaccag ccacaaatgg gacttgcggc 23700 tggagctgcc caagactact caacccgaat aaactacatg agcgcgggac cccacatgat 23760 atcccgggtc aacggaatcc gcgcccaccg aaaccgaatt ctcttggaac aggcggctat 23820 taccaccaca cctcgtaata accttaatcc ccgtagttgg cccgctgccc tggtgtacca 23880 ggaaagtccc gctcccacca ctgtggtact tcccagagac gcccaggccg aagttcagat 23940 gactaactca ggggcgcagc ttgcgggcgg ctttcgtcac agggtgcggt cgcccgggca 24000 gggtataact cacctgacaa tcagagggcg aggtattcag ctcaacgacg agtcggtgag 24060 ctcctcgctt ggtctccgtc cggacgggac atttcagatc ggcggcgccg gccgtccttc 24120 attcacgcct cgtcaggcaa tcctaactct gcagacctcg tcctctgagc cgcgctctgg 24180 aggcattgga actctgcaat ttattgagga gtttgtgcca tcggtctact ttaacccctt 24240 ctcgggacct cccggccact atccggatca atttattcct aactttgacg cggtaaagga 24300 ctcggcggac ggctacgact gaatgttaag tggagaggca gagcaactgc gcctgaaaca 24360 cctggtccac tgtcgccgcc acaagtgctt tgcccgcgac tccggtgagt tttgctactt 24420 tgaattgccc gaggatcata tcgagggccc ggcgcacggc gtccggctta ccgcccaggg 24480 agagcttgcc cgtagcctga ttcgggagtt tacccagcgc cccctgctag ttgagcggga 24540 caggggaccc tgtgttctca ctgtgatttg caactgtcct aaccttggat tacatcaaga 24600 tcctctagtt ataactagag tacccgggga tcttattccc tttaactaat aaaaaaaaat 24660 aataaagcat cacttactta aaatcagtta gcaaatttct gtccagttta ttcagcagca 24720 cctccttgcc ctcctcccag ctctggtatt gcagcttcct cctggctgca aactttctcc 24780 acaatctaaa tggaatgtca gtttcctcct gttcctgtcc atccgcaccc actatcttca 24840 tgttgttgca gatgaagcgc gcaagaccgt ctgaagatac cttcaacccc gtgtatccat 24900 atgacacgga aaccggtcct ccaactgtgc cttttcttac tcctcccttt gtatccccca 24960 atgggtttca agagagtccc cctggggtac tctctttgcg cctatccgaa cctctagtta 25020 cctccaatgg catgcttgcg ctcaaaatgg gcaacggcct ctctctggac gaggccggca 25080 accttacctc ccaaaatgta accactgtga gcccacctct caaaaaaacc aagtcaaaca 25140 taaacctgga aatatctgca cccctcacag ttacctcaga agccctaact gtggctgccg 25200 ccgcacctct aatggtcgcg ggcaacacac tcaccatgca atcacaggcc ccgctaaccg 25260 tgcacgactc caaacttagc attgccaccc aaggacccct cacagtgtca gaaggaaagc 25320 tagccctgca aacatcaggc cccctcacca ccaccgatag cagtaccctt actatcactg 25380 cctcaccccc tctaactact gccactggta gcttgggcat tgacttgaaa gagcccattt 25440 atacacaaaa tggaaaacta ggactaaagt acggggctcc tttgcatgta acagacgacc 25500 taaacacttt gaccgtagca actggtccag gtgtgactat taataatact tccttgcaaa 25560 ctaaagttac tggagccttg ggttttgatt cacaaggcaa tatgcaactt aatgtagcag 25620 gaggactaag gattgattct caaaacagac gccttatact tgatgttagt tatccgtttg 25680 atgctcaaaa ccaactaaat ctaagactag gacagggccc tctttttata aactcagccc 25740 acaacttgga tattaactac aacaaaggcc tttacttgtt tacagcttca aacaattcca 25800 aaaagcttga ggttaaccta agcactgcca aggggttgat gtttgacgct acagccatag 25860 ccattaatgc aggagatggg cttgaatttg gttcacctaa tgcaccaaac acaaatcccc 25920 tcaaaacaaa aattggccat ggcctagaat ttgattcaaa caaggctatg gttcctaaac 25980 taggaactgg ccttagtttt gacagcacag gtgccattac agtaggaaac aaaaataatg 26040 ataagctaac tttgtggacc acaccagctc catctcctaa ctgtagacta aatgcagaga 26100 aagatgctaa actcactttg gtcttaacaa aatgtggcag tcaaatactt gctacagttt 26160 cagttttggc tgttaaaggc agtttggctc caatatctgg aacagttcaa agtgctcatc 26220 ttattataag atttgacgaa aatggagtgc tactaaacaa ttccttcctg gacccagaat 26280 attggaactt tagaaatgga gatcttactg aaggcacagc ctatacaaac gctgttggat 26340 ttatgcctaa cctatcagct tatccaaaat ctcacggtaa aactgccaaa agtaacattg 26400 tcagtcaagt ttacttaaac ggagacaaaa ctaaacctgt aacactaacc attacactaa 26460 acggtacaca ggaaacagga gacacaactc caagtgcata ctctatgtca ttttcatggg 26520 actggtctgg ccacaactac attaatgaaa tatttgccac atcctcttac actttttcat 26580 acattgccca agaataaaga atcgtttgtg ttatgtttca acgtgtttat ttttcaattg 26640 cagaaaattt caagtcattt ttcattcagt agtatagccc caccaccaca tagcttatac 26700 agatcaccgt accttaatca aactcacaga accctagtat tcaacctgcc acctccctcc 26760 caacacacag agtacacagt cctttctccc cggctggcct taaaaagcat catatcatgg 26820 gtaacagaca tattcttagg tgttatattc cacacggttt cctgtcgagc caaacgctca 26880 tcagtgatat taataaactc cccgggcagc tcacttaagt tcatgtcgct gtccagctgc 26940 tgagccacag gctgctgtcc aacttgcggt tgcttaacgg gcggcgaagg agaagtccac 27000 gcctacatgg gggtagagtc ataatcgtgc atcaggatag ggcggtggtg ctgcagcagc 27060 gcgcgaataa actgctgccg ccgccgctcc gtcctgcagg aatacaacat ggcagtggtc 27120 tcctcagcga tgattcgcac cgcccgcagc ataaggcgcc ttgtcctccg ggcacagcag 27180 cgcaccctga tctcacttaa atcagcacag taactgcagc acagcaccac aatattgttc 27240 aaaatcccac agtgcaaggc gctgtatcca aagctcatgg cggggaccac agaacccacg 27300 tggccatcat accacaagcg caggtagatt aagtggcgac ccctcataaa cacgctggac 27360 ataaacatta cctcttttgg catgttgtaa ttcaccacct cccggtacca tataaacctc 27420 tgattaaaca tggcgccatc caccaccatc ctaaaccagc tggccaaaac ctgcccgccg 27480 gctatacact gcagggaacc gggactggaa caatgacagt ggagagccca ggactcgtaa 27540 ccatggatca tcatgctcgt catgatatca atgttggcac aacacaggca cacgtgcata 27600 cacttcctca ggattacaag ctcctcccgc gttagaacca tatcccaggg aacaacccat 27660 tcctgaatca gcgtaaatcc cacactgcag ggaagacctc gcacgtaact cacgttgtgc 27720 attgtcaaag tgttacattc gggcagcagc ggatgatcct ccagtatggt agcgcgggtt 27780 tctgtctcaa aaggaggtag acgatcccta ctgtacggag tgcgccgaga caaccgagat 27840 cgtgttggtc gtagtgtcat gccaaatgga acgccggacg tagtcatatt tcctgaagca 27900 aaaccaggtg cgggcgtgac aaacagatct gcgtctccgg tctcgccgct tagatcgctc 27960 tgtgtagtag ttgtagtata tccactctct caaagcatcc aggcgccccc tggcttcggg 28020 ttctatgtaa actccttcat gcgccgctgc cctgataaca tccaccaccg cagaataagc 28080 cacacccagc caacctacac attcgttctg cgagtcacac acgggaggag cgggaagagc 28140 tggaagaacc atgttttttt ttttattcca aaagattatc caaaacctca aaatgaagat 28200 ctattaagtg aacgcgctcc cctccggtgg cgtggtcaaa ctctacagcc aaagaacaga 28260 taatggcatt tgtaagatgt tgcacaatgg cttccaaaag gcaaacggcc ctcacgtcca 28320 agtggacgta aaggctaaac ccttcagggt gaatctcctc tataaacatt ccagcacctt 28380 caaccatgcc caaataattc tcatctcgcc accttctcaa tatatctcta agcaaatccc 28440 gaatattaag tccggccatt gtaaaaatct gctccagagc gccctccacc ttcagcctca 28500 agcagcgaat catgattgca aaaattcagg ttcctcacag acctgtataa gattcaaaag 28560 cggaacatta acaaaaatac cgcgatcccg taggtccctt cgcagggcca gctgaacata 28620 atcgtgcagg tctgcacgga ccagcgcggc cacttccccg ccaggaacct tgacaaaaga 28680 acccacactg attatgacac gcatactcgg agctatgcta accagcgtag ccccgatgta 28740 agctttcaat agcttgttgc atgggcggcg atataaaatg caaggtgctg ctcaaaaaat 28800 caggcaaagc ctcgcgcaaa aaagaaagca catcgtagtc atgctcatgc agataaaggc 28860 aggtaagctc cggaaccacc acagaaaaag acaccatttt tctctcaaac atgtctgcgg 28920 gtttctgcat aaacacaaaa taaaataaca aaaaaacatt taaacattag aagcctgtct 28980 tacaacagga aaaacaaccc ttataagcat aagacggact acggccatgc cggcgtgacc 29040 gtaaaaaaac tggtcaccgt gattaaaaag caccaccgac agctcctcgg tcatgtccgg 29100 agtcataatg taagactcgg taaacacatc aggttgattc atcggtcagt gctaaaaagc 29160 gaccgaaata gcccggggga atacataccc gcaggcgtag agacaacatt acagccccca 29220 taggaggtat aacaaaatta ataggagaga aaaacacata aacacctgaa aaaccctcct 29280 gcctaggcaa aatagcaccc tcccgctcca gaacaacata cagcgcttca cagcggcagc 29340 ctaacagtca gccttaccag taaaaaagaa aacctattaa aaaaacacca ctcgacacgg 29400 caccagctca atcagtcaca gtgtaaaaaa gggccaagtg cagagcgagt atatatagga 29460 ctaaaaaatg acgtaacggt taaagtccac aaaaaacacc cagaaaaccg cacgcgaacc 29520 tacgcccaga aacgaaagcc aaaaaaccca caacttcctc aaatcgtcac ttccgttttc 29580 ccacgttacg taacttccca ttttaagaaa actacaattc ccaacacata caagttactc 29640 cgccctaaaa cctacgtcac ccgccccgtt cccacgcccc gcgccacgtc acaaactcca 29700 ccccctcatt atcatattgg cttcaatcca aaataaggta tattattgat gatgttaatt 29760 aacatgcatg gatccatatg cggtgtgaaa taccgcacag atgcgtaagg agaaaatacc 29820 gcatcaggcg ctcttccgct tcctcgctca ctgactcgct gcgctcggtc gttcggctgc 29880 ggcgagcggt atcagctcac tcaaaggcgg taatacggtt atccacagaa tcaggggata 29940 acgcaggaaa gaacatgtga gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg 30000 cgttgctggc gtttttccat aggctccgcc cccctgacga gcatcacaaa aatcgacgct 30060 caagtcagag gtggcgaaac ccgacaggac tataaagata ccaggcgttt ccccctggaa 30120 gctccctcgt gcgctctcct gttccgaccc tgccgcttac cggatacctg tccgcctttc 30180 tcccttcggg aagcgtggcg ctttctcata gctcacgctg taggtatctc agttcggtgt 30240 aggtcgttcg ctccaagctg ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg 30300 ccttatccgg taactatcgt cttgagtcca acccggtaag acacgactta tcgccactgg 30360 cagcagccac tggtaacagg attagcagag cgaggtatgt aggcggtgct acagagttct 30420 tgaagtggtg gcctaactac ggctacacta gaaggacagt atttggtatc tgcgctctgc 30480 tgaagccagt taccttcgga aaaagagttg gtagctcttg atccggcaaa caaaccaccg 30540 ctggtagcgg tggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc 30600 aagaagatcc tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt 30660 aagggatttt ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa 30720 aatgaagttt taaatcaatc taaagtatat atgagtaaac ttggtctgac agttaccaat 30780 gcttaatcag tgaggcacct atctcagcga tctgtctatt tcgttcatcc atagttgcct 30840 gactccccgt cgtgtagata actacgatac gggagggctt accatctggc cccagtgctg 30900 caatgatacc gcgagaccca cgctcaccgg ctccagattt atcagcaata aaccagccag 30960 ccggaagggc cgagcgcaga agtggtcctg caactttatc cgcctccatc cagtctatta 31020 attgttgccg ggaagctaga gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg 31080 ccattgctgc agccatgaga ttatcaaaaa ggatcttcac ctagatcctt ttcacgtaga 31140 aagccagtcc gcagaaacgg tgctgacccc ggatgaatgt cagctactgg gctatctgga 31200 caagggaaaa cgcaagcgca aagagaaagc aggtagcttg cagtgggctt acatggcgat 31260 agctagactg ggcggtttta tggacagcaa gcgaaccgga attgccagct ggggcgccct 31320 ctggtaaggt tgggaagccc tgcaaagtaa actggatggc tttctcgccg ccaaggatct 31380 gatggcgcag gggatcaagc tctgatcaag agacaggatg aggatcgttt cgcatgattg 31440 aacaagatgg attgcacgca ggttctccgg ccgcttgggt ggagaggcta ttcggctatg 31500 actgggcaca acagacaatc ggctgctctg atgccgccgt gttccggctg tcagcgcagg 31560 ggcgcccggt tctttttgtc aagaccgacc tgtccggtgc cctgaatgaa ctgcaagacg 31620 aggcagcgcg gctatcgtgg ctggccacga cgggcgttcc ttgcgcagct gtgctcgacg 31680 ttgtcactga agcgggaagg gactggctgc tattgggcga agtgccgggg caggatctcc 31740 tgtcatctca ccttgctcct gccgagaaag tatccatcat ggctgatgca atgcggcggc 31800 tgcatacgct tgatccggct acctgcccat tcgaccacca agcgaaacat cgcatcgagc 31860 gagcacgtac tcggatggaa gccggtcttg tcgatcagga tgatctggac gaagagcatc 31920 aggggctcgc gccagccgaa ctgttcgcca ggctcaaggc gagcatgccc gacggcgagg 31980 atctcgtcgt gacccatggc gatgcctgct tgccgaatat catggtggaa aatggccgct 32040 tttctggatt catcgactgt ggccggctgg gtgtggcgga ccgctatcag gacatagcgt 32100 tggctacccg tgatattgct gaagagcttg gcggcgaatg ggctgaccgc ttcctcgtgc 32160 tttacggtat cgccgctccc gattcgcagc gcatcgcctt ctatcgcctt cttgacgagt 32220 tcttctgaat tttgttaaaa tttttgttaa atcagctcat tttttaacca ataggccgaa 32280 atcggcaaca tcccttataa atcaaaagaa tagaccgcga tagggttgag tgttgttcca 32340 gtttggaaca agagtccact attaaagaac gtggactcca acgtcaaagg gcgaaaaacc 32400 gtctatcagg gcgatggccc actacgtgaa ccatcaccca aatcaagttt tttgcggtcg 32460 aggtgccgta aagctctaaa tcggaaccct aaagggagcc cccgatttag agcttgacgg 32520 ggaaagccgg cgaacgtggc gagaaaggaa gggaagaaag cgaaaggagc gggcgctagg 32580 gcgctggcaa gtgtagcggt cacgctgcgc gtaaccacca cacccgcgcg cttaatgcgc 32640 cgctacaggg cgcgtccatt cgccattcag gatcgaatta attcttaatt aacatcatca 32700 ataatatacc ttattttgga ttgaagccaa tatgataatg agggggtgga gtttgtgacg 32760 tggcgcgggg cgtgggaacg gggcgggtga cgtagtagtg tggcggaagt gtgatgttgc 32820 aagtgtggcg gaacacatgt aagcgacgga tgtggcaaaa gtgacgtttt tggtgtgcgc 32880 cggtgtacac aggaagtgac aattttcgcg cggttttagg cggatgttgt agtaaatttg 32940 ggcgtaaccg agtaagattt ggccattttc gcgggaaaac tgaataagag gaagtgaaat 33000 ctgaataatt ttgtgttact catagcgcgt aatactgcga tctatacatt gaatcaatat 33060 tggcaattag ccatattagt cattggttat atagcataaa tcaatattgg ctattggcca 33120 ttgcatacgt tgtatctata tcataatatg tacatttata ttggctcatg tccaatatga 33180 ccgccatgtt gacattgatt attgactagt agttcatagc ccatatatgg agttccgcgt 33240 tacataactt acggtaaatg gcccgcctgg ctgaccgccc aacgaccccc gcccattgac 33300 gtcaataatg acgtatgttc ccatagtaac gccaataggg actttccatt gacgtcaatg 33360 ggtggagtat ttacggtaaa ctgcccactt ggcagtacat caagtgtatc atatgccaag 33420 tccgccccct attgacgtca atgacggtaa atggcccgcc tggcattatg cccagtacat 33480 gaccttacgg gactttccta cttggcagta catctacgta ttagtcatcg ctattaccat 33540 ggtgatgcgg ttttggcagt acaccaatgg gcgtggatag cggtttgact cacggggatt 33600 tccaagtctc caccccattg acgtcaatgg gagtttgttt tggcaccaaa atcaacggga 33660 ctttccaaaa tgtcgtaata accccgcccc gttgacgcaa atgggcggta ggcgtgtacg 33720 gtgggaggtc tatataagca gagctcgttt agtgaaccgt cagatcctca ctctcttccg 33780 catcgctgtc tgcgagggcc agctgttggg ctcgcggttg aggacaaact cttcgcggtc 33840 tttccagtac tcttggatcg gaaacccgtc ggcctccgaa cggtactccg ccaccgaggg 33900 acctgagcca gtccgcatcg accggatcgg aaaacctctc gagaaaggcg tctaaccagt 33960 cacagtcgca aggtaggctg agcaccgtgg cgggcggcag cgggtggcgg tcggggttgt 34020 ttctggcgga ggtgctgctg atgatgtaat taaagtaggc ggtcttgagc cggcggatgg 34080 tcgaggtgag gtgtggcagg cttgagatcc agctgttggg gtgagtactc cctctcaaaa 34140 gcgggcatga cttctgcgct aagattgtca gtttccaaaa acgaggagga tttgatattc 34200 acctggcccg atctggccat acacttgagt gacaatgaca tccactttgc ctttctctcc 34260 acaggtgtcc actcccaggt ccaagtttgg aagatccaag gccagcacgt tcttcgcgcc 34320 gcgctcgcac agcctctgca gcactcgggc caccagctcc ttcaggcagg acacctggcg 34380 gaaggagggg gcggcggggg gcggccgtgc gtcccagggc acgcacacca ggcactgggc 34440 caccagcgcg cggaaagccg ccgggtcccc gcgctgcacc agccgccagc cctggggccc 34500 caggcgccgc acgaacgtgg ccagcggcag cacctcgcgg tagtggctgc gcagcaggga 34560 gcgcacggct aggcagcggg gagcgcgcgg catcgcgggg gtggccgggg ccagggcttc 34620 ccaagcttcg ttttgcggca ggaaaagtta tcaggcatgc acctggtagc tagtctttaa 34680 accaatagat tgcatcggtt taaaaggcaa gaccgtcaaa ttgcgggaaa ggggtcaaca 34740 gccgttcagt accaagtctc aggggaaact ttgagatggc cttgcaaagg gtatggtaat 34800 aagctgacgg acatggtcct aaccacgcag ccaagtccta agtcaacaga tcttctgttg 34860 atatggatgc agttcacaga ctaaatgtcg gtcggggaag atgtattctt ctcataagat 34920 atagtcggac ctctccttaa tgggagctag cggatgaagt gatgcaacac tggagccgct 34980 gggaactaat ttgtatgcga aagtatattg attagttttg gagtactcga aaacgcccac 35040 catggcttcg tacccctgcc atcaacacgc gtctgcgttc gaccaggctg cgcgttctcg 35100 cggccatagc aaccgacgta cggcgttgcg ccctcgccgg cagcaagaag ccacggaagt 35160 ccgcctggag cagaaaatgc ccacgctact gcgggtttat atagacggtc ctcacgggat 35220 ggggaaaacc accaccacgc aactgctggt ggccctgggt tcgcgcgacg atatcgtcta 35280 cgtacccgag ccgatgactt actggcaggt gctgggggct tccgagacaa tcgcgaacat 35340 ctacaccaca caacaccgcc tcgaccaggg tgagatatcg gccggggacg cggcggtggt 35400 aatgacaagc gcccagataa caatgggcat gccttatgcc gtgaccgacg ccgttctggc 35460 tcctcatgtc gggggggagg ctgggagttc acatgccccg cccccggccc tcaccctcat 35520 cttcgaccgc catcccatcg ccgccctcct gtgctacccg gccgcgcgat accttatggg 35580 cagcatgacc ccccaggccg tgctggcgtt cgtggccctc atcccgccga ccttgcccgg 35640 cacaaacatc gtgttggggg cccttccgga ggacagacac atcgaccgcc tggccaaacg 35700 ccagcgcccc ggcgagcggc ttgacctggc tatgctggcc gcgattcgcc gcgtttacgg 35760 gctgcttgcc aatacggtgc ggtatctgca gggcggcggg tcgtggtggg aggattgggg 35820 acagctttcg gggacggccg tgccgcccca gggtgccgag ccccagagca acgcgggccc 35880 acgaccccat atcggggaca cgttatttac cctgtttcgg gcccccgagt tgctggcccc 35940 caacggcgac ctgtataacg tgtttgcctg ggccttggac gtcttggcca aacgcctccg 36000 tcccatgcac gtctttatcc tggattacga ccaatcgccc gccggctgcc gggacgccct 36060 gctgcaactt acctccggga tggtccagac ccacgtcacc accccaggct ccataccgac 36120 gatctgcgac ctggcgcgca cgtttgcccg ggagatgggg gaggctaact gaggccggcc 36180 aatcaacctc tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct 36240 ccttttacgc tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt 36300 atggctttca ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg 36360 tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact 36420 ggttggggca ttgccaccac ctgtcagctc ctttccggga ctttcgcttt ccccctccct 36480 attgccacgg cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg 36540 ttgggcactg acaattccgt ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc 36600 gcctgtgttg ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc 36660 aatccagcgg accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt 36720 cgccttcgcc ctcagacgag tcggatctcc ctttgggccg cctccccgcg gccggccgct 36780 tcgaaggcga aagatcccaa cgaaaagaga gaccacatgg tccttcttga gtttgtaaca 36840 gctgctggga ttacacatgg catggatgaa ctgtacaact gaggatcccc cgacctcgac 36900 ctctggctaa taaaggaaat ttattttcat tgcaatagtg tgttggaatt ttttgtgtct 36960 ctcactcgga aggacatatg ggagggcaaa tcatttggtc gagatccctc ggagatcgga 37020 tctgggcgtg g 37031 <210> 44 <211> 37238 <212> DNA <213> Artificial Sequence <220> <223> Ad-SD/SA CMV Ribozyme HSV-TK WPRE(forward) <400> 44 ttaagggtgg gaaagaatat ataaggtggg ggtcttatgt agttttgtat ctgttttgca 60 gcagccgccg ccgccatgag caccaactcg tttgatggaa gcattgtgag ctcatatttg 120 acaacgcgca tgcccccatg ggccggggtg cgtcagaatg tgatgggctc cagcattgat 180 ggtcgccccg tcctgcccgc aaactctact accttgacct acgagaccgt gtctggaacg 240 ccgttggaga ctgcagcctc cgccgccgct tcagccgctg cagccaccgc ccgcgggatt 300 gtgactgact ttgctttcct gagcccgctt gcaagcagtg cagcttcccg ttcatccgcc 360 cgcgatgaca agttgacggc tcttttggca caattggatt ctttgacccg ggaacttaat 420 gtcgtttctc agcagctgtt ggatctgcgc cagcaggttt ctgccctgaa ggcttcctcc 480 cctcccaatg cggtttaaaa cataaataaa aaaccagact ctgtttggat ttggatcaag 540 caagtgtctt gctgtcttta tttaggggtt ttgcgcgcgc ggtaggcccg ggaccagcgg 600 tctcggtcgt tgagggtcct gtgtattttt tccaggacgt ggtaaaggtg actctggatg 660 ttcagataca tgggcataag cccgtctctg gggtggaggt agcaccactg cagagcttca 720 tgctgcgggg tggtgttgta gatgatccag tcgtagcagg agcgctgggc gtggtgccta 780 aaaatgtctt tcagtagcaa gctgattgcc aggggcaggc ccttggtgta agtgtttaca 840 aagcggttaa gctgggatgg gtgcatacgt ggggatatga gatgcatctt ggactgtatt 900 tttaggttgg ctatgttccc agccatatcc ctccggggat tcatgttgtg cagaaccacc 960 agcacagtgt atccggtgca cttgggaaat ttgtcatgta gcttagaagg aaatgcgtgg 1020 aagaacttgg agacgccctt gtgacctcca agattttcca tgcattcgtc cataatgatg 1080 gcaatgggcc cacgggcggc ggcctgggcg aagatatttc tgggatcact aacgtcatag 1140 ttgtgttcca ggatgagatc gtcataggcc atttttacaa agcgcgggcg gagggtgcca 1200 gactgcggta taatggttcc atccggccca ggggcgtagt taccctcaca gatttgcatt 1260 tcccacgctt tgagttcaga tggggggatc atgtctacct gcggggcgat gaagaaaacg 1320 gtttccgggg taggggagat cagctgggaa gaaagcaggt tcctgagcag ctgcgactta 1380 ccgcagccgg tgggcccgta aatcacacct attaccgggt gcaactggta gttaagagag 1440 ctgcagctgc cgtcatccct gagcaggggg gccacttcgt taagcatgtc cctgactcgc 1500 atgttttccc tgaccaaatc cgccagaagg cgctcgccgc ccagcgatag cagttcttgc 1560 aaggaagcaa agtttttcaa cggtttgaga ccgtccgccg taggcatgct tttgagcgtt 1620 tgaccaagca gttccaggcg gtcccacagc tcggtcacct gctctacggc atctcgatcc 1680 agcatatctc ctcgtttcgc gggttggggc ggctttcgct gtacggcagt agtcggtgct 1740 cgtccagacg ggccagggtc atgtctttcc acgggcgcag ggtcctcgtc agcgtagtct 1800 gggtcacggt gaaggggtgc gctccgggct gcgcgctggc cagggtgcgc ttgaggctgg 1860 tcctgctggt gctgaagcgc tgccggtctt cgccctgcgc gtcggccagg tagcatttga 1920 ccatggtgtc atagtccagc ccctccgcgg cgtggccctt ggcgcgcagc ttgcccttgg 1980 aggaggcgcc gcacgagggg cagtgcagac ttttgagggc gtagagcttg ggcgcgagaa 2040 ataccgattc cggggagtag gcatccgcgc cgcaggcccc gcagacggtc tcgcattcca 2100 cgagccaggt gagctctggc cgttcggggt caaaaaccag gtttccccca tgctttttga 2160 tgcgtttctt acctctggtt tccatgagcc ggtgtccacg ctcggtgacg aaaaggctgt 2220 ccgtgtcccc gtatacagac ttgagaggcc tgtcctcgag cggtgttccg cggtcctcct 2280 cgtatagaaa ctcggaccac tctgagacaa aggctcgcgt ccaggccagc acgaaggagg 2340 ctaagtggga ggggtagcgg tcgttgtcca ctagggggtc cactcgctcc agggtgtgaa 2400 gacacatgtc gccctcttcg gcatcaagga aggtgattgg tttgtaggtg taggccacgt 2460 gaccgggtgt tcctgaaggg gggctataaa agggggtggg ggcgcgttcg tcctcactct 2520 cttccgcatc gctgtctgcg agggccagct gttggggtga gtactccctc tgaaaagcgg 2580 gcatgacttc tgcgctaaga ttgtcagttt ccaaaaacga ggaggatttg atattcacct 2640 ggcccgcggt gatgcctttg agggtggccg catccatctg gtcagaaaag acaatctttt 2700 tgttgtcaag cttggtggca aacgacccgt agagggcgtt ggacagcaac ttggcgatgg 2760 agcgcagggt ttggtttttg tcgcgatcgg cgcgctcctt ggccgcgatg tttagctgca 2820 cgtattcgcg cgcaacgcac cgccattcgg gaaagacggt ggtgcgctcg tcgggcacca 2880 ggtgcacgcg ccaaccgcgg ttgtgcaggg tgacaaggtc aacgctggtg gctacctctc 2940 cgcgtaggcg ctcgttggtc cagcagaggc ggccgccctt gcgcgagcag aatggcggta 3000 gggggtctag ctgcgtctcg tccggggggt ctgcgtccac ggtaaagacc ccgggcagca 3060 ggcgcgcgtc gaagtagtct atcttgcatc cttgcaagtc tagcgcctgc tgccatgcgc 3120 gggcggcaag cgcgcgctcg tatgggttga gtgggggacc ccatggcatg gggtgggtga 3180 gcgcggaggc gtacatgccg caaatgtcgt aaacgtagag gggctctctg agtattccaa 3240 gatatgtagg gtagcatctt ccaccgcgga tgctggcgcg cacgtaatcg tatagttcgt 3300 gcgagggagc gaggaggtcg ggaccgaggt tgctacgggc gggctgctct gctcggaaga 3360 ctatctgcct gaagatggca tgtgagttgg atgatatggt tggacgctgg aagacgttga 3420 agctggcgtc tgtgagacct accgcgtcac gcacgaagga ggcgtaggag tcgcgcagct 3480 tgttgaccag ctcggcggtg acctgcacgt ctagggcgca gtagtccagg gtttccttga 3540 tgatgtcata cttatcctgt cccttttttt tccacagctc gcggttgagg acaaactctt 3600 cgcggtcttt ccagtactct tggatcggaa acccgtcggc ctccgaacgg taagagccta 3660 gcatgtagaa ctggttgacg gcctggtagg cgcagcatcc cttttctacg ggtagcgcgt 3720 atgcctgcgc ggccttccgg agcgaggtgt gggtgagcgc aaaggtgtcc ctgaccatga 3780 ctttgaggta ctggtatttg aagtcagtgt cgtcgcatcc gccctgctcc cagagcaaaa 3840 agtccgtgcg ctttttggaa cgcggatttg gcagggcgaa ggtgacatcg ttgaagagta 3900 tctttcccgc gcgaggcata aagttgcgtg tgatgcggaa gggtcccggc acctcggaac 3960 ggttgttaat tacctgggcg gcgagcacga tctcgtcaaa gccgttgatg ttgtggccca 4020 caatgtaaag ttccaagaag cgcgggatgc ccttgatgga aggcaatttt ttaagttcct 4080 cgtaggtgag ctcttcaggg gagctgagcc cgtgctctga aagggcccag tctgcaagat 4140 gagggttgga agcgacgaat gagctccaca ggtcacgggc cattagcatt tgcaggtggt 4200 cgcgaaaggt cctaaactgg cgacctatgg ccattttttc tggggtgatg cagtagaagg 4260 taagcgggtc ttgttcccag cggtcccatc caaggttcgc ggctaggtct cgcgcggcag 4320 tcactagagg ctcatctccg ccgaacttca tgaccagcat gaagggcacg agctgcttcc 4380 caaaggcccc catccaagta taggtctcta catcgtaggt gacaaagaga cgctcggtgc 4440 gaggatgcga gccgatcggg aagaactgga tctcccgcca ccaattggag gagtggctat 4500 tgatgtggtg aaagtagaag tccctgcgac gggccgaaca ctcgtgctgg cttttgtaaa 4560 aacgtgcgca gtactggcag cggtgcacgg gctgtacatc ctgcacgagg ttgacctgac 4620 gaccgcgcac aaggaagcag agtgggaatt tgagcccctc gcctggcggg tttggctggt 4680 ggtcttctac ttcggctgct tgtccttgac cgtctggctg ctcgagggga gttacggtgg 4740 atcggaccac cacgccgcgc gagcccaaag tccagatgtc cgcgcgcggc ggtcggagct 4800 tgatgacaac atcgcgcaga tgggagctgt ccatggtctg gagctcccgc ggcgtcaggt 4860 caggcgggag ctcctgcagg tttacctcgc atagacgggt cagggcgcgg gctagatcca 4920 ggtgatacct aatttccagg ggctggttgg tggcggcgtc gatggcttgc aagaggccgc 4980 atccccgcgg cgcgactacg gtaccgcgcg gcgggcggtg ggccgcgggg gtgtccttgg 5040 atgatgcatc taaaagcggt gacgcgggcg agcccccgga ggtagggggg gctccggacc 5100 cgccgggaga gggggcaggg gcacgtcggc gccgcgcgcg ggcaggagct ggtgctgcgc 5160 gcgtaggttg ctggcgaacg cgacgacgcg gcggttgatc tcctgaatct ggcgcctctg 5220 cgtgaagacg acgggcccgg tgagcttgag cctgaaagag agttcgacag aatcaatttc 5280 ggtgtcgttg acggcggcct ggcgcaaaat ctcctgcacg tctcctgagt tgtcttgata 5340 ggcgatctcg gccatgaact gctcgatctc ttcctcctgg agatctccgc gtccggctcg 5400 ctccacggtg gcggcgaggt cgttggaaat gcgggccatg agctgcgaga aggcgttgag 5460 gcctccctcg ttccagacgc ggctgtagac cacgccccct tcggcatcgc gggcgcgcat 5520 gaccacctgc gcgagattga gctccacgtg ccgggcgaag acggcgtagt ttcgcaggcg 5580 ctgaaagagg tagttgaggg tggtggcggt gtgttctgcc acgaagaagt acataaccca 5640 gcgtcgcaac gtggattcgt tgatatcccc caaggcctca aggcgctcca tggcctcgta 5700 gaagtccacg gcgaagttga aaaactggga gttgcgcgcc gacacggtta actcctcctc 5760 cagaagacgg atgagctcgg cgacagtgtc gcgcacctcg cgctcaaagg ctacaggggc 5820 ctcttcttct tcttcaatct cctcttccat aagggcctcc ccttcttctt cttctggcgg 5880 cggtggggga ggggggacac ggcggcgacg acggcgcacc gggaggcggt cgacaaagcg 5940 ctcgatcatc tccccgcggc gacggcgcat ggtctcggtg acggcgcggc cgttctcgcg 6000 ggggcgcagt tggaagacgc cgcccgtcat gtcccggtta tgggttggcg gggggctgcc 6060 atgcggcagg gatacggcgc taacgatgca tctcaacaat tgttgtgtag gtactccgcc 6120 gccgagggac ctgagcgagt ccgcatcgac cggatcggaa aacctctcga gaaaggcgtc 6180 taaccagtca cagtcgcaag gtaggctgag caccgtggcg ggcggcagcg ggcggcggtc 6240 ggggttgttt ctggcggagg tgctgctgat gatgtaatta aagtaggcgg tcttgagacg 6300 gcggatggtc gacagaagca ccatgtcctt gggtccggcc tgctgaatgc gcaggcggtc 6360 ggccatgccc caggcttcgt tttgacatcg gcgcaggtct ttgtagtagt cttgcatgag 6420 cctttctacc ggcacttctt cttctccttc ctcttgtcct gcatctcttg catctatcgc 6480 tgcggcggcg gcggagtttg gccgtaggtg gcgccctctt cctcccatgc gtgtgacccc 6540 gaagcccctc atcggctgaa gcagggctag gtcggcgaca acgcgctcgg ctaatatggc 6600 ctgctgcacc tgcgtgaggg tagactggaa gtcatccatg tccacaaagc ggtggtatgc 6660 gcccgtgttg atggtgtaag tgcagttggc cataacggac cagttaacgg tctggtgacc 6720 cggctgcgag agctcggtgt acctgagacg cgagtaagcc ctcgagtcaa atacgtagtc 6780 gttgcaagtc cgcaccaggt actggtatcc caccaaaaag tgcggcggcg gctggcggta 6840 gaggggccag cgtagggtgg ccggggctcc gggggcgaga tcttccaaca taaggcgatg 6900 atatccgtag atgtacctgg acatccaggt gatgccggcg gcggtggtgg aggcgcgcgg 6960 aaagtcgcgg acgcggttcc agatgttgcg cagcggcaaa aagtgctcca tggtcgggac 7020 gctctggccg gtcaggcgcg cgcaatcgtt gacgctctac cgtgcaaaag gagagcctgt 7080 aagcgggcac tcttccgtgg tctggtggat aaattcgcaa gggtatcatg gcggacgacc 7140 ggggttcgag ccccgtatcc ggccgtccgc cgtgatccat gcggttaccg cccgcgtgtc 7200 gaacccaggt gtgcgacgtc agacaacggg ggagtgctcc ttttggcttc cttccaggcg 7260 cggcggctgc tgcgctagct tttttggcca ctggccgcgc gcagcgtaag cggttaggct 7320 ggaaagcgaa agcattaagt ggctcgctcc ctgtagccgg agggttattt tccaagggtt 7380 gagtcgcggg acccccggtt cgagtctcgg accggccgga ctgcggcgaa cgggggtttg 7440 cctccccgtc atgcaagacc ccgcttgcaa attcctccgg aaacagggac gagccccttt 7500 tttgcttttc ccagatgcat ccggtgctgc ggcagatgcg cccccctcct cagcagcggc 7560 aagagcaaga gcagcggcag acatgcaggg caccctcccc tcctcctacc gcgtcaggag 7620 gggcgacatc cgcggttgac gcggcagcag atggtgatta cgaacccccg cggcgccggg 7680 cccggcacta cctggacttg gaggagggcg agggcctggc gcggctagga gcgccctctc 7740 ctgagcggta cccaagggtg cagctgaagc gtgatacgcg tgaggcgtac gtgccgcggc 7800 agaacctgtt tcgcgaccgc gagggagagg agcccgagga gatgcgggat cgaaagttcc 7860 acgcagggcg cgagctgcgg catggcctga atcgcgagcg gttgctgcgc gaggaggact 7920 ttgagcccga cgcgcgaacc gggattagtc ccgcgcgcgc acacgtggcg gccgccgacc 7980 tggtaaccgc atacgagcag acggtgaacc aggagattaa ctttcaaaaa agctttaaca 8040 accacgtgcg tacgcttgtg gcgcgcgagg aggtggctat aggactgatg catctgtggg 8100 actttgtaag cgcgctggag caaaacccaa atagcaagcc gctcatggcg cagctgttcc 8160 ttatagtgca gcacagcagg gacaacgagg cattcaggga tgcgctgcta aacatagtag 8220 agcccgaggg ccgctggctg ctcgatttga taaacatcct gcagagcata gtggtgcagg 8280 agcgcagctt gagcctggct gacaaggtgg ccgccatcaa ctattccatg cttagcctgg 8340 gcaagtttta cgcccgcaag atataccata ccccttacgt tcccatagac aaggaggtaa 8400 agatcgaggg gttctacatg cgcatggcgc tgaaggtgct taccttgagc gacgacctgg 8460 gcgtttatcg caacgagcgc atccacaagg ccgtgagcgt gagccggcgg cgcgagctca 8520 gcgaccgcga gctgatgcac agcctgcaaa gggccctggc tggcacgggc agcggcgata 8580 gagaggccga gtcctacttt gacgcgggcg ctgacctgcg ctgggcccca agccgacgcg 8640 ccctggaggc agctggggcc ggacctgggc tggcggtggc acccgcgcgc gctggcaacg 8700 tcggcggcgt ggaggaatat gacgaggacg atgagtacga gccagaggac ggcgagtact 8760 aagcggtgat gtttctgatc agatgatgca agacgcaacg gacccggcgg tgcgggcggc 8820 gctgcagagc cagccgtccg gccttaactc cacggacgac tggcgccagg tcatggaccg 8880 catcatgtcg ctgactgcgc gcaatcctga cgcgttccgg cagcagccgc aggccaaccg 8940 gctctccgca attctggaag cggtggtccc ggcgcgcgca aaccccacgc acgagaaggt 9000 gctggcgatc gtaaacgcgc tggccgaaaa cagggccatc cggcccgacg aggccggcct 9060 ggtctacgac gcgctgcttc agcgcgtggc tcgttacaac agcggcaacg tgcagaccaa 9120 cctggaccgg ctggtggggg atgtgcgcga ggccgtggcg cagcgtgagc gcgcgcagca 9180 gcagggcaac ctgggctcca tggttgcact aaacgccttc ctgagtacac agcccgccaa 9240 cgtgccgcgg ggacaggagg actacaccaa ctttgtgagc gcactgcggc taatggtgac 9300 tgagacaccg caaagtgagg tgtaccagtc tgggccagac tattttttcc agaccagtag 9360 acaaggcctg cagaccgtaa acctgagcca ggctttcaaa aacttgcagg ggctgtgggg 9420 ggtgcgggct cccacaggcg accgcgcgac cgtgtctagc ttgctgacgc ccaactcgcg 9480 cctgttgctg ctgctaatag cgcccttcac ggacagtggc agcgtgtccc gggacacata 9540 cctaggtcac ttgctgacac tgtaccgcga ggccataggt caggcgcatg tggacgagca 9600 tactttccag gagattacaa gtgtcagccg cgcgctgggg caggaggaca cgggcagcct 9660 ggaggcaacc ctaaactacc tgctgaccaa ccggcggcag aagatcccct cgttgcacag 9720 tttaaacagc gaggaggagc gcattttgcg ctacgtgcag cagagcgtga gccttaacct 9780 gatgcgcgac ggggtaacgc ccagcgtggc gctggacatg accgcgcgca acatggaacc 9840 gggcatgtat gcctcaaacc ggccgtttat caaccgccta atggactact tgcatcgcgc 9900 ggccgccgtg aaccccgagt atttcaccaa tgccatcttg aacccgcact ggctaccgcc 9960 ccctggtttc tacaccgggg gattcgaggt gcccgagggt aacgatggat tcctctggga 10020 cgacatagac gacagcgtgt tttccccgca accgcagacc ctgctagagt tgcaacagcg 10080 cgagcaggca gaggcggcgc tgcgaaagga aagcttccgc aggccaagca gcttgtccga 10140 tctaggcgct gcggccccgc ggtcagatgc tagtagccca tttccaagct tgatagggtc 10200 tcttaccagc actcgcacca cccgcccgcg cctgctgggc gaggaggagt acctaaacaa 10260 ctcgctgctg cagccgcagc gcgaaaaaaa cctgcctccg gcatttccca acaacgggat 10320 agagagccta gtggacaaga tgagtagatg gaagacgtac gcgcaggagc acagggacgt 10380 gccaggcccg cgcccgccca cccgtcgtca aaggcacgac cgtcagcggg gtctggtgtg 10440 ggaggacgat gactcggcag acgacagcag cgtcctggat ttgggaggga gtggcaaccc 10500 gtttgcgcac cttcgcccca ggctggggag aatgttttaa aaaaaaaaaa gcatgatgca 10560 aaataaaaaa ctcaccaagg ccatggcacc gagcgttggt tttcttgtat tccccttagt 10620 atgcggcgcg cggcgatgta tgaggaaggt cctcctccct cctacgagag tgtggtgagc 10680 gcggcgccag tggcggcggc gctgggttct cccttcgatg ctcccctgga cccgccgttt 10740 gtgcctccgc ggtacctgcg gcctaccggg gggagaaaca gcatccgtta ctctgagttg 10800 gcacccctat tcgacaccac ccgtgtgtac ctggtggaca acaagtcaac ggatgtggca 10860 tccctgaact accagaacga ccacagcaac tttctgacca cggtcattca aaacaatgac 10920 tacagcccgg gggaggcaag cacacagacc atcaatcttg acgaccggtc gcactggggc 10980 ggcgacctga aaaccatcct gcataccaac atgccaaatg tgaacgagtt catgtttacc 11040 aataagttta aggcgcgggt gatggtgtcg cgcttgccta ctaaggacaa tcaggtggag 11100 ctgaaatacg agtgggtgga gttcacgctg cccgagggca actactccga gaccatgacc 11160 atagacctta tgaacaacgc gatcgtggag cactacttga aagtgggcag acagaacggg 11220 gttctggaaa gcgacatcgg ggtaaagttt gacacccgca acttcagact ggggtttgac 11280 cccgtcactg gtcttgtcat gcctggggta tatacaaacg aagccttcca tccagacatc 11340 attttgctgc caggatgcgg ggtggacttc acccacagcc gcctgagcaa cttgttgggc 11400 atccgcaagc ggcaaccctt ccaggagggc tttaggatca cctacgatga tctggagggt 11460 ggtaacattc ccgcactgtt ggatgtggac gcctaccagg cgagcttgaa agatgacacc 11520 gaacagggcg ggggtggcgc aggcggcagc aacagcagtg gcagcggcgc ggaagagaac 11580 tccaacgcgg cagccgcggc aatgcagccg gtggaggaca tgaacgatca tgccattcgc 11640 ggcgacacct ttgccacacg ggctgaggag aagcgcgctg aggccgaagc agcggccgaa 11700 gctgccgccc ccgctgcgca acccgaggtc gagaagcctc agaagaaacc ggtgatcaaa 11760 cccctgacag aggacagcaa gaaacgcagt tacaacctaa taagcaatga cagcaccttc 11820 acccagtacc gcagctggta ccttgcatac aactacggcg accctcagac cggaatccgc 11880 tcatggaccc tgctttgcac tcctgacgta acctgcggct cggagcaggt ctactggtcg 11940 ttgccagaca tgatgcaaga ccccgtgacc ttccgctcca cgcgccagat cagcaacttt 12000 ccggtggtgg gcgccgagct gttgcccgtg cactccaaga gcttctacaa cgaccaggcc 12060 gtctactccc aactcatccg ccagtttacc tctctgaccc acgtgttcaa tcgctttccc 12120 gagaaccaga ttttggcgcg cccgccagcc cccaccatca ccaccgtcag tgaaaacgtt 12180 cctgctctca cagatcacgg gacgctaccg ctgcgcaaca gcatcggagg agtccagcga 12240 gtgaccatta ctgacgccag acgccgcacc tgcccctacg tttacaaggc cctgggcata 12300 gtctcgccgc gcgtcctatc gagccgcact ttttgagcaa gcatgtccat ccttatatcg 12360 cccagcaata acacaggctg gggcctgcgc ttcccaagca agatgtttgg cggggccaag 12420 aagcgctccg accaacaccc agtgcgcgtg cgcgggcact accgcgcgcc ctggggcgcg 12480 cacaaacgcg gccgcactgg gcgcaccacc gtcgatgacg ccatcgacgc ggtggtggag 12540 gaggcgcgca actacacgcc cacgccgcca ccagtgtcca cagtggacgc ggccattcag 12600 accgtggtgc gcggagcccg gcgctatgct aaaatgaaga gacggcggag gcgcgtagca 12660 cgtcgccacc gccgccgacc cggcactgcc gcccaacgcg cggcggcggc cctgcttaac 12720 cgcgcacgtc gcaccggccg acgggcggcc atgcgggccg ctcgaaggct ggccgcgggt 12780 attgtcactg tgccccccag gtccaggcga cgagcggccg ccgcagcagc cgcggccatt 12840 agtgctatga ctcagggtcg caggggcaac gtgtattggg tgcgcgactc ggttagcggc 12900 ctgcgcgtgc ccgtgcgcac ccgccccccg cgcaactaga ttgcaagaaa aaactactta 12960 gactcgtact gttgtatgta tccagcggcg gcggcgcgca acgaagctat gtccaagcgc 13020 aaaatcaaag aagagatgct ccaggtcatc gcgccggaga tctatggccc cccgaagaag 13080 gaagagcagg attacaagcc ccgaaagcta aagcgggtca aaaagaaaaa gaaagatgat 13140 gatgatgaac ttgacgacga ggtggaactg ctgcacgcta ccgcgcccag gcgacgggta 13200 cagtggaaag gtcgacgcgt aaaacgtgtt ttgcgacccg gcaccaccgt agtctttacg 13260 cccggtgagc gctccacccg cacctacaag cgcgtgtatg atgaggtgta cggcgacgag 13320 gacctgcttg agcaggccaa cgagcgcctc ggggagtttg cctacggaaa gcggcataag 13380 gacatgctgg cgttgccgct ggacgagggc aacccaacac ctagcctaaa gcccgtaaca 13440 ctgcagcagg tgctgcccgc gcttgcaccg tccgaagaaa agcgcggcct aaagcgcgag 13500 tctggtgact tggcacccac cgtgcagctg atggtaccca agcgccagcg actggaagat 13560 gtcttggaaa aaatgaccgt ggaacctggg ctggagcccg aggtccgcgt gcggccaatc 13620 aagcaggtgg cgccgggact gggcgtgcag accgtggacg ttcagatacc cactaccagt 13680 agcaccagta ttgccaccgc cacagagggc atggagacac aaacgtcccc ggttgcctca 13740 gcggtggcgg atgccgcggt gcaggcggtc gctgcggccg cgtccaagac ctctacggag 13800 gtgcaaacgg acccgtggat gtttcgcgtt tcagcccccc ggcgcccgcg cggttcgagg 13860 aagtacggcg ccgccagcgc gctactgccc gaatatgccc tacatccttc cattgcgcct 13920 acccccggct atcgtggcta cacctaccgc cccagaagac gagcaactac ccgacgccga 13980 accaccactg gaacccgccg ccgccgtcgc cgtcgccagc ccgtgctggc cccgatttcc 14040 gtgcgcaggg tggctcgcga aggaggcagg accctggtgc tgccaacagc gcgctaccac 14100 cccagcatcg tttaaaagcc ggtctttgtg gttcttgcag atatggccct cacctgccgc 14160 ctccgtttcc cggtgccggg attccgagga agaatgcacc gtaggagggg catggccggc 14220 cacggcctga cgggcggcat gcgtcgtgcg caccaccggc ggcggcgcgc gtcgcaccgt 14280 cgcatgcgcg gcggtatcct gcccctcctt attccactga tcgccgcggc gattggcgcc 14340 gtgcccggaa ttgcatccgt ggccttgcag gcgcagagac actgattaaa aacaagttgc 14400 atgtggaaaa atcaaaataa aaagtctgga ctctcacgct cgcttggtcc tgtaactatt 14460 ttgtagaatg gaagacatca actttgcgtc tctggccccg cgacacggct cgcgcccgtt 14520 catgggaaac tggcaagata tcggcaccag caatatgagc ggtggcgcct tcagctgggg 14580 ctcgctgtgg agcggcatta aaaatttcgg ttccaccgtt aagaactatg gcagcaaggc 14640 ctggaacagc agcacaggcc agatgctgag ggataagttg aaagagcaaa atttccaaca 14700 aaaggtggta gatggcctgg cctctggcat tagcggggtg gtggacctgg ccaaccaggc 14760 agtgcaaaat aagattaaca gtaagcttga tccccgccct cccgtagagg agcctccacc 14820 ggccgtggag acagtgtctc cagaggggcg tggcgaaaag cgtccgcgcc ccgacaggga 14880 agaaactctg gtgacgcaaa tagacgagcc tccctcgtac gaggaggcac taaagcaagg 14940 cctgcccacc acccgtccca tcgcgcccat ggctaccgga gtgctgggcc agcacacacc 15000 cgtaacgctg gacctgcctc cccccgccga cacccagcag aaacctgtgc tgccaggccc 15060 gaccgccgtt gttgtaaccc gtcctagccg cgcgtccctg cgccgcgccg ccagcggtcc 15120 gcgatcgttg cggcccgtag ccagtggcaa ctggcaaagc acactgaaca gcatcgtggg 15180 tctgggggtg caatccctga agcgccgacg atgcttctga atagctaacg tgtcgtatgt 15240 gtgtcatgta tgcgtccatg tcgccgccag aggagctgct gagccgccgc gcgcccgctt 15300 tccaagatgg ctaccccttc gatgatgccg cagtggtctt acatgcacat ctcgggccag 15360 gacgcctcgg agtacctgag ccccgggctg gtgcagtttg cccgcgccac cgagacgtac 15420 ttcagcctga ataacaagtt tagaaacccc acggtggcgc ctacgcacga cgtgaccaca 15480 gaccggtccc agcgtttgac gctgcggttc atccctgtgg accgtgagga tactgcgtac 15540 tcgtacaagg cgcggttcac cctagctgtg ggtgataacc gtgtgctgga catggcttcc 15600 acgtactttg acatccgcgg cgtgctggac aggggcccta cttttaagcc ctactctggc 15660 actgcctaca acgccctggc tcccaagggt gccccaaatc cttgcgaatg ggatgaagct 15720 gctactgctc ttgaaataaa cctagaagaa gaggacgatg acaacgaaga cgaagtagac 15780 gagcaagctg agcagcaaaa aactcacgta tttgggcagg cgccttattc tggtataaat 15840 attacaaagg agggtattca aataggtgtc gaaggtcaaa cacctaaata tgccgataaa 15900 acatttcaac ctgaacctca aataggagaa tctcagtggt acgaaactga aattaatcat 15960 gcagctggga gagtccttaa aaagactacc ccaatgaaac catgttacgg ttcatatgca 16020 aaacccacaa atgaaaatgg agggcaaggc attcttgtaa agcaacaaaa tggaaagcta 16080 gaaagtcaag tggaaatgca atttttctca actactgagg cgaccgcagg caatggtgat 16140 aacttgactc ctaaagtggt attgtacagt gaagatgtag atatagaaac cccagacact 16200 catatttctt acatgcccac tattaaggaa ggtaactcac gagaactaat gggccaacaa 16260 tctatgccca acaggcctaa ttacattgct tttagggaca attttattgg tctaatgtat 16320 tacaacagca cgggtaatat gggtgttctg gcgggccaag catcgcagtt gaatgctgtt 16380 gtagatttgc aagacagaaa cacagagctt tcataccagc ttttgcttga ttccattggt 16440 gatagaacca ggtacttttc tatgtggaat caggctgttg acagctatga tccagatgtt 16500 agaattattg aaaatcatgg aactgaagat gaacttccaa attactgctt tccactggga 16560 ggtgtgatta atacagagac tcttaccaag gtaaaaccta aaacaggtca ggaaaatgga 16620 tgggaaaaag atgctacaga attttcagat aaaaatgaaa taagagttgg aaataatttt 16680 gccatggaaa tcaatctaaa tgccaacctg tggagaaatt tcctgtactc caacatagcg 16740 ctgtatttgc ccgacaagct aaagtacagt ccttccaacg taaaaatttc tgataaccca 16800 aacacctacg actacatgaa caagcgagtg gtggctcccg ggttagtgga ctgctacatt 16860 aaccttggag cacgctggtc ccttgactat atggacaacg tcaacccatt taaccaccac 16920 cgcaatgctg gcctgcgcta ccgctcaatg ttgctgggca atggtcgcta tgtgcccttc 16980 cacatccagg tgcctcagaa gttctttgcc attaaaaacc tccttctcct gccgggctca 17040 tacacctacg agtggaactt caggaaggat gttaacatgg ttctgcagag ctccctagga 17100 aatgacctaa gggttgacgg agccagcatt aagtttgata gcatttgcct ttacgccacc 17160 ttcttcccca tggcccacaa caccgcctcc acgcttgagg ccatgcttag aaacgacacc 17220 aacgaccagt cctttaacga ctatctctcc gccgccaaca tgctctaccc tatacccgcc 17280 aacgctacca acgtgcccat atccatcccc tcccgcaact gggcggcttt ccgcggctgg 17340 gccttcacgc gccttaagac taaggaaacc ccatcactgg gctcgggcta cgacccttat 17400 tacacctact ctggctctat accctaccta gatggaacct tttacctcaa ccacaccttt 17460 aagaaggtgg ccattacctt tgactcttct gtcagctggc ctggcaatga ccgcctgctt 17520 acccccaacg agtttgaaat taagcgctca gttgacgggg agggttacaa cgttgcccag 17580 tgtaacatga ccaaagactg gttcctggta caaatgctag ctaactacaa cattggctac 17640 cagggcttct atatcccaga gagctacaag gaccgcatgt actccttctt tagaaacttc 17700 cagcccatga gccgtcaggt ggtggatgat actaaataca aggactacca acaggtgggc 17760 atcctacacc aacacaacaa ctctggattt gttggctacc ttgcccccac catgcgcgaa 17820 ggacaggcct accctgctaa cttcccctat ccgcttatag gcaagaccgc agttgacagc 17880 attacccaga aaaagtttct ttgcgatcgc accctttggc gcatcccatt ctccagtaac 17940 tttatgtcca tgggcgcact cacagacctg ggccaaaacc ttctctacgc caactccgcc 18000 cacgcgctag acatgacttt tgaggtggat cccatggacg agcccaccct tctttatgtt 18060 ttgtttgaag tctttgacgt ggtccgtgtg caccggccgc accgcggcgt catcgaaacc 18120 gtgtacctgc gcacgccctt ctcggccggc aacgccacaa cataaagaag caagcaacat 18180 caacaacagc tgccgccatg ggctccagtg agcaggaact gaaagccatt gtcaaagatc 18240 ttggttgtgg gccatatttt ttgggcacct atgacaagcg ctttccaggc tttgtttctc 18300 cacacaagct cgcctgcgcc atagtcaata cggccggtcg cgagactggg ggcgtacact 18360 ggatggcctt tgcctggaac ccgcactcaa aaacatgcta cctctttgag ccctttggct 18420 tttctgacca gcgactcaag caggtttacc agtttgagta cgagtcactc ctgcgccgta 18480 gcgccattgc ttcttccccc gaccgctgta taacgctgga aaagtccacc caaagcgtac 18540 aggggcccaa ctcggccgcc tgtggactat tctgctgcat gtttctccac gcctttgcca 18600 actggcccca aactcccatg gatcacaacc ccaccatgaa ccttattacc ggggtaccca 18660 actccatgct caacagtccc caggtacagc ccaccctgcg tcgcaaccag gaacagctct 18720 acagcttcct ggagcgccac tcgccctact tccgcagcca cagtgcgcag attaggagcg 18780 ccacttcttt ttgtcacttg aaaaacatgt aaaaataatg tactagagac actttcaata 18840 aaggcaaatg cttttatttg tacactctcg ggtgattatt tacccccacc cttgccgtct 18900 gcgccgttta aaaatcaaag gggttctgcc gcgcatcgct atgcgccact ggcagggaca 18960 cgttgcgata ctggtgttta gtgctccact taaactcagg cacaaccatc cgcggcagct 19020 cggtgaagtt ttcactccac aggctgcgca ccatcaccaa cgcgtttagc aggtcgggcg 19080 ccgatatctt gaagtcgcag ttggggcctc cgccctgcgc gcgcgagttg cgatacacag 19140 ggttgcagca ctggaacact atcagcgccg ggtggtgcac gctggccagc acgctcttgt 19200 cggagatcag atccgcgtcc aggtcctccg cgttgctcag ggcgaacgga gtcaactttg 19260 gtagctgcct tcccaaaaag ggcgcgtgcc caggctttga gttgcactcg caccgtagtg 19320 gcatcaaaag gtgaccgtgc ccggtctggg cgttaggata cagcgcctgc ataaaagcct 19380 tgatctgctt aaaagccacc tgagcctttg cgccttcaga gaagaacatg ccgcaagact 19440 tgccggaaaa ctgattggcc ggacaggccg cgtcgtgcac gcagcacctt gcgtcggtgt 19500 tggagatctg caccacattt cggccccacc ggttcttcac gatcttggcc ttgctagact 19560 gctccttcag cgcgcgctgc ccgttttcgc tcgtcacatc catttcaatc acgtgctcct 19620 tatttatcat aatgcttccg tgtagacact taagctcgcc ttcgatctca gcgcagcggt 19680 gcagccacaa cgcgcagccc gtgggctcgt gatgcttgta ggtcacctct gcaaacgact 19740 gcaggtacgc ctgcaggaat cgccccatca tcgtcacaaa ggtcttgttg ctggtgaagg 19800 tcagctgcaa cccgcggtgc tcctcgttca gccaggtctt gcatacggcc gccagagctt 19860 ccacttggtc aggcagtagt ttgaagttcg cctttagatc gttatccacg tggtacttgt 19920 ccatcagcgc gcgcgcagcc tccatgccct tctcccacgc agacacgatc ggcacactca 19980 gcgggttcat caccgtaatt tcactttccg cttcgctggg ctcttcctct tcctcttgcg 20040 tccgcatacc acgcgccact gggtcgtctt cattcagccg ccgcactgtg cgcttacctc 20100 ctttgccatg cttgattagc accggtgggt tgctgaaacc caccatttgt agcgccacat 20160 cttctctttc ttcctcgctg tccacgatta cctctggtga tggcgggcgc tcgggcttgg 20220 gagaagggcg cttctttttc ttcttgggcg caatggccaa atccgccgcc gaggtcgatg 20280 gccgcgggct gggtgtgcgc ggcaccagcg cgtcttgtga tgagtcttcc tcgtcctcgg 20340 actcgatacg ccgcctcatc cgcttttttg ggggcgcccg gggaggcggc ggcgacgggg 20400 acggggacga cacgtcctcc atggttgggg gacgtcgcgc cgcaccgcgt ccgcgctcgg 20460 gggtggtttc gcgctgctcc tcttcccgac tggccatttc cttctcctat aggcagaaaa 20520 agatcatgga gtcagtcgag aagaaggaca gcctaaccgc cccctctgag ttcgccacca 20580 ccgcctccac cgatgccgcc aacgcgccta ccaccttccc cgtcgaggca cccccgcttg 20640 aggaggagga agtgattatc gagcaggacc caggttttgt aagcgaagac gacgaggacc 20700 gctcagtacc aacagaggat aaaaagcaag accaggacaa cgcagaggca aacgaggaac 20760 aagtcgggcg gggggacgaa aggcatggcg actacctaga tgtgggagac gacgtgctgt 20820 tgaagcatct gcagcgccag tgcgccatta tctgcgacgc gttgcaagag cgcagcgatg 20880 tgcccctcgc catagcggat gtcagccttg cctacgaacg ccacctattc tcaccgcgcg 20940 taccccccaa acgccaagaa aacggcacat gcgagcccaa cccgcgcctc aacttctacc 21000 ccgtatttgc cgtgccagag gtgcttgcca cctatcacat ctttttccaa aactgcaaga 21060 tacccctatc ctgccgtgcc aaccgcagcc gagcggacaa gcagctggcc ttgcggcagg 21120 gcgctgtcat acctgatatc gcctcgctca acgaagtgcc aaaaatcttt gagggtcttg 21180 gacgcgacga gaagcgcgcg gcaaacgctc tgcaacagga aaacagcgaa aatgaaagtc 21240 actctggagt gttggtggaa ctcgagggtg acaacgcgcg cctagccgta ctaaaacgca 21300 gcatcgaggt cacccacttt gcctacccgg cacttaacct accccccaag gtcatgagca 21360 cagtcatgag tgagctgatc gtgcgccgtg cgcagcccct ggagagggat gcaaatttgc 21420 aagaacaaac agaggagggc ctacccgcag ttggcgacga gcagctagcg cgctggcttc 21480 aaacgcgcga gcctgccgac ttggaggagc gacgcaaact aatgatggcc gcagtgctcg 21540 ttaccgtgga gcttgagtgc atgcagcggt tctttgctga cccggagatg cagcgcaagc 21600 tagaggaaac attgcactac acctttcgac agggctacgt acgccaggcc tgcaagatct 21660 ccaacgtgga gctctgcaac ctggtctcct accttggaat tttgcacgaa aaccgccttg 21720 ggcaaaacgt gcttcattcc acgctcaagg gcgaggcgcg ccgcgactac gtccgcgact 21780 gcgtttactt atttctatgc tacacctggc agacggccat gggcgtttgg cagcagtgct 21840 tggaggagtg caacctcaag gagctgcaga aactgctaaa gcaaaacttg aaggacctat 21900 ggacggcctt caacgagcgc tccgtggccg cgcacctggc ggacatcatt ttccccgaac 21960 gcctgcttaa aaccctgcaa cagggtctgc cagacttcac cagtcaaagc atgttgcaga 22020 actttaggaa ctttatccta gagcgctcag gaatcttgcc cgccacctgc tgtgcacttc 22080 ctagcgactt tgtgcccatt aagtaccgcg aatgccctcc gccgctttgg ggccactgct 22140 accttctgca gctagccaac taccttgcct accactctga cataatggaa gacgtgagcg 22200 gtgacggtct actggagtgt cactgtcgct gcaacctatg caccccgcac cgctccctgg 22260 tttgcaattc gcagctgctt aacgaaagtc aaattatcgg tacctttgag ctgcagggtc 22320 cctcgcctga cgaaaagtcc gcggctccgg ggttgaaact cactccgggg ctgtggacgt 22380 cggcttacct tcgcaaattt gtacctgagg actaccacgc ccacgagatt aggttctacg 22440 aagaccaatc ccgcccgcca aatgcggagc ttaccgcctg cgtcattacc cagggccaca 22500 ttcttggcca attgcaagcc atcaacaaag cccgccaaga gtttctgcta cgaaagggac 22560 ggggggttta cttggacccc cagtccggcg aggagctcaa cccaatcccc ccgccgccgc 22620 agccctatca gcagcagccg cgggcccttg cttcccagga tggcacccaa aaagaagctg 22680 cagctgccgc cgccacccac ggacgaggag gaatactggg acagtcaggc agaggaggtt 22740 ttggacgagg aggaggagga catgatggaa gactgggaga gcctagacga ggaagcttcc 22800 gaggtcgaag aggtgtcaga cgaaacaccg tcaccctcgg tcgcattccc ctcgccggcg 22860 ccccagaaat cggcaaccgg ttccagcatg gctacaacct ccgctcctca ggcgccgccg 22920 gcactgcccg ttcgccgacc caaccgtaga tgggacacca ctggaaccag ggccggtaag 22980 tccaagcagc cgccgccgtt agcccaagag caacaacagc gccaaggcta ccgctcatgg 23040 cgcgggcaca agaacgccat agttgcttgc ttgcaagact gtgggggcaa catctccttc 23100 gcccgccgct ttcttctcta ccatcacggc gtggccttcc cccgtaacat cctgcattac 23160 taccgtcatc tctacagccc atactgcacc ggcggcagcg gcagcggcag caacagcagc 23220 ggccacacag aagcaaaggc gaccggatag caagactctg acaaagccca agaaatccac 23280 agcggcggca gcagcaggag gaggagcgct gcgtctggcg cccaacgaac ccgtatcgac 23340 ccgcgagctt agaaacagga tttttcccac tctgtatgct atatttcaac agagcagggg 23400 ccaagaacaa gagctgaaaa taaaaaacag gtctctgcga tccctcaccc gcagctgcct 23460 gtatcacaaa agcgaagatc agcttcggcg cacgctggaa gacgcggagg ctctcttcag 23520 taaatactgc gcgctgactc ttaaggacta gtttcgcgcc ctttctcaaa tttaagcgcg 23580 aaaactacgt catctccagc ggccacaccc ggcgccagca cctgtcgtca gcgccattat 23640 gagcaaggaa attcccacgc cctacatgtg gagttaccag ccacaaatgg gacttgcggc 23700 tggagctgcc caagactact caacccgaat aaactacatg agcgcgggac cccacatgat 23760 atcccgggtc aacggaatcc gcgcccaccg aaaccgaatt ctcttggaac aggcggctat 23820 taccaccaca cctcgtaata accttaatcc ccgtagttgg cccgctgccc tggtgtacca 23880 ggaaagtccc gctcccacca ctgtggtact tcccagagac gcccaggccg aagttcagat 23940 gactaactca ggggcgcagc ttgcgggcgg ctttcgtcac agggtgcggt cgcccgggca 24000 gggtataact cacctgacaa tcagagggcg aggtattcag ctcaacgacg agtcggtgag 24060 ctcctcgctt ggtctccgtc cggacgggac atttcagatc ggcggcgccg gccgtccttc 24120 attcacgcct cgtcaggcaa tcctaactct gcagacctcg tcctctgagc cgcgctctgg 24180 aggcattgga actctgcaat ttattgagga gtttgtgcca tcggtctact ttaacccctt 24240 ctcgggacct cccggccact atccggatca atttattcct aactttgacg cggtaaagga 24300 ctcggcggac ggctacgact gaatgttaag tggagaggca gagcaactgc gcctgaaaca 24360 cctggtccac tgtcgccgcc acaagtgctt tgcccgcgac tccggtgagt tttgctactt 24420 tgaattgccc gaggatcata tcgagggccc ggcgcacggc gtccggctta ccgcccaggg 24480 agagcttgcc cgtagcctga ttcgggagtt tacccagcgc cccctgctag ttgagcggga 24540 caggggaccc tgtgttctca ctgtgatttg caactgtcct aaccttggat tacatcaaga 24600 tcctctagtt ataactagag tacccgggga tcttattccc tttaactaat aaaaaaaaat 24660 aataaagcat cacttactta aaatcagtta gcaaatttct gtccagttta ttcagcagca 24720 cctccttgcc ctcctcccag ctctggtatt gcagcttcct cctggctgca aactttctcc 24780 acaatctaaa tggaatgtca gtttcctcct gttcctgtcc atccgcaccc actatcttca 24840 tgttgttgca gatgaagcgc gcaagaccgt ctgaagatac cttcaacccc gtgtatccat 24900 atgacacgga aaccggtcct ccaactgtgc cttttcttac tcctcccttt gtatccccca 24960 atgggtttca agagagtccc cctggggtac tctctttgcg cctatccgaa cctctagtta 25020 cctccaatgg catgcttgcg ctcaaaatgg gcaacggcct ctctctggac gaggccggca 25080 accttacctc ccaaaatgta accactgtga gcccacctct caaaaaaacc aagtcaaaca 25140 taaacctgga aatatctgca cccctcacag ttacctcaga agccctaact gtggctgccg 25200 ccgcacctct aatggtcgcg ggcaacacac tcaccatgca atcacaggcc ccgctaaccg 25260 tgcacgactc caaacttagc attgccaccc aaggacccct cacagtgtca gaaggaaagc 25320 tagccctgca aacatcaggc cccctcacca ccaccgatag cagtaccctt actatcactg 25380 cctcaccccc tctaactact gccactggta gcttgggcat tgacttgaaa gagcccattt 25440 atacacaaaa tggaaaacta ggactaaagt acggggctcc tttgcatgta acagacgacc 25500 taaacacttt gaccgtagca actggtccag gtgtgactat taataatact tccttgcaaa 25560 ctaaagttac tggagccttg ggttttgatt cacaaggcaa tatgcaactt aatgtagcag 25620 gaggactaag gattgattct caaaacagac gccttatact tgatgttagt tatccgtttg 25680 atgctcaaaa ccaactaaat ctaagactag gacagggccc tctttttata aactcagccc 25740 acaacttgga tattaactac aacaaaggcc tttacttgtt tacagcttca aacaattcca 25800 aaaagcttga ggttaaccta agcactgcca aggggttgat gtttgacgct acagccatag 25860 ccattaatgc aggagatggg cttgaatttg gttcacctaa tgcaccaaac acaaatcccc 25920 tcaaaacaaa aattggccat ggcctagaat ttgattcaaa caaggctatg gttcctaaac 25980 taggaactgg ccttagtttt gacagcacag gtgccattac agtaggaaac aaaaataatg 26040 ataagctaac tttgtggacc acaccagctc catctcctaa ctgtagacta aatgcagaga 26100 aagatgctaa actcactttg gtcttaacaa aatgtggcag tcaaatactt gctacagttt 26160 cagttttggc tgttaaaggc agtttggctc caatatctgg aacagttcaa agtgctcatc 26220 ttattataag atttgacgaa aatggagtgc tactaaacaa ttccttcctg gacccagaat 26280 attggaactt tagaaatgga gatcttactg aaggcacagc ctatacaaac gctgttggat 26340 ttatgcctaa cctatcagct tatccaaaat ctcacggtaa aactgccaaa agtaacattg 26400 tcagtcaagt ttacttaaac ggagacaaaa ctaaacctgt aacactaacc attacactaa 26460 acggtacaca ggaaacagga gacacaactc caagtgcata ctctatgtca ttttcatggg 26520 actggtctgg ccacaactac attaatgaaa tatttgccac atcctcttac actttttcat 26580 acattgccca agaataaaga atcgtttgtg ttatgtttca acgtgtttat ttttcaattg 26640 cagaaaattt caagtcattt ttcattcagt agtatagccc caccaccaca tagcttatac 26700 agatcaccgt accttaatca aactcacaga accctagtat tcaacctgcc acctccctcc 26760 caacacacag agtacacagt cctttctccc cggctggcct taaaaagcat catatcatgg 26820 gtaacagaca tattcttagg tgttatattc cacacggttt cctgtcgagc caaacgctca 26880 tcagtgatat taataaactc cccgggcagc tcacttaagt tcatgtcgct gtccagctgc 26940 tgagccacag gctgctgtcc aacttgcggt tgcttaacgg gcggcgaagg agaagtccac 27000 gcctacatgg gggtagagtc ataatcgtgc atcaggatag ggcggtggtg ctgcagcagc 27060 gcgcgaataa actgctgccg ccgccgctcc gtcctgcagg aatacaacat ggcagtggtc 27120 tcctcagcga tgattcgcac cgcccgcagc ataaggcgcc ttgtcctccg ggcacagcag 27180 cgcaccctga tctcacttaa atcagcacag taactgcagc acagcaccac aatattgttc 27240 aaaatcccac agtgcaaggc gctgtatcca aagctcatgg cggggaccac agaacccacg 27300 tggccatcat accacaagcg caggtagatt aagtggcgac ccctcataaa cacgctggac 27360 ataaacatta cctcttttgg catgttgtaa ttcaccacct cccggtacca tataaacctc 27420 tgattaaaca tggcgccatc caccaccatc ctaaaccagc tggccaaaac ctgcccgccg 27480 gctatacact gcagggaacc gggactggaa caatgacagt ggagagccca ggactcgtaa 27540 ccatggatca tcatgctcgt catgatatca atgttggcac aacacaggca cacgtgcata 27600 cacttcctca ggattacaag ctcctcccgc gttagaacca tatcccaggg aacaacccat 27660 tcctgaatca gcgtaaatcc cacactgcag ggaagacctc gcacgtaact cacgttgtgc 27720 attgtcaaag tgttacattc gggcagcagc ggatgatcct ccagtatggt agcgcgggtt 27780 tctgtctcaa aaggaggtag acgatcccta ctgtacggag tgcgccgaga caaccgagat 27840 cgtgttggtc gtagtgtcat gccaaatgga acgccggacg tagtcatatt tcctgaagca 27900 aaaccaggtg cgggcgtgac aaacagatct gcgtctccgg tctcgccgct tagatcgctc 27960 tgtgtagtag ttgtagtata tccactctct caaagcatcc aggcgccccc tggcttcggg 28020 ttctatgtaa actccttcat gcgccgctgc cctgataaca tccaccaccg cagaataagc 28080 cacacccagc caacctacac attcgttctg cgagtcacac acgggaggag cgggaagagc 28140 tggaagaacc atgttttttt ttttattcca aaagattatc caaaacctca aaatgaagat 28200 ctattaagtg aacgcgctcc cctccggtgg cgtggtcaaa ctctacagcc aaagaacaga 28260 taatggcatt tgtaagatgt tgcacaatgg cttccaaaag gcaaacggcc ctcacgtcca 28320 agtggacgta aaggctaaac ccttcagggt gaatctcctc tataaacatt ccagcacctt 28380 caaccatgcc caaataattc tcatctcgcc accttctcaa tatatctcta agcaaatccc 28440 gaatattaag tccggccatt gtaaaaatct gctccagagc gccctccacc ttcagcctca 28500 agcagcgaat catgattgca aaaattcagg ttcctcacag acctgtataa gattcaaaag 28560 cggaacatta acaaaaatac cgcgatcccg taggtccctt cgcagggcca gctgaacata 28620 atcgtgcagg tctgcacgga ccagcgcggc cacttccccg ccaggaacct tgacaaaaga 28680 acccacactg attatgacac gcatactcgg agctatgcta accagcgtag ccccgatgta 28740 agctttcaat agcttgttgc atgggcggcg atataaaatg caaggtgctg ctcaaaaaat 28800 caggcaaagc ctcgcgcaaa aaagaaagca catcgtagtc atgctcatgc agataaaggc 28860 aggtaagctc cggaaccacc acagaaaaag acaccatttt tctctcaaac atgtctgcgg 28920 gtttctgcat aaacacaaaa taaaataaca aaaaaacatt taaacattag aagcctgtct 28980 tacaacagga aaaacaaccc ttataagcat aagacggact acggccatgc cggcgtgacc 29040 gtaaaaaaac tggtcaccgt gattaaaaag caccaccgac agctcctcgg tcatgtccgg 29100 agtcataatg taagactcgg taaacacatc aggttgattc atcggtcagt gctaaaaagc 29160 gaccgaaata gcccggggga atacataccc gcaggcgtag agacaacatt acagccccca 29220 taggaggtat aacaaaatta ataggagaga aaaacacata aacacctgaa aaaccctcct 29280 gcctaggcaa aatagcaccc tcccgctcca gaacaacata cagcgcttca cagcggcagc 29340 ctaacagtca gccttaccag taaaaaagaa aacctattaa aaaaacacca ctcgacacgg 29400 caccagctca atcagtcaca gtgtaaaaaa gggccaagtg cagagcgagt atatatagga 29460 ctaaaaaatg acgtaacggt taaagtccac aaaaaacacc cagaaaaccg cacgcgaacc 29520 tacgcccaga aacgaaagcc aaaaaaccca caacttcctc aaatcgtcac ttccgttttc 29580 ccacgttacg taacttccca ttttaagaaa actacaattc ccaacacata caagttactc 29640 cgccctaaaa cctacgtcac ccgccccgtt cccacgcccc gcgccacgtc acaaactcca 29700 ccccctcatt atcatattgg cttcaatcca aaataaggta tattattgat gatgttaatt 29760 aacatgcatg gatccatatg cggtgtgaaa taccgcacag atgcgtaagg agaaaatacc 29820 gcatcaggcg ctcttccgct tcctcgctca ctgactcgct gcgctcggtc gttcggctgc 29880 ggcgagcggt atcagctcac tcaaaggcgg taatacggtt atccacagaa tcaggggata 29940 acgcaggaaa gaacatgtga gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg 30000 cgttgctggc gtttttccat aggctccgcc cccctgacga gcatcacaaa aatcgacgct 30060 caagtcagag gtggcgaaac ccgacaggac tataaagata ccaggcgttt ccccctggaa 30120 gctccctcgt gcgctctcct gttccgaccc tgccgcttac cggatacctg tccgcctttc 30180 tcccttcggg aagcgtggcg ctttctcata gctcacgctg taggtatctc agttcggtgt 30240 aggtcgttcg ctccaagctg ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg 30300 ccttatccgg taactatcgt cttgagtcca acccggtaag acacgactta tcgccactgg 30360 cagcagccac tggtaacagg attagcagag cgaggtatgt aggcggtgct acagagttct 30420 tgaagtggtg gcctaactac ggctacacta gaaggacagt atttggtatc tgcgctctgc 30480 tgaagccagt taccttcgga aaaagagttg gtagctcttg atccggcaaa caaaccaccg 30540 ctggtagcgg tggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc 30600 aagaagatcc tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt 30660 aagggatttt ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa 30720 aatgaagttt taaatcaatc taaagtatat atgagtaaac ttggtctgac agttaccaat 30780 gcttaatcag tgaggcacct atctcagcga tctgtctatt tcgttcatcc atagttgcct 30840 gactccccgt cgtgtagata actacgatac gggagggctt accatctggc cccagtgctg 30900 caatgatacc gcgagaccca cgctcaccgg ctccagattt atcagcaata aaccagccag 30960 ccggaagggc cgagcgcaga agtggtcctg caactttatc cgcctccatc cagtctatta 31020 attgttgccg ggaagctaga gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg 31080 ccattgctgc agccatgaga ttatcaaaaa ggatcttcac ctagatcctt ttcacgtaga 31140 aagccagtcc gcagaaacgg tgctgacccc ggatgaatgt cagctactgg gctatctgga 31200 caagggaaaa cgcaagcgca aagagaaagc aggtagcttg cagtgggctt acatggcgat 31260 agctagactg ggcggtttta tggacagcaa gcgaaccgga attgccagct ggggcgccct 31320 ctggtaaggt tgggaagccc tgcaaagtaa actggatggc tttctcgccg ccaaggatct 31380 gatggcgcag gggatcaagc tctgatcaag agacaggatg aggatcgttt cgcatgattg 31440 aacaagatgg attgcacgca ggttctccgg ccgcttgggt ggagaggcta ttcggctatg 31500 actgggcaca acagacaatc ggctgctctg atgccgccgt gttccggctg tcagcgcagg 31560 ggcgcccggt tctttttgtc aagaccgacc tgtccggtgc cctgaatgaa ctgcaagacg 31620 aggcagcgcg gctatcgtgg ctggccacga cgggcgttcc ttgcgcagct gtgctcgacg 31680 ttgtcactga agcgggaagg gactggctgc tattgggcga agtgccgggg caggatctcc 31740 tgtcatctca ccttgctcct gccgagaaag tatccatcat ggctgatgca atgcggcggc 31800 tgcatacgct tgatccggct acctgcccat tcgaccacca agcgaaacat cgcatcgagc 31860 gagcacgtac tcggatggaa gccggtcttg tcgatcagga tgatctggac gaagagcatc 31920 aggggctcgc gccagccgaa ctgttcgcca ggctcaaggc gagcatgccc gacggcgagg 31980 atctcgtcgt gacccatggc gatgcctgct tgccgaatat catggtggaa aatggccgct 32040 tttctggatt catcgactgt ggccggctgg gtgtggcgga ccgctatcag gacatagcgt 32100 tggctacccg tgatattgct gaagagcttg gcggcgaatg ggctgaccgc ttcctcgtgc 32160 tttacggtat cgccgctccc gattcgcagc gcatcgcctt ctatcgcctt cttgacgagt 32220 tcttctgaat tttgttaaaa tttttgttaa atcagctcat tttttaacca ataggccgaa 32280 atcggcaaca tcccttataa atcaaaagaa tagaccgcga tagggttgag tgttgttcca 32340 gtttggaaca agagtccact attaaagaac gtggactcca acgtcaaagg gcgaaaaacc 32400 gtctatcagg gcgatggccc actacgtgaa ccatcaccca aatcaagttt tttgcggtcg 32460 aggtgccgta aagctctaaa tcggaaccct aaagggagcc cccgatttag agcttgacgg 32520 ggaaagccgg cgaacgtggc gagaaaggaa gggaagaaag cgaaaggagc gggcgctagg 32580 gcgctggcaa gtgtagcggt cacgctgcgc gtaaccacca cacccgcgcg cttaatgcgc 32640 cgctacaggg cgcgtccatt cgccattcag gatcgaatta attcttaatt aacatcatca 32700 ataatatacc ttattttgga ttgaagccaa tatgataatg agggggtgga gtttgtgacg 32760 tggcgcgggg cgtgggaacg gggcgggtga cgtagtagtg tggcggaagt gtgatgttgc 32820 aagtgtggcg gaacacatgt aagcgacgga tgtggcaaaa gtgacgtttt tggtgtgcgc 32880 cggtgtacac aggaagtgac aattttcgcg cggttttagg cggatgttgt agtaaatttg 32940 ggcgtaaccg agtaagattt ggccattttc gcgggaaaac tgaataagag gaagtgaaat 33000 ctgaataatt ttgtgttact catagcgcgt aatactgcga tctatacatt gaatcaatat 33060 tggcaattag ccatattagt cattggttat atagcataaa tcaatattgg ctattggcca 33120 ttgcatacgt tgtatctata tcataatatg tacatttata ttggctcatg tccaatatga 33180 ccgccatgtt gacattgatt attgactagt agttcatagc ccatatatgg agttccgcgt 33240 tacataactt acggtaaatg gcccgcctgg ctgaccgccc aacgaccccc gcccattgac 33300 gtcaataatg acgtatgttc ccatagtaac gccaataggg actttccatt gacgtcaatg 33360 ggtggagtat ttacggtaaa ctgcccactt ggcagtacat caagtgtatc atatgccaag 33420 tccgccccct attgacgtca atgacggtaa atggcccgcc tggcattatg cccagtacat 33480 gaccttacgg gactttccta cttggcagta catctacgta ttagtcatcg ctattaccat 33540 ggtgatgcgg ttttggcagt acaccaatgg gcgtggatag cggtttgact cacggggatt 33600 tccaagtctc caccccattg acgtcaatgg gagtttgttt tggcaccaaa atcaacggga 33660 ctttccaaaa tgtcgtaata accccgcccc gttgacgcaa atgggcggta ggcgtgtacg 33720 gtgggaggtc tatataagca gagctcgttt agtgaaccgt cagatcctca ctctcttccg 33780 catcgctgtc tgcgagggcc agctgttggg ctcgcggttg aggacaaact cttcgcggtc 33840 tttccagtac tcttggatcg gaaacccgtc ggcctccgaa cggtactccg ccaccgaggg 33900 acctgagcca gtccgcatcg accggatcgg aaaacctctc gagaaaggcg tctaaccagt 33960 cacagtcgca aggtaggctg agcaccgtgg cgggcggcag cgggtggcgg tcggggttgt 34020 ttctggcgga ggtgctgctg atgatgtaat taaagtaggc ggtcttgagc cggcggatgg 34080 tcgaggtgag gtgtggcagg cttgagatcc agctgttggg gtgagtactc cctctcaaaa 34140 gcgggcatga cttctgcgct aagattgtca gtttccaaaa acgaggagga tttgatattc 34200 acctggcccg atctggccat acacttgagt gacaatgaca tccactttgc ctttctctcc 34260 acaggtgtcc actcccaggt ccaagtttgg aagatctgaa ctgaaaaacc agaaagttaa 34320 ctggtaagtt tagtcttttt gtcttttatt tcaggtcccg gatccggtgg tggtgcaaat 34380 caaagaactg ctcctcagtg gatgttgcct ttacttctag gcctgtacgg aagtgttact 34440 tctgctctaa aagctgcgga attgtaccca ggcctaggct tttgcaaaaa gcttcgaatc 34500 gcgaaaggcc agcacgttct tcgcgccgcg ctcgcacagc ctctgcagca ctcgggccac 34560 cagctccttc aggcaggaca cctggcggaa ggagggggcg gcggggggcg gccgtgcgtc 34620 ccagggcacg cacaccaggc actgggccac cagcgcgcgg aaagccgccg ggtccccgcg 34680 ctgcaccagc cgccagccct ggggccccag gcgccgcacg aacgtggcca gcggcagcac 34740 ctcgcggtag tggctgcgca gcagggagcg cacggctagg cagcggggag cgcgcggcat 34800 cgcgggggtg gccggggcca gggcttccca agcttcgttt tgcggcagga aaagttatca 34860 ggcatgcacc tggtagctag tctttaaacc aatagattgc atcggtttaa aaggcaagac 34920 cgtcaaattg cgggaaaggg gtcaacagcc gttcagtacc aagtctcagg ggaaactttg 34980 agatggcctt gcaaagggta tggtaataag ctgacggaca tggtcctaac cacgcagcca 35040 agtcctaagt caacagatct tctgttgata tggatgcagt tcacagacta aatgtcggtc 35100 ggggaagatg tattcttctc ataagatata gtcggacctc tccttaatgg gagctagcgg 35160 atgaagtgat gcaacactgg agccgctggg aactaatttg tatgcgaaag tatattgatt 35220 agttttggag tactcgaaaa cgcccaccat ggcttcgtac ccctgccatc aacacgcgtc 35280 tgcgttcgac caggctgcgc gttctcgcgg ccatagcaac cgacgtacgg cgttgcgccc 35340 tcgccggcag caagaagcca cggaagtccg cctggagcag aaaatgccca cgctactgcg 35400 ggtttatata gacggtcctc acgggatggg gaaaaccacc accacgcaac tgctggtggc 35460 cctgggttcg cgcgacgata tcgtctacgt acccgagccg atgacttact ggcaggtgct 35520 gggggcttcc gagacaatcg cgaacatcta caccacacaa caccgcctcg accagggtga 35580 gatatcggcc ggggacgcgg cggtggtaat gacaagcgcc cagataacaa tgggcatgcc 35640 ttatgccgtg accgacgccg ttctggctcc tcatgtcggg ggggaggctg ggagttcaca 35700 tgccccgccc ccggccctca ccctcatctt cgaccgccat cccatcgccg ccctcctgtg 35760 ctacccggcc gcgcgatacc ttatgggcag catgaccccc caggccgtgc tggcgttcgt 35820 ggccctcatc ccgccgacct tgcccggcac aaacatcgtg ttgggggccc ttccggagga 35880 cagacacatc gaccgcctgg ccaaacgcca gcgccccggc gagcggcttg acctggctat 35940 gctggccgcg attcgccgcg tttacgggct gcttgccaat acggtgcggt atctgcaggg 36000 cggcgggtcg tggtgggagg attggggaca gctttcgggg acggccgtgc cgccccaggg 36060 tgccgagccc cagagcaacg cgggcccacg accccatatc ggggacacgt tatttaccct 36120 gtttcgggcc cccgagttgc tggcccccaa cggcgacctg tataacgtgt ttgcctgggc 36180 cttggacgtc ttggccaaac gcctccgtcc catgcacgtc tttatcctgg attacgacca 36240 atcgcccgcc ggctgccggg acgccctgct gcaacttacc tccgggatgg tccagaccca 36300 cgtcaccacc ccaggctcca taccgacgat ctgcgacctg gcgcgcacgt ttgcccggga 36360 gatgggggag gctaactgag gccggccaat caacctctgg attacaaaat ttgtgaaaga 36420 ttgactggta ttcttaacta tgttgctcct tttacgctat gtggatacgc tgctttaatg 36480 cctttgtatc atgctattgc ttcccgtatg gctttcattt tctcctcctt gtataaatcc 36540 tggttgctgt ctctttatga ggagttgtgg cccgttgtca ggcaacgtgg cgtggtgtgc 36600 actgtgtttg ctgacgcaac ccccactggt tggggcattg ccaccacctg tcagctcctt 36660 tccgggactt tcgctttccc cctccctatt gccacggcgg aactcatcgc cgcctgcctt 36720 gcccgctgct ggacaggggc tcggctgttg ggcactgaca attccgtggt gttgtcgggg 36780 aaatcatcgt cctttccttg gctgctcgcc tgtgttgcca cctggattct gcgcgggacg 36840 tccttctgct acgtcccttc ggccctcaat ccagcggacc ttccttcccg cggcctgctg 36900 ccggctctgc ggcctcttcc gcgtcttcgc cttcgccctc agacgagtcg gatctccctt 36960 tgggccgcct ccccgcggcc ggccgcttcg aaggcgaaag atcccaacga aaagagagac 37020 cacatggtcc ttcttgagtt tgtaacagct gctgggatta cacatggcat ggatgaactg 37080 tacaactgag gatcccccga cctcgacctc tggctaataa aggaaattta ttttcattgc 37140 aatagtgtgt tggaattttt tgtgtctctc actcggaagg acatatggga gggcaaatca 37200 tttggtcgag atccctcgga gatcggatct gggcgtgg 37238 <210> 45 <211> 40537 <212> DNA <213> Artificial Sequence <220> <223> Ad-PEPCK SD/SA Ribozyme HSV-TK <400> 45 ttaagggtgg gaaagaatat ataaggtggg ggtcttatgt agttttgtat ctgttttgca 60 gcagccgccg ccgccatgag caccaactcg tttgatggaa gcattgtgag ctcatatttg 120 acaacgcgca tgcccccatg ggccggggtg cgtcagaatg tgatgggctc cagcattgat 180 ggtcgccccg tcctgcccgc aaactctact accttgacct acgagaccgt gtctggaacg 240 ccgttggaga ctgcagcctc cgccgccgct tcagccgctg cagccaccgc ccgcgggatt 300 gtgactgact ttgctttcct gagcccgctt gcaagcagtg cagcttcccg ttcatccgcc 360 cgcgatgaca agttgacggc tcttttggca caattggatt ctttgacccg ggaacttaat 420 gtcgtttctc agcagctgtt ggatctgcgc cagcaggttt ctgccctgaa ggcttcctcc 480 cctcccaatg cggtttaaaa cataaataaa aaaccagact ctgtttggat ttggatcaag 540 caagtgtctt gctgtcttta tttaggggtt ttgcgcgcgc ggtaggcccg ggaccagcgg 600 tctcggtcgt tgagggtcct gtgtattttt tccaggacgt ggtaaaggtg actctggatg 660 ttcagataca tgggcataag cccgtctctg gggtggaggt agcaccactg cagagcttca 720 tgctgcgggg tggtgttgta gatgatccag tcgtagcagg agcgctgggc gtggtgccta 780 aaaatgtctt tcagtagcaa gctgattgcc aggggcaggc ccttggtgta agtgtttaca 840 aagcggttaa gctgggatgg gtgcatacgt ggggatatga gatgcatctt ggactgtatt 900 tttaggttgg ctatgttccc agccatatcc ctccggggat tcatgttgtg cagaaccacc 960 agcacagtgt atccggtgca cttgggaaat ttgtcatgta gcttagaagg aaatgcgtgg 1020 aagaacttgg agacgccctt gtgacctcca agattttcca tgcattcgtc cataatgatg 1080 gcaatgggcc cacgggcggc ggcctgggcg aagatatttc tgggatcact aacgtcatag 1140 ttgtgttcca ggatgagatc gtcataggcc atttttacaa agcgcgggcg gagggtgcca 1200 gactgcggta taatggttcc atccggccca ggggcgtagt taccctcaca gatttgcatt 1260 tcccacgctt tgagttcaga tggggggatc atgtctacct gcggggcgat gaagaaaacg 1320 gtttccgggg taggggagat cagctgggaa gaaagcaggt tcctgagcag ctgcgactta 1380 ccgcagccgg tgggcccgta aatcacacct attaccgggt gcaactggta gttaagagag 1440 ctgcagctgc cgtcatccct gagcaggggg gccacttcgt taagcatgtc cctgactcgc 1500 atgttttccc tgaccaaatc cgccagaagg cgctcgccgc ccagcgatag cagttcttgc 1560 aaggaagcaa agtttttcaa cggtttgaga ccgtccgccg taggcatgct tttgagcgtt 1620 tgaccaagca gttccaggcg gtcccacagc tcggtcacct gctctacggc atctcgatcc 1680 agcatatctc ctcgtttcgc gggttggggc ggctttcgct gtacggcagt agtcggtgct 1740 cgtccagacg ggccagggtc atgtctttcc acgggcgcag ggtcctcgtc agcgtagtct 1800 gggtcacggt gaaggggtgc gctccgggct gcgcgctggc cagggtgcgc ttgaggctgg 1860 tcctgctggt gctgaagcgc tgccggtctt cgccctgcgc gtcggccagg tagcatttga 1920 ccatggtgtc atagtccagc ccctccgcgg cgtggccctt ggcgcgcagc ttgcccttgg 1980 aggaggcgcc gcacgagggg cagtgcagac ttttgagggc gtagagcttg ggcgcgagaa 2040 ataccgattc cggggagtag gcatccgcgc cgcaggcccc gcagacggtc tcgcattcca 2100 cgagccaggt gagctctggc cgttcggggt caaaaaccag gtttccccca tgctttttga 2160 tgcgtttctt acctctggtt tccatgagcc ggtgtccacg ctcggtgacg aaaaggctgt 2220 ccgtgtcccc gtatacagac ttgagaggcc tgtcctcgag cggtgttccg cggtcctcct 2280 cgtatagaaa ctcggaccac tctgagacaa aggctcgcgt ccaggccagc acgaaggagg 2340 ctaagtggga ggggtagcgg tcgttgtcca ctagggggtc cactcgctcc agggtgtgaa 2400 gacacatgtc gccctcttcg gcatcaagga aggtgattgg tttgtaggtg taggccacgt 2460 gaccgggtgt tcctgaaggg gggctataaa agggggtggg ggcgcgttcg tcctcactct 2520 cttccgcatc gctgtctgcg agggccagct gttggggtga gtactccctc tgaaaagcgg 2580 gcatgacttc tgcgctaaga ttgtcagttt ccaaaaacga ggaggatttg atattcacct 2640 ggcccgcggt gatgcctttg agggtggccg catccatctg gtcagaaaag acaatctttt 2700 tgttgtcaag cttggtggca aacgacccgt agagggcgtt ggacagcaac ttggcgatgg 2760 agcgcagggt ttggtttttg tcgcgatcgg cgcgctcctt ggccgcgatg tttagctgca 2820 cgtattcgcg cgcaacgcac cgccattcgg gaaagacggt ggtgcgctcg tcgggcacca 2880 ggtgcacgcg ccaaccgcgg ttgtgcaggg tgacaaggtc aacgctggtg gctacctctc 2940 cgcgtaggcg ctcgttggtc cagcagaggc ggccgccctt gcgcgagcag aatggcggta 3000 gggggtctag ctgcgtctcg tccggggggt ctgcgtccac ggtaaagacc ccgggcagca 3060 ggcgcgcgtc gaagtagtct atcttgcatc cttgcaagtc tagcgcctgc tgccatgcgc 3120 gggcggcaag cgcgcgctcg tatgggttga gtgggggacc ccatggcatg gggtgggtga 3180 gcgcggaggc gtacatgccg caaatgtcgt aaacgtagag gggctctctg agtattccaa 3240 gatatgtagg gtagcatctt ccaccgcgga tgctggcgcg cacgtaatcg tatagttcgt 3300 gcgagggagc gaggaggtcg ggaccgaggt tgctacgggc gggctgctct gctcggaaga 3360 ctatctgcct gaagatggca tgtgagttgg atgatatggt tggacgctgg aagacgttga 3420 agctggcgtc tgtgagacct accgcgtcac gcacgaagga ggcgtaggag tcgcgcagct 3480 tgttgaccag ctcggcggtg acctgcacgt ctagggcgca gtagtccagg gtttccttga 3540 tgatgtcata cttatcctgt cccttttttt tccacagctc gcggttgagg acaaactctt 3600 cgcggtcttt ccagtactct tggatcggaa acccgtcggc ctccgaacgg taagagccta 3660 gcatgtagaa ctggttgacg gcctggtagg cgcagcatcc cttttctacg ggtagcgcgt 3720 atgcctgcgc ggccttccgg agcgaggtgt gggtgagcgc aaaggtgtcc ctgaccatga 3780 ctttgaggta ctggtatttg aagtcagtgt cgtcgcatcc gccctgctcc cagagcaaaa 3840 agtccgtgcg ctttttggaa cgcggatttg gcagggcgaa ggtgacatcg ttgaagagta 3900 tctttcccgc gcgaggcata aagttgcgtg tgatgcggaa gggtcccggc acctcggaac 3960 ggttgttaat tacctgggcg gcgagcacga tctcgtcaaa gccgttgatg ttgtggccca 4020 caatgtaaag ttccaagaag cgcgggatgc ccttgatgga aggcaatttt ttaagttcct 4080 cgtaggtgag ctcttcaggg gagctgagcc cgtgctctga aagggcccag tctgcaagat 4140 gagggttgga agcgacgaat gagctccaca ggtcacgggc cattagcatt tgcaggtggt 4200 cgcgaaaggt cctaaactgg cgacctatgg ccattttttc tggggtgatg cagtagaagg 4260 taagcgggtc ttgttcccag cggtcccatc caaggttcgc ggctaggtct cgcgcggcag 4320 tcactagagg ctcatctccg ccgaacttca tgaccagcat gaagggcacg agctgcttcc 4380 caaaggcccc catccaagta taggtctcta catcgtaggt gacaaagaga cgctcggtgc 4440 gaggatgcga gccgatcggg aagaactgga tctcccgcca ccaattggag gagtggctat 4500 tgatgtggtg aaagtagaag tccctgcgac gggccgaaca ctcgtgctgg cttttgtaaa 4560 aacgtgcgca gtactggcag cggtgcacgg gctgtacatc ctgcacgagg ttgacctgac 4620 gaccgcgcac aaggaagcag agtgggaatt tgagcccctc gcctggcggg tttggctggt 4680 ggtcttctac ttcggctgct tgtccttgac cgtctggctg ctcgagggga gttacggtgg 4740 atcggaccac cacgccgcgc gagcccaaag tccagatgtc cgcgcgcggc ggtcggagct 4800 tgatgacaac atcgcgcaga tgggagctgt ccatggtctg gagctcccgc ggcgtcaggt 4860 caggcgggag ctcctgcagg tttacctcgc atagacgggt cagggcgcgg gctagatcca 4920 ggtgatacct aatttccagg ggctggttgg tggcggcgtc gatggcttgc aagaggccgc 4980 atccccgcgg cgcgactacg gtaccgcgcg gcgggcggtg ggccgcgggg gtgtccttgg 5040 atgatgcatc taaaagcggt gacgcgggcg agcccccgga ggtagggggg gctccggacc 5100 cgccgggaga gggggcaggg gcacgtcggc gccgcgcgcg ggcaggagct ggtgctgcgc 5160 gcgtaggttg ctggcgaacg cgacgacgcg gcggttgatc tcctgaatct ggcgcctctg 5220 cgtgaagacg acgggcccgg tgagcttgag cctgaaagag agttcgacag aatcaatttc 5280 ggtgtcgttg acggcggcct ggcgcaaaat ctcctgcacg tctcctgagt tgtcttgata 5340 ggcgatctcg gccatgaact gctcgatctc ttcctcctgg agatctccgc gtccggctcg 5400 ctccacggtg gcggcgaggt cgttggaaat gcgggccatg agctgcgaga aggcgttgag 5460 gcctccctcg ttccagacgc ggctgtagac cacgccccct tcggcatcgc gggcgcgcat 5520 gaccacctgc gcgagattga gctccacgtg ccgggcgaag acggcgtagt ttcgcaggcg 5580 ctgaaagagg tagttgaggg tggtggcggt gtgttctgcc acgaagaagt acataaccca 5640 gcgtcgcaac gtggattcgt tgatatcccc caaggcctca aggcgctcca tggcctcgta 5700 gaagtccacg gcgaagttga aaaactggga gttgcgcgcc gacacggtta actcctcctc 5760 cagaagacgg atgagctcgg cgacagtgtc gcgcacctcg cgctcaaagg ctacaggggc 5820 ctcttcttct tcttcaatct cctcttccat aagggcctcc ccttcttctt cttctggcgg 5880 cggtggggga ggggggacac ggcggcgacg acggcgcacc gggaggcggt cgacaaagcg 5940 ctcgatcatc tccccgcggc gacggcgcat ggtctcggtg acggcgcggc cgttctcgcg 6000 ggggcgcagt tggaagacgc cgcccgtcat gtcccggtta tgggttggcg gggggctgcc 6060 atgcggcagg gatacggcgc taacgatgca tctcaacaat tgttgtgtag gtactccgcc 6120 gccgagggac ctgagcgagt ccgcatcgac cggatcggaa aacctctcga gaaaggcgtc 6180 taaccagtca cagtcgcaag gtaggctgag caccgtggcg ggcggcagcg ggcggcggtc 6240 ggggttgttt ctggcggagg tgctgctgat gatgtaatta aagtaggcgg tcttgagacg 6300 gcggatggtc gacagaagca ccatgtcctt gggtccggcc tgctgaatgc gcaggcggtc 6360 ggccatgccc caggcttcgt tttgacatcg gcgcaggtct ttgtagtagt cttgcatgag 6420 cctttctacc ggcacttctt cttctccttc ctcttgtcct gcatctcttg catctatcgc 6480 tgcggcggcg gcggagtttg gccgtaggtg gcgccctctt cctcccatgc gtgtgacccc 6540 gaagcccctc atcggctgaa gcagggctag gtcggcgaca acgcgctcgg ctaatatggc 6600 ctgctgcacc tgcgtgaggg tagactggaa gtcatccatg tccacaaagc ggtggtatgc 6660 gcccgtgttg atggtgtaag tgcagttggc cataacggac cagttaacgg tctggtgacc 6720 cggctgcgag agctcggtgt acctgagacg cgagtaagcc ctcgagtcaa atacgtagtc 6780 gttgcaagtc cgcaccaggt actggtatcc caccaaaaag tgcggcggcg gctggcggta 6840 gaggggccag cgtagggtgg ccggggctcc gggggcgaga tcttccaaca taaggcgatg 6900 atatccgtag atgtacctgg acatccaggt gatgccggcg gcggtggtgg aggcgcgcgg 6960 aaagtcgcgg acgcggttcc agatgttgcg cagcggcaaa aagtgctcca tggtcgggac 7020 gctctggccg gtcaggcgcg cgcaatcgtt gacgctctac cgtgcaaaag gagagcctgt 7080 aagcgggcac tcttccgtgg tctggtggat aaattcgcaa gggtatcatg gcggacgacc 7140 ggggttcgag ccccgtatcc ggccgtccgc cgtgatccat gcggttaccg cccgcgtgtc 7200 gaacccaggt gtgcgacgtc agacaacggg ggagtgctcc ttttggcttc cttccaggcg 7260 cggcggctgc tgcgctagct tttttggcca ctggccgcgc gcagcgtaag cggttaggct 7320 ggaaagcgaa agcattaagt ggctcgctcc ctgtagccgg agggttattt tccaagggtt 7380 gagtcgcggg acccccggtt cgagtctcgg accggccgga ctgcggcgaa cgggggtttg 7440 cctccccgtc atgcaagacc ccgcttgcaa attcctccgg aaacagggac gagccccttt 7500 tttgcttttc ccagatgcat ccggtgctgc ggcagatgcg cccccctcct cagcagcggc 7560 aagagcaaga gcagcggcag acatgcaggg caccctcccc tcctcctacc gcgtcaggag 7620 gggcgacatc cgcggttgac gcggcagcag atggtgatta cgaacccccg cggcgccggg 7680 cccggcacta cctggacttg gaggagggcg agggcctggc gcggctagga gcgccctctc 7740 ctgagcggta cccaagggtg cagctgaagc gtgatacgcg tgaggcgtac gtgccgcggc 7800 agaacctgtt tcgcgaccgc gagggagagg agcccgagga gatgcgggat cgaaagttcc 7860 acgcagggcg cgagctgcgg catggcctga atcgcgagcg gttgctgcgc gaggaggact 7920 ttgagcccga cgcgcgaacc gggattagtc ccgcgcgcgc acacgtggcg gccgccgacc 7980 tggtaaccgc atacgagcag acggtgaacc aggagattaa ctttcaaaaa agctttaaca 8040 accacgtgcg tacgcttgtg gcgcgcgagg aggtggctat aggactgatg catctgtggg 8100 actttgtaag cgcgctggag caaaacccaa atagcaagcc gctcatggcg cagctgttcc 8160 ttatagtgca gcacagcagg gacaacgagg cattcaggga tgcgctgcta aacatagtag 8220 agcccgaggg ccgctggctg ctcgatttga taaacatcct gcagagcata gtggtgcagg 8280 agcgcagctt gagcctggct gacaaggtgg ccgccatcaa ctattccatg cttagcctgg 8340 gcaagtttta cgcccgcaag atataccata ccccttacgt tcccatagac aaggaggtaa 8400 agatcgaggg gttctacatg cgcatggcgc tgaaggtgct taccttgagc gacgacctgg 8460 gcgtttatcg caacgagcgc atccacaagg ccgtgagcgt gagccggcgg cgcgagctca 8520 gcgaccgcga gctgatgcac agcctgcaaa gggccctggc tggcacgggc agcggcgata 8580 gagaggccga gtcctacttt gacgcgggcg ctgacctgcg ctgggcccca agccgacgcg 8640 ccctggaggc agctggggcc ggacctgggc tggcggtggc acccgcgcgc gctggcaacg 8700 tcggcggcgt ggaggaatat gacgaggacg atgagtacga gccagaggac ggcgagtact 8760 aagcggtgat gtttctgatc agatgatgca agacgcaacg gacccggcgg tgcgggcggc 8820 gctgcagagc cagccgtccg gccttaactc cacggacgac tggcgccagg tcatggaccg 8880 catcatgtcg ctgactgcgc gcaatcctga cgcgttccgg cagcagccgc aggccaaccg 8940 gctctccgca attctggaag cggtggtccc ggcgcgcgca aaccccacgc acgagaaggt 9000 gctggcgatc gtaaacgcgc tggccgaaaa cagggccatc cggcccgacg aggccggcct 9060 ggtctacgac gcgctgcttc agcgcgtggc tcgttacaac agcggcaacg tgcagaccaa 9120 cctggaccgg ctggtggggg atgtgcgcga ggccgtggcg cagcgtgagc gcgcgcagca 9180 gcagggcaac ctgggctcca tggttgcact aaacgccttc ctgagtacac agcccgccaa 9240 cgtgccgcgg ggacaggagg actacaccaa ctttgtgagc gcactgcggc taatggtgac 9300 tgagacaccg caaagtgagg tgtaccagtc tgggccagac tattttttcc agaccagtag 9360 acaaggcctg cagaccgtaa acctgagcca ggctttcaaa aacttgcagg ggctgtgggg 9420 ggtgcgggct cccacaggcg accgcgcgac cgtgtctagc ttgctgacgc ccaactcgcg 9480 cctgttgctg ctgctaatag cgcccttcac ggacagtggc agcgtgtccc gggacacata 9540 cctaggtcac ttgctgacac tgtaccgcga ggccataggt caggcgcatg tggacgagca 9600 tactttccag gagattacaa gtgtcagccg cgcgctgggg caggaggaca cgggcagcct 9660 ggaggcaacc ctaaactacc tgctgaccaa ccggcggcag aagatcccct cgttgcacag 9720 tttaaacagc gaggaggagc gcattttgcg ctacgtgcag cagagcgtga gccttaacct 9780 gatgcgcgac ggggtaacgc ccagcgtggc gctggacatg accgcgcgca acatggaacc 9840 gggcatgtat gcctcaaacc ggccgtttat caaccgccta atggactact tgcatcgcgc 9900 ggccgccgtg aaccccgagt atttcaccaa tgccatcttg aacccgcact ggctaccgcc 9960 ccctggtttc tacaccgggg gattcgaggt gcccgagggt aacgatggat tcctctggga 10020 cgacatagac gacagcgtgt tttccccgca accgcagacc ctgctagagt tgcaacagcg 10080 cgagcaggca gaggcggcgc tgcgaaagga aagcttccgc aggccaagca gcttgtccga 10140 tctaggcgct gcggccccgc ggtcagatgc tagtagccca tttccaagct tgatagggtc 10200 tcttaccagc actcgcacca cccgcccgcg cctgctgggc gaggaggagt acctaaacaa 10260 ctcgctgctg cagccgcagc gcgaaaaaaa cctgcctccg gcatttccca acaacgggat 10320 agagagccta gtggacaaga tgagtagatg gaagacgtac gcgcaggagc acagggacgt 10380 gccaggcccg cgcccgccca cccgtcgtca aaggcacgac cgtcagcggg gtctggtgtg 10440 ggaggacgat gactcggcag acgacagcag cgtcctggat ttgggaggga gtggcaaccc 10500 gtttgcgcac cttcgcccca ggctggggag aatgttttaa aaaaaaaaaa gcatgatgca 10560 aaataaaaaa ctcaccaagg ccatggcacc gagcgttggt tttcttgtat tccccttagt 10620 atgcggcgcg cggcgatgta tgaggaaggt cctcctccct cctacgagag tgtggtgagc 10680 gcggcgccag tggcggcggc gctgggttct cccttcgatg ctcccctgga cccgccgttt 10740 gtgcctccgc ggtacctgcg gcctaccggg gggagaaaca gcatccgtta ctctgagttg 10800 gcacccctat tcgacaccac ccgtgtgtac ctggtggaca acaagtcaac ggatgtggca 10860 tccctgaact accagaacga ccacagcaac tttctgacca cggtcattca aaacaatgac 10920 tacagcccgg gggaggcaag cacacagacc atcaatcttg acgaccggtc gcactggggc 10980 ggcgacctga aaaccatcct gcataccaac atgccaaatg tgaacgagtt catgtttacc 11040 aataagttta aggcgcgggt gatggtgtcg cgcttgccta ctaaggacaa tcaggtggag 11100 ctgaaatacg agtgggtgga gttcacgctg cccgagggca actactccga gaccatgacc 11160 atagacctta tgaacaacgc gatcgtggag cactacttga aagtgggcag acagaacggg 11220 gttctggaaa gcgacatcgg ggtaaagttt gacacccgca acttcagact ggggtttgac 11280 cccgtcactg gtcttgtcat gcctggggta tatacaaacg aagccttcca tccagacatc 11340 attttgctgc caggatgcgg ggtggacttc acccacagcc gcctgagcaa cttgttgggc 11400 atccgcaagc ggcaaccctt ccaggagggc tttaggatca cctacgatga tctggagggt 11460 ggtaacattc ccgcactgtt ggatgtggac gcctaccagg cgagcttgaa agatgacacc 11520 gaacagggcg ggggtggcgc aggcggcagc aacagcagtg gcagcggcgc ggaagagaac 11580 tccaacgcgg cagccgcggc aatgcagccg gtggaggaca tgaacgatca tgccattcgc 11640 ggcgacacct ttgccacacg ggctgaggag aagcgcgctg aggccgaagc agcggccgaa 11700 gctgccgccc ccgctgcgca acccgaggtc gagaagcctc agaagaaacc ggtgatcaaa 11760 cccctgacag aggacagcaa gaaacgcagt tacaacctaa taagcaatga cagcaccttc 11820 acccagtacc gcagctggta ccttgcatac aactacggcg accctcagac cggaatccgc 11880 tcatggaccc tgctttgcac tcctgacgta acctgcggct cggagcaggt ctactggtcg 11940 ttgccagaca tgatgcaaga ccccgtgacc ttccgctcca cgcgccagat cagcaacttt 12000 ccggtggtgg gcgccgagct gttgcccgtg cactccaaga gcttctacaa cgaccaggcc 12060 gtctactccc aactcatccg ccagtttacc tctctgaccc acgtgttcaa tcgctttccc 12120 gagaaccaga ttttggcgcg cccgccagcc cccaccatca ccaccgtcag tgaaaacgtt 12180 cctgctctca cagatcacgg gacgctaccg ctgcgcaaca gcatcggagg agtccagcga 12240 gtgaccatta ctgacgccag acgccgcacc tgcccctacg tttacaaggc cctgggcata 12300 gtctcgccgc gcgtcctatc gagccgcact ttttgagcaa gcatgtccat ccttatatcg 12360 cccagcaata acacaggctg gggcctgcgc ttcccaagca agatgtttgg cggggccaag 12420 aagcgctccg accaacaccc agtgcgcgtg cgcgggcact accgcgcgcc ctggggcgcg 12480 cacaaacgcg gccgcactgg gcgcaccacc gtcgatgacg ccatcgacgc ggtggtggag 12540 gaggcgcgca actacacgcc cacgccgcca ccagtgtcca cagtggacgc ggccattcag 12600 accgtggtgc gcggagcccg gcgctatgct aaaatgaaga gacggcggag gcgcgtagca 12660 cgtcgccacc gccgccgacc cggcactgcc gcccaacgcg cggcggcggc cctgcttaac 12720 cgcgcacgtc gcaccggccg acgggcggcc atgcgggccg ctcgaaggct ggccgcgggt 12780 attgtcactg tgccccccag gtccaggcga cgagcggccg ccgcagcagc cgcggccatt 12840 agtgctatga ctcagggtcg caggggcaac gtgtattggg tgcgcgactc ggttagcggc 12900 ctgcgcgtgc ccgtgcgcac ccgccccccg cgcaactaga ttgcaagaaa aaactactta 12960 gactcgtact gttgtatgta tccagcggcg gcggcgcgca acgaagctat gtccaagcgc 13020 aaaatcaaag aagagatgct ccaggtcatc gcgccggaga tctatggccc cccgaagaag 13080 gaagagcagg attacaagcc ccgaaagcta aagcgggtca aaaagaaaaa gaaagatgat 13140 gatgatgaac ttgacgacga ggtggaactg ctgcacgcta ccgcgcccag gcgacgggta 13200 cagtggaaag gtcgacgcgt aaaacgtgtt ttgcgacccg gcaccaccgt agtctttacg 13260 cccggtgagc gctccacccg cacctacaag cgcgtgtatg atgaggtgta cggcgacgag 13320 gacctgcttg agcaggccaa cgagcgcctc ggggagtttg cctacggaaa gcggcataag 13380 gacatgctgg cgttgccgct ggacgagggc aacccaacac ctagcctaaa gcccgtaaca 13440 ctgcagcagg tgctgcccgc gcttgcaccg tccgaagaaa agcgcggcct aaagcgcgag 13500 tctggtgact tggcacccac cgtgcagctg atggtaccca agcgccagcg actggaagat 13560 gtcttggaaa aaatgaccgt ggaacctggg ctggagcccg aggtccgcgt gcggccaatc 13620 aagcaggtgg cgccgggact gggcgtgcag accgtggacg ttcagatacc cactaccagt 13680 agcaccagta ttgccaccgc cacagagggc atggagacac aaacgtcccc ggttgcctca 13740 gcggtggcgg atgccgcggt gcaggcggtc gctgcggccg cgtccaagac ctctacggag 13800 gtgcaaacgg acccgtggat gtttcgcgtt tcagcccccc ggcgcccgcg cggttcgagg 13860 aagtacggcg ccgccagcgc gctactgccc gaatatgccc tacatccttc cattgcgcct 13920 acccccggct atcgtggcta cacctaccgc cccagaagac gagcaactac ccgacgccga 13980 accaccactg gaacccgccg ccgccgtcgc cgtcgccagc ccgtgctggc cccgatttcc 14040 gtgcgcaggg tggctcgcga aggaggcagg accctggtgc tgccaacagc gcgctaccac 14100 cccagcatcg tttaaaagcc ggtctttgtg gttcttgcag atatggccct cacctgccgc 14160 ctccgtttcc cggtgccggg attccgagga agaatgcacc gtaggagggg catggccggc 14220 cacggcctga cgggcggcat gcgtcgtgcg caccaccggc ggcggcgcgc gtcgcaccgt 14280 cgcatgcgcg gcggtatcct gcccctcctt attccactga tcgccgcggc gattggcgcc 14340 gtgcccggaa ttgcatccgt ggccttgcag gcgcagagac actgattaaa aacaagttgc 14400 atgtggaaaa atcaaaataa aaagtctgga ctctcacgct cgcttggtcc tgtaactatt 14460 ttgtagaatg gaagacatca actttgcgtc tctggccccg cgacacggct cgcgcccgtt 14520 catgggaaac tggcaagata tcggcaccag caatatgagc ggtggcgcct tcagctgggg 14580 ctcgctgtgg agcggcatta aaaatttcgg ttccaccgtt aagaactatg gcagcaaggc 14640 ctggaacagc agcacaggcc agatgctgag ggataagttg aaagagcaaa atttccaaca 14700 aaaggtggta gatggcctgg cctctggcat tagcggggtg gtggacctgg ccaaccaggc 14760 agtgcaaaat aagattaaca gtaagcttga tccccgccct cccgtagagg agcctccacc 14820 ggccgtggag acagtgtctc cagaggggcg tggcgaaaag cgtccgcgcc ccgacaggga 14880 agaaactctg gtgacgcaaa tagacgagcc tccctcgtac gaggaggcac taaagcaagg 14940 cctgcccacc acccgtccca tcgcgcccat ggctaccgga gtgctgggcc agcacacacc 15000 cgtaacgctg gacctgcctc cccccgccga cacccagcag aaacctgtgc tgccaggccc 15060 gaccgccgtt gttgtaaccc gtcctagccg cgcgtccctg cgccgcgccg ccagcggtcc 15120 gcgatcgttg cggcccgtag ccagtggcaa ctggcaaagc acactgaaca gcatcgtggg 15180 tctgggggtg caatccctga agcgccgacg atgcttctga atagctaacg tgtcgtatgt 15240 gtgtcatgta tgcgtccatg tcgccgccag aggagctgct gagccgccgc gcgcccgctt 15300 tccaagatgg ctaccccttc gatgatgccg cagtggtctt acatgcacat ctcgggccag 15360 gacgcctcgg agtacctgag ccccgggctg gtgcagtttg cccgcgccac cgagacgtac 15420 ttcagcctga ataacaagtt tagaaacccc acggtggcgc ctacgcacga cgtgaccaca 15480 gaccggtccc agcgtttgac gctgcggttc atccctgtgg accgtgagga tactgcgtac 15540 tcgtacaagg cgcggttcac cctagctgtg ggtgataacc gtgtgctgga catggcttcc 15600 acgtactttg acatccgcgg cgtgctggac aggggcccta cttttaagcc ctactctggc 15660 actgcctaca acgccctggc tcccaagggt gccccaaatc cttgcgaatg ggatgaagct 15720 gctactgctc ttgaaataaa cctagaagaa gaggacgatg acaacgaaga cgaagtagac 15780 gagcaagctg agcagcaaaa aactcacgta tttgggcagg cgccttattc tggtataaat 15840 attacaaagg agggtattca aataggtgtc gaaggtcaaa cacctaaata tgccgataaa 15900 acatttcaac ctgaacctca aataggagaa tctcagtggt acgaaactga aattaatcat 15960 gcagctggga gagtccttaa aaagactacc ccaatgaaac catgttacgg ttcatatgca 16020 aaacccacaa atgaaaatgg agggcaaggc attcttgtaa agcaacaaaa tggaaagcta 16080 gaaagtcaag tggaaatgca atttttctca actactgagg cgaccgcagg caatggtgat 16140 aacttgactc ctaaagtggt attgtacagt gaagatgtag atatagaaac cccagacact 16200 catatttctt acatgcccac tattaaggaa ggtaactcac gagaactaat gggccaacaa 16260 tctatgccca acaggcctaa ttacattgct tttagggaca attttattgg tctaatgtat 16320 tacaacagca cgggtaatat gggtgttctg gcgggccaag catcgcagtt gaatgctgtt 16380 gtagatttgc aagacagaaa cacagagctt tcataccagc ttttgcttga ttccattggt 16440 gatagaacca ggtacttttc tatgtggaat caggctgttg acagctatga tccagatgtt 16500 agaattattg aaaatcatgg aactgaagat gaacttccaa attactgctt tccactggga 16560 ggtgtgatta atacagagac tcttaccaag gtaaaaccta aaacaggtca ggaaaatgga 16620 tgggaaaaag atgctacaga attttcagat aaaaatgaaa taagagttgg aaataatttt 16680 gccatggaaa tcaatctaaa tgccaacctg tggagaaatt tcctgtactc caacatagcg 16740 ctgtatttgc ccgacaagct aaagtacagt ccttccaacg taaaaatttc tgataaccca 16800 aacacctacg actacatgaa caagcgagtg gtggctcccg ggttagtgga ctgctacatt 16860 aaccttggag cacgctggtc ccttgactat atggacaacg tcaacccatt taaccaccac 16920 cgcaatgctg gcctgcgcta ccgctcaatg ttgctgggca atggtcgcta tgtgcccttc 16980 cacatccagg tgcctcagaa gttctttgcc attaaaaacc tccttctcct gccgggctca 17040 tacacctacg agtggaactt caggaaggat gttaacatgg ttctgcagag ctccctagga 17100 aatgacctaa gggttgacgg agccagcatt aagtttgata gcatttgcct ttacgccacc 17160 ttcttcccca tggcccacaa caccgcctcc acgcttgagg ccatgcttag aaacgacacc 17220 aacgaccagt cctttaacga ctatctctcc gccgccaaca tgctctaccc tatacccgcc 17280 aacgctacca acgtgcccat atccatcccc tcccgcaact gggcggcttt ccgcggctgg 17340 gccttcacgc gccttaagac taaggaaacc ccatcactgg gctcgggcta cgacccttat 17400 tacacctact ctggctctat accctaccta gatggaacct tttacctcaa ccacaccttt 17460 aagaaggtgg ccattacctt tgactcttct gtcagctggc ctggcaatga ccgcctgctt 17520 acccccaacg agtttgaaat taagcgctca gttgacgggg agggttacaa cgttgcccag 17580 tgtaacatga ccaaagactg gttcctggta caaatgctag ctaactacaa cattggctac 17640 cagggcttct atatcccaga gagctacaag gaccgcatgt actccttctt tagaaacttc 17700 cagcccatga gccgtcaggt ggtggatgat actaaataca aggactacca acaggtgggc 17760 atcctacacc aacacaacaa ctctggattt gttggctacc ttgcccccac catgcgcgaa 17820 ggacaggcct accctgctaa cttcccctat ccgcttatag gcaagaccgc agttgacagc 17880 attacccaga aaaagtttct ttgcgatcgc accctttggc gcatcccatt ctccagtaac 17940 tttatgtcca tgggcgcact cacagacctg ggccaaaacc ttctctacgc caactccgcc 18000 cacgcgctag acatgacttt tgaggtggat cccatggacg agcccaccct tctttatgtt 18060 ttgtttgaag tctttgacgt ggtccgtgtg caccggccgc accgcggcgt catcgaaacc 18120 gtgtacctgc gcacgccctt ctcggccggc aacgccacaa cataaagaag caagcaacat 18180 caacaacagc tgccgccatg ggctccagtg agcaggaact gaaagccatt gtcaaagatc 18240 ttggttgtgg gccatatttt ttgggcacct atgacaagcg ctttccaggc tttgtttctc 18300 cacacaagct cgcctgcgcc atagtcaata cggccggtcg cgagactggg ggcgtacact 18360 ggatggcctt tgcctggaac ccgcactcaa aaacatgcta cctctttgag ccctttggct 18420 tttctgacca gcgactcaag caggtttacc agtttgagta cgagtcactc ctgcgccgta 18480 gcgccattgc ttcttccccc gaccgctgta taacgctgga aaagtccacc caaagcgtac 18540 aggggcccaa ctcggccgcc tgtggactat tctgctgcat gtttctccac gcctttgcca 18600 actggcccca aactcccatg gatcacaacc ccaccatgaa ccttattacc ggggtaccca 18660 actccatgct caacagtccc caggtacagc ccaccctgcg tcgcaaccag gaacagctct 18720 acagcttcct ggagcgccac tcgccctact tccgcagcca cagtgcgcag attaggagcg 18780 ccacttcttt ttgtcacttg aaaaacatgt aaaaataatg tactagagac actttcaata 18840 aaggcaaatg cttttatttg tacactctcg ggtgattatt tacccccacc cttgccgtct 18900 gcgccgttta aaaatcaaag gggttctgcc gcgcatcgct atgcgccact ggcagggaca 18960 cgttgcgata ctggtgttta gtgctccact taaactcagg cacaaccatc cgcggcagct 19020 cggtgaagtt ttcactccac aggctgcgca ccatcaccaa cgcgtttagc aggtcgggcg 19080 ccgatatctt gaagtcgcag ttggggcctc cgccctgcgc gcgcgagttg cgatacacag 19140 ggttgcagca ctggaacact atcagcgccg ggtggtgcac gctggccagc acgctcttgt 19200 cggagatcag atccgcgtcc aggtcctccg cgttgctcag ggcgaacgga gtcaactttg 19260 gtagctgcct tcccaaaaag ggcgcgtgcc caggctttga gttgcactcg caccgtagtg 19320 gcatcaaaag gtgaccgtgc ccggtctggg cgttaggata cagcgcctgc ataaaagcct 19380 tgatctgctt aaaagccacc tgagcctttg cgccttcaga gaagaacatg ccgcaagact 19440 tgccggaaaa ctgattggcc ggacaggccg cgtcgtgcac gcagcacctt gcgtcggtgt 19500 tggagatctg caccacattt cggccccacc ggttcttcac gatcttggcc ttgctagact 19560 gctccttcag cgcgcgctgc ccgttttcgc tcgtcacatc catttcaatc acgtgctcct 19620 tatttatcat aatgcttccg tgtagacact taagctcgcc ttcgatctca gcgcagcggt 19680 gcagccacaa cgcgcagccc gtgggctcgt gatgcttgta ggtcacctct gcaaacgact 19740 gcaggtacgc ctgcaggaat cgccccatca tcgtcacaaa ggtcttgttg ctggtgaagg 19800 tcagctgcaa cccgcggtgc tcctcgttca gccaggtctt gcatacggcc gccagagctt 19860 ccacttggtc aggcagtagt ttgaagttcg cctttagatc gttatccacg tggtacttgt 19920 ccatcagcgc gcgcgcagcc tccatgccct tctcccacgc agacacgatc ggcacactca 19980 gcgggttcat caccgtaatt tcactttccg cttcgctggg ctcttcctct tcctcttgcg 20040 tccgcatacc acgcgccact gggtcgtctt cattcagccg ccgcactgtg cgcttacctc 20100 ctttgccatg cttgattagc accggtgggt tgctgaaacc caccatttgt agcgccacat 20160 cttctctttc ttcctcgctg tccacgatta cctctggtga tggcgggcgc tcgggcttgg 20220 gagaagggcg cttctttttc ttcttgggcg caatggccaa atccgccgcc gaggtcgatg 20280 gccgcgggct gggtgtgcgc ggcaccagcg cgtcttgtga tgagtcttcc tcgtcctcgg 20340 actcgatacg ccgcctcatc cgcttttttg ggggcgcccg gggaggcggc ggcgacgggg 20400 acggggacga cacgtcctcc atggttgggg gacgtcgcgc cgcaccgcgt ccgcgctcgg 20460 gggtggtttc gcgctgctcc tcttcccgac tggccatttc cttctcctat aggcagaaaa 20520 agatcatgga gtcagtcgag aagaaggaca gcctaaccgc cccctctgag ttcgccacca 20580 ccgcctccac cgatgccgcc aacgcgccta ccaccttccc cgtcgaggca cccccgcttg 20640 aggaggagga agtgattatc gagcaggacc caggttttgt aagcgaagac gacgaggacc 20700 gctcagtacc aacagaggat aaaaagcaag accaggacaa cgcagaggca aacgaggaac 20760 aagtcgggcg gggggacgaa aggcatggcg actacctaga tgtgggagac gacgtgctgt 20820 tgaagcatct gcagcgccag tgcgccatta tctgcgacgc gttgcaagag cgcagcgatg 20880 tgcccctcgc catagcggat gtcagccttg cctacgaacg ccacctattc tcaccgcgcg 20940 taccccccaa acgccaagaa aacggcacat gcgagcccaa cccgcgcctc aacttctacc 21000 ccgtatttgc cgtgccagag gtgcttgcca cctatcacat ctttttccaa aactgcaaga 21060 tacccctatc ctgccgtgcc aaccgcagcc gagcggacaa gcagctggcc ttgcggcagg 21120 gcgctgtcat acctgatatc gcctcgctca acgaagtgcc aaaaatcttt gagggtcttg 21180 gacgcgacga gaagcgcgcg gcaaacgctc tgcaacagga aaacagcgaa aatgaaagtc 21240 actctggagt gttggtggaa ctcgagggtg acaacgcgcg cctagccgta ctaaaacgca 21300 gcatcgaggt cacccacttt gcctacccgg cacttaacct accccccaag gtcatgagca 21360 cagtcatgag tgagctgatc gtgcgccgtg cgcagcccct ggagagggat gcaaatttgc 21420 aagaacaaac agaggagggc ctacccgcag ttggcgacga gcagctagcg cgctggcttc 21480 aaacgcgcga gcctgccgac ttggaggagc gacgcaaact aatgatggcc gcagtgctcg 21540 ttaccgtgga gcttgagtgc atgcagcggt tctttgctga cccggagatg cagcgcaagc 21600 tagaggaaac attgcactac acctttcgac agggctacgt acgccaggcc tgcaagatct 21660 ccaacgtgga gctctgcaac ctggtctcct accttggaat tttgcacgaa aaccgccttg 21720 ggcaaaacgt gcttcattcc acgctcaagg gcgaggcgcg ccgcgactac gtccgcgact 21780 gcgtttactt atttctatgc tacacctggc agacggccat gggcgtttgg cagcagtgct 21840 tggaggagtg caacctcaag gagctgcaga aactgctaaa gcaaaacttg aaggacctat 21900 ggacggcctt caacgagcgc tccgtggccg cgcacctggc ggacatcatt ttccccgaac 21960 gcctgcttaa aaccctgcaa cagggtctgc cagacttcac cagtcaaagc atgttgcaga 22020 actttaggaa ctttatccta gagcgctcag gaatcttgcc cgccacctgc tgtgcacttc 22080 ctagcgactt tgtgcccatt aagtaccgcg aatgccctcc gccgctttgg ggccactgct 22140 accttctgca gctagccaac taccttgcct accactctga cataatggaa gacgtgagcg 22200 gtgacggtct actggagtgt cactgtcgct gcaacctatg caccccgcac cgctccctgg 22260 tttgcaattc gcagctgctt aacgaaagtc aaattatcgg tacctttgag ctgcagggtc 22320 cctcgcctga cgaaaagtcc gcggctccgg ggttgaaact cactccgggg ctgtggacgt 22380 cggcttacct tcgcaaattt gtacctgagg actaccacgc ccacgagatt aggttctacg 22440 aagaccaatc ccgcccgcca aatgcggagc ttaccgcctg cgtcattacc cagggccaca 22500 ttcttggcca attgcaagcc atcaacaaag cccgccaaga gtttctgcta cgaaagggac 22560 ggggggttta cttggacccc cagtccggcg aggagctcaa cccaatcccc ccgccgccgc 22620 agccctatca gcagcagccg cgggcccttg cttcccagga tggcacccaa aaagaagctg 22680 cagctgccgc cgccacccac ggacgaggag gaatactggg acagtcaggc agaggaggtt 22740 ttggacgagg aggaggagga catgatggaa gactgggaga gcctagacga ggaagcttcc 22800 gaggtcgaag aggtgtcaga cgaaacaccg tcaccctcgg tcgcattccc ctcgccggcg 22860 ccccagaaat cggcaaccgg ttccagcatg gctacaacct ccgctcctca ggcgccgccg 22920 gcactgcccg ttcgccgacc caaccgtaga tgggacacca ctggaaccag ggccggtaag 22980 tccaagcagc cgccgccgtt agcccaagag caacaacagc gccaaggcta ccgctcatgg 23040 cgcgggcaca agaacgccat agttgcttgc ttgcaagact gtgggggcaa catctccttc 23100 gcccgccgct ttcttctcta ccatcacggc gtggccttcc cccgtaacat cctgcattac 23160 taccgtcatc tctacagccc atactgcacc ggcggcagcg gcagcggcag caacagcagc 23220 ggccacacag aagcaaaggc gaccggatag caagactctg acaaagccca agaaatccac 23280 agcggcggca gcagcaggag gaggagcgct gcgtctggcg cccaacgaac ccgtatcgac 23340 ccgcgagctt agaaacagga tttttcccac tctgtatgct atatttcaac agagcagggg 23400 ccaagaacaa gagctgaaaa taaaaaacag gtctctgcga tccctcaccc gcagctgcct 23460 gtatcacaaa agcgaagatc agcttcggcg cacgctggaa gacgcggagg ctctcttcag 23520 taaatactgc gcgctgactc ttaaggacta gtttcgcgcc ctttctcaaa tttaagcgcg 23580 aaaactacgt catctccagc ggccacaccc ggcgccagca cctgtcgtca gcgccattat 23640 gagcaaggaa attcccacgc cctacatgtg gagttaccag ccacaaatgg gacttgcggc 23700 tggagctgcc caagactact caacccgaat aaactacatg agcgcgggac cccacatgat 23760 atcccgggtc aacggaatcc gcgcccaccg aaaccgaatt ctcttggaac aggcggctat 23820 taccaccaca cctcgtaata accttaatcc ccgtagttgg cccgctgccc tggtgtacca 23880 ggaaagtccc gctcccacca ctgtggtact tcccagagac gcccaggccg aagttcagat 23940 gactaactca ggggcgcagc ttgcgggcgg ctttcgtcac agggtgcggt cgcccgggca 24000 gggtataact cacctgacaa tcagagggcg aggtattcag ctcaacgacg agtcggtgag 24060 ctcctcgctt ggtctccgtc cggacgggac atttcagatc ggcggcgccg gccgtccttc 24120 attcacgcct cgtcaggcaa tcctaactct gcagacctcg tcctctgagc cgcgctctgg 24180 aggcattgga actctgcaat ttattgagga gtttgtgcca tcggtctact ttaacccctt 24240 ctcgggacct cccggccact atccggatca atttattcct aactttgacg cggtaaagga 24300 ctcggcggac ggctacgact gaatgttaag tggagaggca gagcaactgc gcctgaaaca 24360 cctggtccac tgtcgccgcc acaagtgctt tgcccgcgac tccggtgagt tttgctactt 24420 tgaattgccc gaggatcata tcgagggccc ggcgcacggc gtccggctta ccgcccaggg 24480 agagcttgcc cgtagcctga ttcgggagtt tacccagcgc cccctgctag ttgagcggga 24540 caggggaccc tgtgttctca ctgtgatttg caactgtcct aaccttggat tacatcaaga 24600 tcctctagtt ataactagag tacccgggga tcttattccc tttaactaat aaaaaaaaat 24660 aataaagcat cacttactta aaatcagtta gcaaatttct gtccagttta ttcagcagca 24720 cctccttgcc ctcctcccag ctctggtatt gcagcttcct cctggctgca aactttctcc 24780 acaatctaaa tggaatgtca gtttcctcct gttcctgtcc atccgcaccc actatcttca 24840 tgttgttgca gatgaagcgc gcaagaccgt ctgaagatac cttcaacccc gtgtatccat 24900 atgacacgga aaccggtcct ccaactgtgc cttttcttac tcctcccttt gtatccccca 24960 atgggtttca agagagtccc cctggggtac tctctttgcg cctatccgaa cctctagtta 25020 cctccaatgg catgcttgcg ctcaaaatgg gcaacggcct ctctctggac gaggccggca 25080 accttacctc ccaaaatgta accactgtga gcccacctct caaaaaaacc aagtcaaaca 25140 taaacctgga aatatctgca cccctcacag ttacctcaga agccctaact gtggctgccg 25200 ccgcacctct aatggtcgcg ggcaacacac tcaccatgca atcacaggcc ccgctaaccg 25260 tgcacgactc caaacttagc attgccaccc aaggacccct cacagtgtca gaaggaaagc 25320 tagccctgca aacatcaggc cccctcacca ccaccgatag cagtaccctt actatcactg 25380 cctcaccccc tctaactact gccactggta gcttgggcat tgacttgaaa gagcccattt 25440 atacacaaaa tggaaaacta ggactaaagt acggggctcc tttgcatgta acagacgacc 25500 taaacacttt gaccgtagca actggtccag gtgtgactat taataatact tccttgcaaa 25560 ctaaagttac tggagccttg ggttttgatt cacaaggcaa tatgcaactt aatgtagcag 25620 gaggactaag gattgattct caaaacagac gccttatact tgatgttagt tatccgtttg 25680 atgctcaaaa ccaactaaat ctaagactag gacagggccc tctttttata aactcagccc 25740 acaacttgga tattaactac aacaaaggcc tttacttgtt tacagcttca aacaattcca 25800 aaaagcttga ggttaaccta agcactgcca aggggttgat gtttgacgct acagccatag 25860 ccattaatgc aggagatggg cttgaatttg gttcacctaa tgcaccaaac acaaatcccc 25920 tcaaaacaaa aattggccat ggcctagaat ttgattcaaa caaggctatg gttcctaaac 25980 taggaactgg ccttagtttt gacagcacag gtgccattac agtaggaaac aaaaataatg 26040 ataagctaac tttgtggacc acaccagctc catctcctaa ctgtagacta aatgcagaga 26100 aagatgctaa actcactttg gtcttaacaa aatgtggcag tcaaatactt gctacagttt 26160 cagttttggc tgttaaaggc agtttggctc caatatctgg aacagttcaa agtgctcatc 26220 ttattataag atttgacgaa aatggagtgc tactaaacaa ttccttcctg gacccagaat 26280 attggaactt tagaaatgga gatcttactg aaggcacagc ctatacaaac gctgttggat 26340 ttatgcctaa cctatcagct tatccaaaat ctcacggtaa aactgccaaa agtaacattg 26400 tcagtcaagt ttacttaaac ggagacaaaa ctaaacctgt aacactaacc attacactaa 26460 acggtacaca ggaaacagga gacacaactc caagtgcata ctctatgtca ttttcatggg 26520 actggtctgg ccacaactac attaatgaaa tatttgccac atcctcttac actttttcat 26580 acattgccca agaataaaga atcgtttgtg ttatgtttca acgtgtttat ttttcaattg 26640 cagaaaattt caagtcattt ttcattcagt agtatagccc caccaccaca tagcttatac 26700 agatcaccgt accttaatca aactcacaga accctagtat tcaacctgcc acctccctcc 26760 caacacacag agtacacagt cctttctccc cggctggcct taaaaagcat catatcatgg 26820 gtaacagaca tattcttagg tgttatattc cacacggttt cctgtcgagc caaacgctca 26880 tcagtgatat taataaactc cccgggcagc tcacttaagt tcatgtcgct gtccagctgc 26940 tgagccacag gctgctgtcc aacttgcggt tgcttaacgg gcggcgaagg agaagtccac 27000 gcctacatgg gggtagagtc ataatcgtgc atcaggatag ggcggtggtg ctgcagcagc 27060 gcgcgaataa actgctgccg ccgccgctcc gtcctgcagg aatacaacat ggcagtggtc 27120 tcctcagcga tgattcgcac cgcccgcagc ataaggcgcc ttgtcctccg ggcacagcag 27180 cgcaccctga tctcacttaa atcagcacag taactgcagc acagcaccac aatattgttc 27240 aaaatcccac agtgcaaggc gctgtatcca aagctcatgg cggggaccac agaacccacg 27300 tggccatcat accacaagcg caggtagatt aagtggcgac ccctcataaa cacgctggac 27360 ataaacatta cctcttttgg catgttgtaa ttcaccacct cccggtacca tataaacctc 27420 tgattaaaca tggcgccatc caccaccatc ctaaaccagc tggccaaaac ctgcccgccg 27480 gctatacact gcagggaacc gggactggaa caatgacagt ggagagccca ggactcgtaa 27540 ccatggatca tcatgctcgt catgatatca atgttggcac aacacaggca cacgtgcata 27600 cacttcctca ggattacaag ctcctcccgc gttagaacca tatcccaggg aacaacccat 27660 tcctgaatca gcgtaaatcc cacactgcag ggaagacctc gcacgtaact cacgttgtgc 27720 attgtcaaag tgttacattc gggcagcagc ggatgatcct ccagtatggt agcgcgggtt 27780 tctgtctcaa aaggaggtag acgatcccta ctgtacggag tgcgccgaga caaccgagat 27840 cgtgttggtc gtagtgtcat gccaaatgga acgccggacg tagtcatatt tcctgaagca 27900 aaaccaggtg cgggcgtgac aaacagatct gcgtctccgg tctcgccgct tagatcgctc 27960 tgtgtagtag ttgtagtata tccactctct caaagcatcc aggcgccccc tggcttcggg 28020 ttctatgtaa actccttcat gcgccgctgc cctgataaca tccaccaccg cagaataagc 28080 cacacccagc caacctacac attcgttctg cgagtcacac acgggaggag cgggaagagc 28140 tggaagaacc atgttttttt ttttattcca aaagattatc caaaacctca aaatgaagat 28200 ctattaagtg aacgcgctcc cctccggtgg cgtggtcaaa ctctacagcc aaagaacaga 28260 taatggcatt tgtaagatgt tgcacaatgg cttccaaaag gcaaacggcc ctcacgtcca 28320 agtggacgta aaggctaaac ccttcagggt gaatctcctc tataaacatt ccagcacctt 28380 caaccatgcc caaataattc tcatctcgcc accttctcaa tatatctcta agcaaatccc 28440 gaatattaag tccggccatt gtaaaaatct gctccagagc gccctccacc ttcagcctca 28500 agcagcgaat catgattgca aaaattcagg ttcctcacag acctgtataa gattcaaaag 28560 cggaacatta acaaaaatac cgcgatcccg taggtccctt cgcagggcca gctgaacata 28620 atcgtgcagg tctgcacgga ccagcgcggc cacttccccg ccaggaacct tgacaaaaga 28680 acccacactg attatgacac gcatactcgg agctatgcta accagcgtag ccccgatgta 28740 agctttcaat agcttgttgc atgggcggcg atataaaatg caaggtgctg ctcaaaaaat 28800 caggcaaagc ctcgcgcaaa aaagaaagca catcgtagtc atgctcatgc agataaaggc 28860 aggtaagctc cggaaccacc acagaaaaag acaccatttt tctctcaaac atgtctgcgg 28920 gtttctgcat aaacacaaaa taaaataaca aaaaaacatt taaacattag aagcctgtct 28980 tacaacagga aaaacaaccc ttataagcat aagacggact acggccatgc cggcgtgacc 29040 gtaaaaaaac tggtcaccgt gattaaaaag caccaccgac agctcctcgg tcatgtccgg 29100 agtcataatg taagactcgg taaacacatc aggttgattc atcggtcagt gctaaaaagc 29160 gaccgaaata gcccggggga atacataccc gcaggcgtag agacaacatt acagccccca 29220 taggaggtat aacaaaatta ataggagaga aaaacacata aacacctgaa aaaccctcct 29280 gcctaggcaa aatagcaccc tcccgctcca gaacaacata cagcgcttca cagcggcagc 29340 ctaacagtca gccttaccag taaaaaagaa aacctattaa aaaaacacca ctcgacacgg 29400 caccagctca atcagtcaca gtgtaaaaaa gggccaagtg cagagcgagt atatatagga 29460 ctaaaaaatg acgtaacggt taaagtccac aaaaaacacc cagaaaaccg cacgcgaacc 29520 tacgcccaga aacgaaagcc aaaaaaccca caacttcctc aaatcgtcac ttccgttttc 29580 ccacgttacg taacttccca ttttaagaaa actacaattc ccaacacata caagttactc 29640 cgccctaaaa cctacgtcac ccgccccgtt cccacgcccc gcgccacgtc acaaactcca 29700 ccccctcatt atcatattgg cttcaatcca aaataaggta tattattgat gatgttaatt 29760 aacatgcatg gatccatatg cggtgtgaaa taccgcacag atgcgtaagg agaaaatacc 29820 gcatcaggcg ctcttccgct tcctcgctca ctgactcgct gcgctcggtc gttcggctgc 29880 ggcgagcggt atcagctcac tcaaaggcgg taatacggtt atccacagaa tcaggggata 29940 acgcaggaaa gaacatgtga gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg 30000 cgttgctggc gtttttccat aggctccgcc cccctgacga gcatcacaaa aatcgacgct 30060 caagtcagag gtggcgaaac ccgacaggac tataaagata ccaggcgttt ccccctggaa 30120 gctccctcgt gcgctctcct gttccgaccc tgccgcttac cggatacctg tccgcctttc 30180 tcccttcggg aagcgtggcg ctttctcata gctcacgctg taggtatctc agttcggtgt 30240 aggtcgttcg ctccaagctg ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg 30300 ccttatccgg taactatcgt cttgagtcca acccggtaag acacgactta tcgccactgg 30360 cagcagccac tggtaacagg attagcagag cgaggtatgt aggcggtgct acagagttct 30420 tgaagtggtg gcctaactac ggctacacta gaaggacagt atttggtatc tgcgctctgc 30480 tgaagccagt taccttcgga aaaagagttg gtagctcttg atccggcaaa caaaccaccg 30540 ctggtagcgg tggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc 30600 aagaagatcc tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt 30660 aagggatttt ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa 30720 aatgaagttt taaatcaatc taaagtatat atgagtaaac ttggtctgac agttaccaat 30780 gcttaatcag tgaggcacct atctcagcga tctgtctatt tcgttcatcc atagttgcct 30840 gactccccgt cgtgtagata actacgatac gggagggctt accatctggc cccagtgctg 30900 caatgatacc gcgagaccca cgctcaccgg ctccagattt atcagcaata aaccagccag 30960 ccggaagggc cgagcgcaga agtggtcctg caactttatc cgcctccatc cagtctatta 31020 attgttgccg ggaagctaga gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg 31080 ccattgctgc agccatgaga ttatcaaaaa ggatcttcac ctagatcctt ttcacgtaga 31140 aagccagtcc gcagaaacgg tgctgacccc ggatgaatgt cagctactgg gctatctgga 31200 caagggaaaa cgcaagcgca aagagaaagc aggtagcttg cagtgggctt acatggcgat 31260 agctagactg ggcggtttta tggacagcaa gcgaaccgga attgccagct ggggcgccct 31320 ctggtaaggt tgggaagccc tgcaaagtaa actggatggc tttctcgccg ccaaggatct 31380 gatggcgcag gggatcaagc tctgatcaag agacaggatg aggatcgttt cgcatgattg 31440 aacaagatgg attgcacgca ggttctccgg ccgcttgggt ggagaggcta ttcggctatg 31500 actgggcaca acagacaatc ggctgctctg atgccgccgt gttccggctg tcagcgcagg 31560 ggcgcccggt tctttttgtc aagaccgacc tgtccggtgc cctgaatgaa ctgcaagacg 31620 aggcagcgcg gctatcgtgg ctggccacga cgggcgttcc ttgcgcagct gtgctcgacg 31680 ttgtcactga agcgggaagg gactggctgc tattgggcga agtgccgggg caggatctcc 31740 tgtcatctca ccttgctcct gccgagaaag tatccatcat ggctgatgca atgcggcggc 31800 tgcatacgct tgatccggct acctgcccat tcgaccacca agcgaaacat cgcatcgagc 31860 gagcacgtac tcggatggaa gccggtcttg tcgatcagga tgatctggac gaagagcatc 31920 aggggctcgc gccagccgaa ctgttcgcca ggctcaaggc gagcatgccc gacggcgagg 31980 atctcgtcgt gacccatggc gatgcctgct tgccgaatat catggtggaa aatggccgct 32040 tttctggatt catcgactgt ggccggctgg gtgtggcgga ccgctatcag gacatagcgt 32100 tggctacccg tgatattgct gaagagcttg gcggcgaatg ggctgaccgc ttcctcgtgc 32160 tttacggtat cgccgctccc gattcgcagc gcatcgcctt ctatcgcctt cttgacgagt 32220 tcttctgaat tttgttaaaa tttttgttaa atcagctcat tttttaacca ataggccgaa 32280 atcggcaaca tcccttataa atcaaaagaa tagaccgcga tagggttgag tgttgttcca 32340 gtttggaaca agagtccact attaaagaac gtggactcca acgtcaaagg gcgaaaaacc 32400 gtctatcagg gcgatggccc actacgtgaa ccatcaccca aatcaagttt tttgcggtcg 32460 aggtgccgta aagctctaaa tcggaaccct aaagggagcc cccgatttag agcttgacgg 32520 ggaaagccgg cgaacgtggc gagaaaggaa gggaagaaag cgaaaggagc gggcgctagg 32580 gcgctggcaa gtgtagcggt cacgctgcgc gtaaccacca cacccgcgcg cttaatgcgc 32640 cgctacaggg cgcgtccatt cgccattcag gatcgaatta attcttaatt aacatcatca 32700 ataatatacc ttattttgga ttgaagccaa tatgataatg agggggtgga gtttgtgacg 32760 tggcgcgggg cgtgggaacg gggcgggtga cgtagtagtg tggcggaagt gtgatgttgc 32820 aagtgtggcg gaacacatgt aagcgacgga tgtggcaaaa gtgacgtttt tggtgtgcgc 32880 cggtgtacac aggaagtgac aattttcgcg cggttttagg cggatgttgt agtaaatttg 32940 ggcgtaaccg agtaagattt ggccattttc gcgggaaaac tgaataagag gaagtgaaat 33000 ctgaataatt ttgtgttact catagcgcgt aatactgcga tctatacatt gaatcaatat 33060 tggcaattag ccatattagt cattggttat atagcataaa tcaatattgg ctattggcca 33120 ttgcatacgt tgtatctata tcataatatg tacatttata ttggctcatg tccaatatga 33180 ccgccatgtt gacattgatt attgactagt ggcgcgccgt cgacgagctc tttggggagt 33240 cctaagaggg cagctggcaa tggacaccta gcagtccctt tgagacttat ttcagatgga 33300 gctgtagaaa gatgccatgg ctcacagtgc ctccctggga agggggcaga gggctgccca 33360 gtgaggcctc ttgcgagcag gaaatcacca gagacaagga aagaccagac cccaggatga 33420 cctcagttag gccttgcccg actgtcctca gagtcccatt ctctgtgtcc tggttctttt 33480 agaagatcat ggacctccag gtcatttcgt aaccggaatc tgcctgcggg gggttttgac 33540 aagctatggt atagtgtatg tgggggtact gacgaattgg aagatcatgg agaccccttc 33600 tcctcctcca tcattggtct gccacatccc tcccaggcga ctcacagcag agagaccttg 33660 gatgtatgta gggtgcttta aaactccagc tgagttacag tctctccttt ctgttttcac 33720 cttaaccttc cagggatgca aacccacgac aggtttagca gcagagtgga ggctggccat 33780 gaatctcaga gaaagtgctc actggaaagg ctggtttagc ccaggcctga tgtggaggca 33840 ctgagctgga cgttctagcg gggttgacac ccaacagttt acataggggg aggccacccc 33900 tcctgagcag tctcggtgac ttgaagagga agccgcttct tctgtaccaa cacagaagct 33960 ccagcgaacc cccagaatgc tggcagtgtg ggtgctatgt aaaagtattt acatagcttt 34020 gtagagtgag ccaagcccag tctgtttggg atgactcttc acagtgcctc gaatctgtca 34080 cacgtcttag taagcagagt cacagagttt ctgtcacatc atcctcctgc ctacagggaa 34140 gtaggccatg tccctgcccc ctactctgag cccagctgtg ggagccagcc ctgcccaatg 34200 ggctctctct gattggcttc tcactcactt ctaaactcca gtgagcaact tctctcggct 34260 cgttcaattg gcgtgaaggt ctgtgtcttg cagagaaggt tcttcacaac tgggataaag 34320 agatctgaac tgaaaaacca gaaagttaac tggtaagttt agtctttttg tcttttattt 34380 caggtcccgg atccggtggt ggtgcaaatc aaagaactgc tcctcagtgg atgttgcctt 34440 tacttctagg cctgtacgga agtgttactt ctgctctaaa agctgcggaa ttgtacccag 34500 gcctaggctt ttgcaaaaag cttcgaatcg cgaaaggcca gcacgttctt cgcgccgcgc 34560 tcgcacagcc tctgcagcac tcgggccacc agctccttca ggcaggacac ctggcggaag 34620 gagggggcgg cggggggcgg ccgtgcgtcc cagggcacgc acaccaggca ctgggccacc 34680 agcgcgcgga aagccgccgg gtccccgcgc tgcaccagcc gccagccctg gggccccagg 34740 cgccgcacga acgtggccag cggcagcacc tcgcggtagt ggctgcgcag cagggagcgc 34800 acggctaggc agcggggagc gcgcggcatc gcgggggtgg ccggggccag ggcttcccaa 34860 gcttcgtttt gcggcaggaa aagttatcag gcatgcacct ggtagctagt ctttaaacca 34920 atagattgca tcggtttaaa aggcaagacc gtcaaattgc gggaaagggg tcaacagccg 34980 ttcagtacca agtctcaggg gaaactttga gatggccttg caaagggtat ggtaataagc 35040 tgacggacat ggtcctaacc acgcagccaa gtcctaagtc aacagatctt ctgttgatat 35100 ggatgcagtt cacagactaa atgtcggtcg gggaagatgt attcttctca taagatatag 35160 tcggacctct ccttaatggg agctagcgga tgaagtgatg caacactgga gccgctggga 35220 actaatttgt atgcgaaagt atattgatta gttttggagt actcgcgaaa acgcccacca 35280 tggcttcgta cccctgccat caacacgcgt ctgcgttcga ccaggctgcg cgttctcgcg 35340 gccatagcaa ccgacgtacg gcgttgcgcc ctcgccggca gcaagaagcc acggaagtcc 35400 gcctggagca gaaaatgccc acgctactgc gggtttatat agacggtcct cacgggatgg 35460 ggaaaaccac caccacgcaa ctgctggtgg ccctgggttc gcgcgacgat atcgtctacg 35520 tacccgagcc gatgacttac tggcaggtgc tgggggcttc cgagacaatc gcgaacatct 35580 acaccacaca acaccgcctc gaccagggtg agatatcggc cggggacgcg gcggtggtaa 35640 tgacaagcgc ccagataaca atgggcatgc cttatgccgt gaccgacgcc gttctggctc 35700 ctcatatcgg gggggaggct gggagctcac atgccccgcc cccggccctc accctcatct 35760 tcgaccgcca tcccatcgcc gccctcctgt gctacccggc cgcgcgatac cttatgggca 35820 gcatgacccc ccaggccgtg ctggcgttcg tggccctcat cccgccgacc ttgcccggca 35880 caaacatcgt gttgggggcc cttccggagg acagacacat cgaccgcctg gccaaacgcc 35940 agcgccccgg cgagcggctt gacctggcta tgctggccgc gattcgccgc gtttacgggc 36000 tgcttgccaa tacggtgcgg tatctgcagg gcggcgggtc gtggtgggag gattggggac 36060 agctttcggg gacggccgtg ccgccccagg gtgccgagcc ccagagcaac gcgggcccac 36120 gaccccatat cggggacacg ttatttaccc tgtttcgggc ccccgagttg ctggccccca 36180 acggcgacct gtataacgtg tttgcctggg ccttggacgt cttggccaaa cgcctccgtc 36240 ccatgcacgt ctttatcctg gattacgacc aatcgcccgc cggctgccgg gacgccctgc 36300 tgcaacttac ctccgggatg gtccagaccc acgtcaccac cccaggctcc ataccgacga 36360 tctgcgacct ggcgcgcacg tttgcccggg agatggggga ggctaactga agcggccgca 36420 cctggtagct agtctttaaa ccaatagatt gcatcggttt aaaaggcaag accgtcaaat 36480 tgcgggaaag gggtcaacag ccgttcagta ccaagtctca ggggaaactt tgagatggcc 36540 ttgcaaaggg tatggtaata agctgacgga catggtccta accacgcagc caagtcctaa 36600 gtcaacagat cttctgttga tatggatgca gttcacagac taaatgtcgg tcggggaaga 36660 tgtattcttc tcataagata tagtcggacc tctccttaat gggagctagc ggatgaagtg 36720 atgcaacact ggagccgctg ggaactaatt tgtatgcgaa agtatattga ttagttttgg 36780 agtactcgcg aaaacgccca ccatggcttc gtacccctgc catcaacacg cgtctgcgtt 36840 cgaccaggct gcgcgttctc gcggccatag caaccgacgt acggcgttgc gccctcgccg 36900 gcagcaagaa gccacggaag tccgcctgga gcagaaaatg cccacgctac tgcgggttta 36960 tatagacggt cctcacggga tggggaaaac caccaccacg caactgctgg tggccctggg 37020 ttcgcgcgac gatatcgtct acgtacccga gccgatgact tactggcagg tgctgggggc 37080 ttccgagaca atcgcgaaca tctacaccac acaacaccgc ctcgaccagg gtgagatatc 37140 ggccggggac gcggcggtgg taatgacaag cgcccagata acaatgggca tgccttatgc 37200 cgtgaccgac gccgttctgg ctcctcatat cgggggggag gctgggagct cacatgcccc 37260 gcccccggcc ctcaccctca tcttcgaccg ccatcccatc gccgccctcc tgtgctaccc 37320 ggccgcgcga taccttatgg gcagcatgac cccccaggcc gtgctggcgt tcgtggccct 37380 catcccgccg accttgcccg gcacaaacat cgtgttgggg gcccttccgg aggacagaca 37440 catcgaccgc ctggccaaac gccagcgccc cggcgagcgg cttgacctgg ctatgctggc 37500 cgcgattcgc cgcgtttacg ggctgcttgc caatacggtg cggtatctgc agggcggcgg 37560 gtcgtggtgg gaggattggg gacagctttc ggggacggcc gtgccgcccc agggtgccga 37620 gccccagagc aacgcgggcc cacgacccca tatcggggac acgttattta ccctgtttcg 37680 ggcccccgag ttgctggccc ccaacggcga cctgtataac gtgtttgcct gggccttgga 37740 cgtcttggcc aaacgcctcc gtcccatgca cgtctttatc ctggattacg accaatcgcc 37800 cgccggctgc cgggacgccc tgctgcaact tacctccggg atggtccaga cccacgtcac 37860 caccccaggc tccataccga cgatctgcga cctggcgcgc acgtttgccc gggagatggg 37920 ggaggctaac tgaagcggcc gcgggtggca tccctgtgac ccctccccag tgcctctcct 37980 ggccctggaa gttgccactc cagtgcccac cagccttgtc ctaataaaat taagttgcat 38040 cattttgtct gactaggtgt ccttctataa tattatgggg tggagggggg tggtatggag 38100 caaggggcaa gttgggaaga caacctgtag ggcctgcggg gtctattggg aaccaagctg 38160 gagtgcagtg gcacaatctt ggctcactgc aatctccgcc tcctgggttc aagcgattct 38220 cctgcctcag cctcccgagt tgttgggatt ccaggcatgc atgaccaggc tcagctaatt 38280 tttgtttttt tggtagagac ggggtttcac catattggcc aggctggtct ccaactccta 38340 atctcaggtg atctacccac cttggcctcc caaattgctg ggattacagg cgtgaaccac 38400 tgctcccttc cctgtccttc tgattttaaa ataactatac cagcaggagg acgtccagac 38460 acagcatagg ctacctggcc atgcccaacc ggtgggacat ttgagttgct tgcttggcac 38520 tgtcctctca tgcgttgggt ccactcagta gatgcctgca ggctcagagg cacacaggag 38580 tttctgggct caccctgccc ccttccaacc cctcagttcc catcctccag cagctgtttg 38640 tgtgctgcct ctgaagtcca cactgaacaa acttcagcct actcatgtcc ctaaaatggg 38700 caaacattgc aagcagcaaa cagcaaacac acagccctcc ctgcctgctg accttggagc 38760 tggggcagag gtcagagacc tctctgggcc catgccacct ccaacatcca ctcgacccct 38820 tggaatttcg gtggagagga gcagaggttg tcctggcgtg gtttaggtag tgtgagaggg 38880 tccgggttca aaaccacttg ctgggtgggg agtcgtcagt aagtggctat gccccgaccc 38940 cgaagcctgt ttccccatct gtacaatgga aatgataaag acgcccatct gatagggttt 39000 ttgtggcaaa taaacatttg gtttttttgt tttgttttgt tttgtttttt gagatggagg 39060 tttgctctgt cgcccaggct ggagtgcagt gacacaatct catctcacca caaccttccc 39120 ctgcctcagc ctcccaagta gctgggatta caagcatgtg ccaccacacc tggctaattt 39180 tctattttta gtagagacgg gtttctccat gttggtcagc ctcagcctcc caagtaactg 39240 ggattacagg cctgtgccac cacacccggc taattttttc tatttttgac agggacgggg 39300 tttcaccatg ttggtcaggc tggtctagaa ctcctgacct caaatgatcc acccacctag 39360 gcctcccaaa gtgcacagat tacaggcgtg ggccaccgca cctggccaaa tttttaattt 39420 ttttctagag atagggtctt actgtgttgc ccaggctggt gtcaaactcc tgggctcaag 39480 cagatcctcc tgcctcagct tcccaaagtg gtgggattat aggtgtgagc cactgcgccc 39540 agtcagtagc cccctctttg cccctcactg agccctactg gatgttcttg gttgtgtgac 39600 agtttcccca tctattaaac agaaacccct atagcagagg ggaggatgag gttggaaaat 39660 caggagcatt gttattctat tcttgtggga tcggggaagc agacatctgg gtggatgttt 39720 ggggaatgct gggctcagtt gaggaagtag gggggcccct ggggcttaca gggactggaa 39780 gctctgagct ggccagaggg atgttgcaat cctgccaggg tcttgtctat gctgtccctt 39840 tcacaaccat ccccctaccg ccaggctgac acgtggttgt gggggcacaa ggccagccga 39900 actagagtct gaggctgggc tgaggacacc ctccccatca gctgccaggg tcactggcgg 39960 tcaaaggcag ctggtgggga aggaattgga ctccagccct gggggacgga tgtggtgatg 40020 gtgggaagca ggcttggtgc caggaggggc atcagagggt gaataagagc agatagagtg 40080 tttgggggag gtagccagcc aaagggggtg aggcccggtg gaagggaaga aggggcatac 40140 actcagagct ttgcagctga aggttttaat tttttgagat ggggtctcac tctgtctcac 40200 caggctggag tgcagtggcg caatcacagc tcactgcaga cgcgtgaatt cctcgagtct 40260 agaggagcat gcgcgtcggc gcgccttcga aggcgaaaga tcccaacgaa aagagagacc 40320 acatggtcct tcttgagttt gtaacagctg ctgggattac acatggcatg gatgaactgt 40380 acaactgagg atcccccgac ctcgacctct ggctaataaa ggaaatttat tttcattgca 40440 atagtgtgtt ggaatttttt gtgtctctca ctcggaagga catatgggag ggcaaatcat 40500 ttggtcgaga tccctcggag atcggatctg ggcgtgg 40537 <210> 46 <211> 40950 <212> DNA <213> Artificial Sequence <220> <223> Ad-PEPCK Ribozyme HSV-TK WPRE <400> 46 ttaagggtgg gaaagaatat ataaggtggg ggtcttatgt agttttgtat ctgttttgca 60 gcagccgccg ccgccatgag caccaactcg tttgatggaa gcattgtgag ctcatatttg 120 acaacgcgca tgcccccatg ggccggggtg cgtcagaatg tgatgggctc cagcattgat 180 ggtcgccccg tcctgcccgc aaactctact accttgacct acgagaccgt gtctggaacg 240 ccgttggaga ctgcagcctc cgccgccgct tcagccgctg cagccaccgc ccgcgggatt 300 gtgactgact ttgctttcct gagcccgctt gcaagcagtg cagcttcccg ttcatccgcc 360 cgcgatgaca agttgacggc tcttttggca caattggatt ctttgacccg ggaacttaat 420 gtcgtttctc agcagctgtt ggatctgcgc cagcaggttt ctgccctgaa ggcttcctcc 480 cctcccaatg cggtttaaaa cataaataaa aaaccagact ctgtttggat ttggatcaag 540 caagtgtctt gctgtcttta tttaggggtt ttgcgcgcgc ggtaggcccg ggaccagcgg 600 tctcggtcgt tgagggtcct gtgtattttt tccaggacgt ggtaaaggtg actctggatg 660 ttcagataca tgggcataag cccgtctctg gggtggaggt agcaccactg cagagcttca 720 tgctgcgggg tggtgttgta gatgatccag tcgtagcagg agcgctgggc gtggtgccta 780 aaaatgtctt tcagtagcaa gctgattgcc aggggcaggc ccttggtgta agtgtttaca 840 aagcggttaa gctgggatgg gtgcatacgt ggggatatga gatgcatctt ggactgtatt 900 tttaggttgg ctatgttccc agccatatcc ctccggggat tcatgttgtg cagaaccacc 960 agcacagtgt atccggtgca cttgggaaat ttgtcatgta gcttagaagg aaatgcgtgg 1020 aagaacttgg agacgccctt gtgacctcca agattttcca tgcattcgtc cataatgatg 1080 gcaatgggcc cacgggcggc ggcctgggcg aagatatttc tgggatcact aacgtcatag 1140 ttgtgttcca ggatgagatc gtcataggcc atttttacaa agcgcgggcg gagggtgcca 1200 gactgcggta taatggttcc atccggccca ggggcgtagt taccctcaca gatttgcatt 1260 tcccacgctt tgagttcaga tggggggatc atgtctacct gcggggcgat gaagaaaacg 1320 gtttccgggg taggggagat cagctgggaa gaaagcaggt tcctgagcag ctgcgactta 1380 ccgcagccgg tgggcccgta aatcacacct attaccgggt gcaactggta gttaagagag 1440 ctgcagctgc cgtcatccct gagcaggggg gccacttcgt taagcatgtc cctgactcgc 1500 atgttttccc tgaccaaatc cgccagaagg cgctcgccgc ccagcgatag cagttcttgc 1560 aaggaagcaa agtttttcaa cggtttgaga ccgtccgccg taggcatgct tttgagcgtt 1620 tgaccaagca gttccaggcg gtcccacagc tcggtcacct gctctacggc atctcgatcc 1680 agcatatctc ctcgtttcgc gggttggggc ggctttcgct gtacggcagt agtcggtgct 1740 cgtccagacg ggccagggtc atgtctttcc acgggcgcag ggtcctcgtc agcgtagtct 1800 gggtcacggt gaaggggtgc gctccgggct gcgcgctggc cagggtgcgc ttgaggctgg 1860 tcctgctggt gctgaagcgc tgccggtctt cgccctgcgc gtcggccagg tagcatttga 1920 ccatggtgtc atagtccagc ccctccgcgg cgtggccctt ggcgcgcagc ttgcccttgg 1980 aggaggcgcc gcacgagggg cagtgcagac ttttgagggc gtagagcttg ggcgcgagaa 2040 ataccgattc cggggagtag gcatccgcgc cgcaggcccc gcagacggtc tcgcattcca 2100 cgagccaggt gagctctggc cgttcggggt caaaaaccag gtttccccca tgctttttga 2160 tgcgtttctt acctctggtt tccatgagcc ggtgtccacg ctcggtgacg aaaaggctgt 2220 ccgtgtcccc gtatacagac ttgagaggcc tgtcctcgag cggtgttccg cggtcctcct 2280 cgtatagaaa ctcggaccac tctgagacaa aggctcgcgt ccaggccagc acgaaggagg 2340 ctaagtggga ggggtagcgg tcgttgtcca ctagggggtc cactcgctcc agggtgtgaa 2400 gacacatgtc gccctcttcg gcatcaagga aggtgattgg tttgtaggtg taggccacgt 2460 gaccgggtgt tcctgaaggg gggctataaa agggggtggg ggcgcgttcg tcctcactct 2520 cttccgcatc gctgtctgcg agggccagct gttggggtga gtactccctc tgaaaagcgg 2580 gcatgacttc tgcgctaaga ttgtcagttt ccaaaaacga ggaggatttg atattcacct 2640 ggcccgcggt gatgcctttg agggtggccg catccatctg gtcagaaaag acaatctttt 2700 tgttgtcaag cttggtggca aacgacccgt agagggcgtt ggacagcaac ttggcgatgg 2760 agcgcagggt ttggtttttg tcgcgatcgg cgcgctcctt ggccgcgatg tttagctgca 2820 cgtattcgcg cgcaacgcac cgccattcgg gaaagacggt ggtgcgctcg tcgggcacca 2880 ggtgcacgcg ccaaccgcgg ttgtgcaggg tgacaaggtc aacgctggtg gctacctctc 2940 cgcgtaggcg ctcgttggtc cagcagaggc ggccgccctt gcgcgagcag aatggcggta 3000 gggggtctag ctgcgtctcg tccggggggt ctgcgtccac ggtaaagacc ccgggcagca 3060 ggcgcgcgtc gaagtagtct atcttgcatc cttgcaagtc tagcgcctgc tgccatgcgc 3120 gggcggcaag cgcgcgctcg tatgggttga gtgggggacc ccatggcatg gggtgggtga 3180 gcgcggaggc gtacatgccg caaatgtcgt aaacgtagag gggctctctg agtattccaa 3240 gatatgtagg gtagcatctt ccaccgcgga tgctggcgcg cacgtaatcg tatagttcgt 3300 gcgagggagc gaggaggtcg ggaccgaggt tgctacgggc gggctgctct gctcggaaga 3360 ctatctgcct gaagatggca tgtgagttgg atgatatggt tggacgctgg aagacgttga 3420 agctggcgtc tgtgagacct accgcgtcac gcacgaagga ggcgtaggag tcgcgcagct 3480 tgttgaccag ctcggcggtg acctgcacgt ctagggcgca gtagtccagg gtttccttga 3540 tgatgtcata cttatcctgt cccttttttt tccacagctc gcggttgagg acaaactctt 3600 cgcggtcttt ccagtactct tggatcggaa acccgtcggc ctccgaacgg taagagccta 3660 gcatgtagaa ctggttgacg gcctggtagg cgcagcatcc cttttctacg ggtagcgcgt 3720 atgcctgcgc ggccttccgg agcgaggtgt gggtgagcgc aaaggtgtcc ctgaccatga 3780 ctttgaggta ctggtatttg aagtcagtgt cgtcgcatcc gccctgctcc cagagcaaaa 3840 agtccgtgcg ctttttggaa cgcggatttg gcagggcgaa ggtgacatcg ttgaagagta 3900 tctttcccgc gcgaggcata aagttgcgtg tgatgcggaa gggtcccggc acctcggaac 3960 ggttgttaat tacctgggcg gcgagcacga tctcgtcaaa gccgttgatg ttgtggccca 4020 caatgtaaag ttccaagaag cgcgggatgc ccttgatgga aggcaatttt ttaagttcct 4080 cgtaggtgag ctcttcaggg gagctgagcc cgtgctctga aagggcccag tctgcaagat 4140 gagggttgga agcgacgaat gagctccaca ggtcacgggc cattagcatt tgcaggtggt 4200 cgcgaaaggt cctaaactgg cgacctatgg ccattttttc tggggtgatg cagtagaagg 4260 taagcgggtc ttgttcccag cggtcccatc caaggttcgc ggctaggtct cgcgcggcag 4320 tcactagagg ctcatctccg ccgaacttca tgaccagcat gaagggcacg agctgcttcc 4380 caaaggcccc catccaagta taggtctcta catcgtaggt gacaaagaga cgctcggtgc 4440 gaggatgcga gccgatcggg aagaactgga tctcccgcca ccaattggag gagtggctat 4500 tgatgtggtg aaagtagaag tccctgcgac gggccgaaca ctcgtgctgg cttttgtaaa 4560 aacgtgcgca gtactggcag cggtgcacgg gctgtacatc ctgcacgagg ttgacctgac 4620 gaccgcgcac aaggaagcag agtgggaatt tgagcccctc gcctggcggg tttggctggt 4680 ggtcttctac ttcggctgct tgtccttgac cgtctggctg ctcgagggga gttacggtgg 4740 atcggaccac cacgccgcgc gagcccaaag tccagatgtc cgcgcgcggc ggtcggagct 4800 tgatgacaac atcgcgcaga tgggagctgt ccatggtctg gagctcccgc ggcgtcaggt 4860 caggcgggag ctcctgcagg tttacctcgc atagacgggt cagggcgcgg gctagatcca 4920 ggtgatacct aatttccagg ggctggttgg tggcggcgtc gatggcttgc aagaggccgc 4980 atccccgcgg cgcgactacg gtaccgcgcg gcgggcggtg ggccgcgggg gtgtccttgg 5040 atgatgcatc taaaagcggt gacgcgggcg agcccccgga ggtagggggg gctccggacc 5100 cgccgggaga gggggcaggg gcacgtcggc gccgcgcgcg ggcaggagct ggtgctgcgc 5160 gcgtaggttg ctggcgaacg cgacgacgcg gcggttgatc tcctgaatct ggcgcctctg 5220 cgtgaagacg acgggcccgg tgagcttgag cctgaaagag agttcgacag aatcaatttc 5280 ggtgtcgttg acggcggcct ggcgcaaaat ctcctgcacg tctcctgagt tgtcttgata 5340 ggcgatctcg gccatgaact gctcgatctc ttcctcctgg agatctccgc gtccggctcg 5400 ctccacggtg gcggcgaggt cgttggaaat gcgggccatg agctgcgaga aggcgttgag 5460 gcctccctcg ttccagacgc ggctgtagac cacgccccct tcggcatcgc gggcgcgcat 5520 gaccacctgc gcgagattga gctccacgtg ccgggcgaag acggcgtagt ttcgcaggcg 5580 ctgaaagagg tagttgaggg tggtggcggt gtgttctgcc acgaagaagt acataaccca 5640 gcgtcgcaac gtggattcgt tgatatcccc caaggcctca aggcgctcca tggcctcgta 5700 gaagtccacg gcgaagttga aaaactggga gttgcgcgcc gacacggtta actcctcctc 5760 cagaagacgg atgagctcgg cgacagtgtc gcgcacctcg cgctcaaagg ctacaggggc 5820 ctcttcttct tcttcaatct cctcttccat aagggcctcc ccttcttctt cttctggcgg 5880 cggtggggga ggggggacac ggcggcgacg acggcgcacc gggaggcggt cgacaaagcg 5940 ctcgatcatc tccccgcggc gacggcgcat ggtctcggtg acggcgcggc cgttctcgcg 6000 ggggcgcagt tggaagacgc cgcccgtcat gtcccggtta tgggttggcg gggggctgcc 6060 atgcggcagg gatacggcgc taacgatgca tctcaacaat tgttgtgtag gtactccgcc 6120 gccgagggac ctgagcgagt ccgcatcgac cggatcggaa aacctctcga gaaaggcgtc 6180 taaccagtca cagtcgcaag gtaggctgag caccgtggcg ggcggcagcg ggcggcggtc 6240 ggggttgttt ctggcggagg tgctgctgat gatgtaatta aagtaggcgg tcttgagacg 6300 gcggatggtc gacagaagca ccatgtcctt gggtccggcc tgctgaatgc gcaggcggtc 6360 ggccatgccc caggcttcgt tttgacatcg gcgcaggtct ttgtagtagt cttgcatgag 6420 cctttctacc ggcacttctt cttctccttc ctcttgtcct gcatctcttg catctatcgc 6480 tgcggcggcg gcggagtttg gccgtaggtg gcgccctctt cctcccatgc gtgtgacccc 6540 gaagcccctc atcggctgaa gcagggctag gtcggcgaca acgcgctcgg ctaatatggc 6600 ctgctgcacc tgcgtgaggg tagactggaa gtcatccatg tccacaaagc ggtggtatgc 6660 gcccgtgttg atggtgtaag tgcagttggc cataacggac cagttaacgg tctggtgacc 6720 cggctgcgag agctcggtgt acctgagacg cgagtaagcc ctcgagtcaa atacgtagtc 6780 gttgcaagtc cgcaccaggt actggtatcc caccaaaaag tgcggcggcg gctggcggta 6840 gaggggccag cgtagggtgg ccggggctcc gggggcgaga tcttccaaca taaggcgatg 6900 atatccgtag atgtacctgg acatccaggt gatgccggcg gcggtggtgg aggcgcgcgg 6960 aaagtcgcgg acgcggttcc agatgttgcg cagcggcaaa aagtgctcca tggtcgggac 7020 gctctggccg gtcaggcgcg cgcaatcgtt gacgctctac cgtgcaaaag gagagcctgt 7080 aagcgggcac tcttccgtgg tctggtggat aaattcgcaa gggtatcatg gcggacgacc 7140 ggggttcgag ccccgtatcc ggccgtccgc cgtgatccat gcggttaccg cccgcgtgtc 7200 gaacccaggt gtgcgacgtc agacaacggg ggagtgctcc ttttggcttc cttccaggcg 7260 cggcggctgc tgcgctagct tttttggcca ctggccgcgc gcagcgtaag cggttaggct 7320 ggaaagcgaa agcattaagt ggctcgctcc ctgtagccgg agggttattt tccaagggtt 7380 gagtcgcggg acccccggtt cgagtctcgg accggccgga ctgcggcgaa cgggggtttg 7440 cctccccgtc atgcaagacc ccgcttgcaa attcctccgg aaacagggac gagccccttt 7500 tttgcttttc ccagatgcat ccggtgctgc ggcagatgcg cccccctcct cagcagcggc 7560 aagagcaaga gcagcggcag acatgcaggg caccctcccc tcctcctacc gcgtcaggag 7620 gggcgacatc cgcggttgac gcggcagcag atggtgatta cgaacccccg cggcgccggg 7680 cccggcacta cctggacttg gaggagggcg agggcctggc gcggctagga gcgccctctc 7740 ctgagcggta cccaagggtg cagctgaagc gtgatacgcg tgaggcgtac gtgccgcggc 7800 agaacctgtt tcgcgaccgc gagggagagg agcccgagga gatgcgggat cgaaagttcc 7860 acgcagggcg cgagctgcgg catggcctga atcgcgagcg gttgctgcgc gaggaggact 7920 ttgagcccga cgcgcgaacc gggattagtc ccgcgcgcgc acacgtggcg gccgccgacc 7980 tggtaaccgc atacgagcag acggtgaacc aggagattaa ctttcaaaaa agctttaaca 8040 accacgtgcg tacgcttgtg gcgcgcgagg aggtggctat aggactgatg catctgtggg 8100 actttgtaag cgcgctggag caaaacccaa atagcaagcc gctcatggcg cagctgttcc 8160 ttatagtgca gcacagcagg gacaacgagg cattcaggga tgcgctgcta aacatagtag 8220 agcccgaggg ccgctggctg ctcgatttga taaacatcct gcagagcata gtggtgcagg 8280 agcgcagctt gagcctggct gacaaggtgg ccgccatcaa ctattccatg cttagcctgg 8340 gcaagtttta cgcccgcaag atataccata ccccttacgt tcccatagac aaggaggtaa 8400 agatcgaggg gttctacatg cgcatggcgc tgaaggtgct taccttgagc gacgacctgg 8460 gcgtttatcg caacgagcgc atccacaagg ccgtgagcgt gagccggcgg cgcgagctca 8520 gcgaccgcga gctgatgcac agcctgcaaa gggccctggc tggcacgggc agcggcgata 8580 gagaggccga gtcctacttt gacgcgggcg ctgacctgcg ctgggcccca agccgacgcg 8640 ccctggaggc agctggggcc ggacctgggc tggcggtggc acccgcgcgc gctggcaacg 8700 tcggcggcgt ggaggaatat gacgaggacg atgagtacga gccagaggac ggcgagtact 8760 aagcggtgat gtttctgatc agatgatgca agacgcaacg gacccggcgg tgcgggcggc 8820 gctgcagagc cagccgtccg gccttaactc cacggacgac tggcgccagg tcatggaccg 8880 catcatgtcg ctgactgcgc gcaatcctga cgcgttccgg cagcagccgc aggccaaccg 8940 gctctccgca attctggaag cggtggtccc ggcgcgcgca aaccccacgc acgagaaggt 9000 gctggcgatc gtaaacgcgc tggccgaaaa cagggccatc cggcccgacg aggccggcct 9060 ggtctacgac gcgctgcttc agcgcgtggc tcgttacaac agcggcaacg tgcagaccaa 9120 cctggaccgg ctggtggggg atgtgcgcga ggccgtggcg cagcgtgagc gcgcgcagca 9180 gcagggcaac ctgggctcca tggttgcact aaacgccttc ctgagtacac agcccgccaa 9240 cgtgccgcgg ggacaggagg actacaccaa ctttgtgagc gcactgcggc taatggtgac 9300 tgagacaccg caaagtgagg tgtaccagtc tgggccagac tattttttcc agaccagtag 9360 acaaggcctg cagaccgtaa acctgagcca ggctttcaaa aacttgcagg ggctgtgggg 9420 ggtgcgggct cccacaggcg accgcgcgac cgtgtctagc ttgctgacgc ccaactcgcg 9480 cctgttgctg ctgctaatag cgcccttcac ggacagtggc agcgtgtccc gggacacata 9540 cctaggtcac ttgctgacac tgtaccgcga ggccataggt caggcgcatg tggacgagca 9600 tactttccag gagattacaa gtgtcagccg cgcgctgggg caggaggaca cgggcagcct 9660 ggaggcaacc ctaaactacc tgctgaccaa ccggcggcag aagatcccct cgttgcacag 9720 tttaaacagc gaggaggagc gcattttgcg ctacgtgcag cagagcgtga gccttaacct 9780 gatgcgcgac ggggtaacgc ccagcgtggc gctggacatg accgcgcgca acatggaacc 9840 gggcatgtat gcctcaaacc ggccgtttat caaccgccta atggactact tgcatcgcgc 9900 ggccgccgtg aaccccgagt atttcaccaa tgccatcttg aacccgcact ggctaccgcc 9960 ccctggtttc tacaccgggg gattcgaggt gcccgagggt aacgatggat tcctctggga 10020 cgacatagac gacagcgtgt tttccccgca accgcagacc ctgctagagt tgcaacagcg 10080 cgagcaggca gaggcggcgc tgcgaaagga aagcttccgc aggccaagca gcttgtccga 10140 tctaggcgct gcggccccgc ggtcagatgc tagtagccca tttccaagct tgatagggtc 10200 tcttaccagc actcgcacca cccgcccgcg cctgctgggc gaggaggagt acctaaacaa 10260 ctcgctgctg cagccgcagc gcgaaaaaaa cctgcctccg gcatttccca acaacgggat 10320 agagagccta gtggacaaga tgagtagatg gaagacgtac gcgcaggagc acagggacgt 10380 gccaggcccg cgcccgccca cccgtcgtca aaggcacgac cgtcagcggg gtctggtgtg 10440 ggaggacgat gactcggcag acgacagcag cgtcctggat ttgggaggga gtggcaaccc 10500 gtttgcgcac cttcgcccca ggctggggag aatgttttaa aaaaaaaaaa gcatgatgca 10560 aaataaaaaa ctcaccaagg ccatggcacc gagcgttggt tttcttgtat tccccttagt 10620 atgcggcgcg cggcgatgta tgaggaaggt cctcctccct cctacgagag tgtggtgagc 10680 gcggcgccag tggcggcggc gctgggttct cccttcgatg ctcccctgga cccgccgttt 10740 gtgcctccgc ggtacctgcg gcctaccggg gggagaaaca gcatccgtta ctctgagttg 10800 gcacccctat tcgacaccac ccgtgtgtac ctggtggaca acaagtcaac ggatgtggca 10860 tccctgaact accagaacga ccacagcaac tttctgacca cggtcattca aaacaatgac 10920 tacagcccgg gggaggcaag cacacagacc atcaatcttg acgaccggtc gcactggggc 10980 ggcgacctga aaaccatcct gcataccaac atgccaaatg tgaacgagtt catgtttacc 11040 aataagttta aggcgcgggt gatggtgtcg cgcttgccta ctaaggacaa tcaggtggag 11100 ctgaaatacg agtgggtgga gttcacgctg cccgagggca actactccga gaccatgacc 11160 atagacctta tgaacaacgc gatcgtggag cactacttga aagtgggcag acagaacggg 11220 gttctggaaa gcgacatcgg ggtaaagttt gacacccgca acttcagact ggggtttgac 11280 cccgtcactg gtcttgtcat gcctggggta tatacaaacg aagccttcca tccagacatc 11340 attttgctgc caggatgcgg ggtggacttc acccacagcc gcctgagcaa cttgttgggc 11400 atccgcaagc ggcaaccctt ccaggagggc tttaggatca cctacgatga tctggagggt 11460 ggtaacattc ccgcactgtt ggatgtggac gcctaccagg cgagcttgaa agatgacacc 11520 gaacagggcg ggggtggcgc aggcggcagc aacagcagtg gcagcggcgc ggaagagaac 11580 tccaacgcgg cagccgcggc aatgcagccg gtggaggaca tgaacgatca tgccattcgc 11640 ggcgacacct ttgccacacg ggctgaggag aagcgcgctg aggccgaagc agcggccgaa 11700 gctgccgccc ccgctgcgca acccgaggtc gagaagcctc agaagaaacc ggtgatcaaa 11760 cccctgacag aggacagcaa gaaacgcagt tacaacctaa taagcaatga cagcaccttc 11820 acccagtacc gcagctggta ccttgcatac aactacggcg accctcagac cggaatccgc 11880 tcatggaccc tgctttgcac tcctgacgta acctgcggct cggagcaggt ctactggtcg 11940 ttgccagaca tgatgcaaga ccccgtgacc ttccgctcca cgcgccagat cagcaacttt 12000 ccggtggtgg gcgccgagct gttgcccgtg cactccaaga gcttctacaa cgaccaggcc 12060 gtctactccc aactcatccg ccagtttacc tctctgaccc acgtgttcaa tcgctttccc 12120 gagaaccaga ttttggcgcg cccgccagcc cccaccatca ccaccgtcag tgaaaacgtt 12180 cctgctctca cagatcacgg gacgctaccg ctgcgcaaca gcatcggagg agtccagcga 12240 gtgaccatta ctgacgccag acgccgcacc tgcccctacg tttacaaggc cctgggcata 12300 gtctcgccgc gcgtcctatc gagccgcact ttttgagcaa gcatgtccat ccttatatcg 12360 cccagcaata acacaggctg gggcctgcgc ttcccaagca agatgtttgg cggggccaag 12420 aagcgctccg accaacaccc agtgcgcgtg cgcgggcact accgcgcgcc ctggggcgcg 12480 cacaaacgcg gccgcactgg gcgcaccacc gtcgatgacg ccatcgacgc ggtggtggag 12540 gaggcgcgca actacacgcc cacgccgcca ccagtgtcca cagtggacgc ggccattcag 12600 accgtggtgc gcggagcccg gcgctatgct aaaatgaaga gacggcggag gcgcgtagca 12660 cgtcgccacc gccgccgacc cggcactgcc gcccaacgcg cggcggcggc cctgcttaac 12720 cgcgcacgtc gcaccggccg acgggcggcc atgcgggccg ctcgaaggct ggccgcgggt 12780 attgtcactg tgccccccag gtccaggcga cgagcggccg ccgcagcagc cgcggccatt 12840 agtgctatga ctcagggtcg caggggcaac gtgtattggg tgcgcgactc ggttagcggc 12900 ctgcgcgtgc ccgtgcgcac ccgccccccg cgcaactaga ttgcaagaaa aaactactta 12960 gactcgtact gttgtatgta tccagcggcg gcggcgcgca acgaagctat gtccaagcgc 13020 aaaatcaaag aagagatgct ccaggtcatc gcgccggaga tctatggccc cccgaagaag 13080 gaagagcagg attacaagcc ccgaaagcta aagcgggtca aaaagaaaaa gaaagatgat 13140 gatgatgaac ttgacgacga ggtggaactg ctgcacgcta ccgcgcccag gcgacgggta 13200 cagtggaaag gtcgacgcgt aaaacgtgtt ttgcgacccg gcaccaccgt agtctttacg 13260 cccggtgagc gctccacccg cacctacaag cgcgtgtatg atgaggtgta cggcgacgag 13320 gacctgcttg agcaggccaa cgagcgcctc ggggagtttg cctacggaaa gcggcataag 13380 gacatgctgg cgttgccgct ggacgagggc aacccaacac ctagcctaaa gcccgtaaca 13440 ctgcagcagg tgctgcccgc gcttgcaccg tccgaagaaa agcgcggcct aaagcgcgag 13500 tctggtgact tggcacccac cgtgcagctg atggtaccca agcgccagcg actggaagat 13560 gtcttggaaa aaatgaccgt ggaacctggg ctggagcccg aggtccgcgt gcggccaatc 13620 aagcaggtgg cgccgggact gggcgtgcag accgtggacg ttcagatacc cactaccagt 13680 agcaccagta ttgccaccgc cacagagggc atggagacac aaacgtcccc ggttgcctca 13740 gcggtggcgg atgccgcggt gcaggcggtc gctgcggccg cgtccaagac ctctacggag 13800 gtgcaaacgg acccgtggat gtttcgcgtt tcagcccccc ggcgcccgcg cggttcgagg 13860 aagtacggcg ccgccagcgc gctactgccc gaatatgccc tacatccttc cattgcgcct 13920 acccccggct atcgtggcta cacctaccgc cccagaagac gagcaactac ccgacgccga 13980 accaccactg gaacccgccg ccgccgtcgc cgtcgccagc ccgtgctggc cccgatttcc 14040 gtgcgcaggg tggctcgcga aggaggcagg accctggtgc tgccaacagc gcgctaccac 14100 cccagcatcg tttaaaagcc ggtctttgtg gttcttgcag atatggccct cacctgccgc 14160 ctccgtttcc cggtgccggg attccgagga agaatgcacc gtaggagggg catggccggc 14220 cacggcctga cgggcggcat gcgtcgtgcg caccaccggc ggcggcgcgc gtcgcaccgt 14280 cgcatgcgcg gcggtatcct gcccctcctt attccactga tcgccgcggc gattggcgcc 14340 gtgcccggaa ttgcatccgt ggccttgcag gcgcagagac actgattaaa aacaagttgc 14400 atgtggaaaa atcaaaataa aaagtctgga ctctcacgct cgcttggtcc tgtaactatt 14460 ttgtagaatg gaagacatca actttgcgtc tctggccccg cgacacggct cgcgcccgtt 14520 catgggaaac tggcaagata tcggcaccag caatatgagc ggtggcgcct tcagctgggg 14580 ctcgctgtgg agcggcatta aaaatttcgg ttccaccgtt aagaactatg gcagcaaggc 14640 ctggaacagc agcacaggcc agatgctgag ggataagttg aaagagcaaa atttccaaca 14700 aaaggtggta gatggcctgg cctctggcat tagcggggtg gtggacctgg ccaaccaggc 14760 agtgcaaaat aagattaaca gtaagcttga tccccgccct cccgtagagg agcctccacc 14820 ggccgtggag acagtgtctc cagaggggcg tggcgaaaag cgtccgcgcc ccgacaggga 14880 agaaactctg gtgacgcaaa tagacgagcc tccctcgtac gaggaggcac taaagcaagg 14940 cctgcccacc acccgtccca tcgcgcccat ggctaccgga gtgctgggcc agcacacacc 15000 cgtaacgctg gacctgcctc cccccgccga cacccagcag aaacctgtgc tgccaggccc 15060 gaccgccgtt gttgtaaccc gtcctagccg cgcgtccctg cgccgcgccg ccagcggtcc 15120 gcgatcgttg cggcccgtag ccagtggcaa ctggcaaagc acactgaaca gcatcgtggg 15180 tctgggggtg caatccctga agcgccgacg atgcttctga atagctaacg tgtcgtatgt 15240 gtgtcatgta tgcgtccatg tcgccgccag aggagctgct gagccgccgc gcgcccgctt 15300 tccaagatgg ctaccccttc gatgatgccg cagtggtctt acatgcacat ctcgggccag 15360 gacgcctcgg agtacctgag ccccgggctg gtgcagtttg cccgcgccac cgagacgtac 15420 ttcagcctga ataacaagtt tagaaacccc acggtggcgc ctacgcacga cgtgaccaca 15480 gaccggtccc agcgtttgac gctgcggttc atccctgtgg accgtgagga tactgcgtac 15540 tcgtacaagg cgcggttcac cctagctgtg ggtgataacc gtgtgctgga catggcttcc 15600 acgtactttg acatccgcgg cgtgctggac aggggcccta cttttaagcc ctactctggc 15660 actgcctaca acgccctggc tcccaagggt gccccaaatc cttgcgaatg ggatgaagct 15720 gctactgctc ttgaaataaa cctagaagaa gaggacgatg acaacgaaga cgaagtagac 15780 gagcaagctg agcagcaaaa aactcacgta tttgggcagg cgccttattc tggtataaat 15840 attacaaagg agggtattca aataggtgtc gaaggtcaaa cacctaaata tgccgataaa 15900 acatttcaac ctgaacctca aataggagaa tctcagtggt acgaaactga aattaatcat 15960 gcagctggga gagtccttaa aaagactacc ccaatgaaac catgttacgg ttcatatgca 16020 aaacccacaa atgaaaatgg agggcaaggc attcttgtaa agcaacaaaa tggaaagcta 16080 gaaagtcaag tggaaatgca atttttctca actactgagg cgaccgcagg caatggtgat 16140 aacttgactc ctaaagtggt attgtacagt gaagatgtag atatagaaac cccagacact 16200 catatttctt acatgcccac tattaaggaa ggtaactcac gagaactaat gggccaacaa 16260 tctatgccca acaggcctaa ttacattgct tttagggaca attttattgg tctaatgtat 16320 tacaacagca cgggtaatat gggtgttctg gcgggccaag catcgcagtt gaatgctgtt 16380 gtagatttgc aagacagaaa cacagagctt tcataccagc ttttgcttga ttccattggt 16440 gatagaacca ggtacttttc tatgtggaat caggctgttg acagctatga tccagatgtt 16500 agaattattg aaaatcatgg aactgaagat gaacttccaa attactgctt tccactggga 16560 ggtgtgatta atacagagac tcttaccaag gtaaaaccta aaacaggtca ggaaaatgga 16620 tgggaaaaag atgctacaga attttcagat aaaaatgaaa taagagttgg aaataatttt 16680 gccatggaaa tcaatctaaa tgccaacctg tggagaaatt tcctgtactc caacatagcg 16740 ctgtatttgc ccgacaagct aaagtacagt ccttccaacg taaaaatttc tgataaccca 16800 aacacctacg actacatgaa caagcgagtg gtggctcccg ggttagtgga ctgctacatt 16860 aaccttggag cacgctggtc ccttgactat atggacaacg tcaacccatt taaccaccac 16920 cgcaatgctg gcctgcgcta ccgctcaatg ttgctgggca atggtcgcta tgtgcccttc 16980 cacatccagg tgcctcagaa gttctttgcc attaaaaacc tccttctcct gccgggctca 17040 tacacctacg agtggaactt caggaaggat gttaacatgg ttctgcagag ctccctagga 17100 aatgacctaa gggttgacgg agccagcatt aagtttgata gcatttgcct ttacgccacc 17160 ttcttcccca tggcccacaa caccgcctcc acgcttgagg ccatgcttag aaacgacacc 17220 aacgaccagt cctttaacga ctatctctcc gccgccaaca tgctctaccc tatacccgcc 17280 aacgctacca acgtgcccat atccatcccc tcccgcaact gggcggcttt ccgcggctgg 17340 gccttcacgc gccttaagac taaggaaacc ccatcactgg gctcgggcta cgacccttat 17400 tacacctact ctggctctat accctaccta gatggaacct tttacctcaa ccacaccttt 17460 aagaaggtgg ccattacctt tgactcttct gtcagctggc ctggcaatga ccgcctgctt 17520 acccccaacg agtttgaaat taagcgctca gttgacgggg agggttacaa cgttgcccag 17580 tgtaacatga ccaaagactg gttcctggta caaatgctag ctaactacaa cattggctac 17640 cagggcttct atatcccaga gagctacaag gaccgcatgt actccttctt tagaaacttc 17700 cagcccatga gccgtcaggt ggtggatgat actaaataca aggactacca acaggtgggc 17760 atcctacacc aacacaacaa ctctggattt gttggctacc ttgcccccac catgcgcgaa 17820 ggacaggcct accctgctaa cttcccctat ccgcttatag gcaagaccgc agttgacagc 17880 attacccaga aaaagtttct ttgcgatcgc accctttggc gcatcccatt ctccagtaac 17940 tttatgtcca tgggcgcact cacagacctg ggccaaaacc ttctctacgc caactccgcc 18000 cacgcgctag acatgacttt tgaggtggat cccatggacg agcccaccct tctttatgtt 18060 ttgtttgaag tctttgacgt ggtccgtgtg caccggccgc accgcggcgt catcgaaacc 18120 gtgtacctgc gcacgccctt ctcggccggc aacgccacaa cataaagaag caagcaacat 18180 caacaacagc tgccgccatg ggctccagtg agcaggaact gaaagccatt gtcaaagatc 18240 ttggttgtgg gccatatttt ttgggcacct atgacaagcg ctttccaggc tttgtttctc 18300 cacacaagct cgcctgcgcc atagtcaata cggccggtcg cgagactggg ggcgtacact 18360 ggatggcctt tgcctggaac ccgcactcaa aaacatgcta cctctttgag ccctttggct 18420 tttctgacca gcgactcaag caggtttacc agtttgagta cgagtcactc ctgcgccgta 18480 gcgccattgc ttcttccccc gaccgctgta taacgctgga aaagtccacc caaagcgtac 18540 aggggcccaa ctcggccgcc tgtggactat tctgctgcat gtttctccac gcctttgcca 18600 actggcccca aactcccatg gatcacaacc ccaccatgaa ccttattacc ggggtaccca 18660 actccatgct caacagtccc caggtacagc ccaccctgcg tcgcaaccag gaacagctct 18720 acagcttcct ggagcgccac tcgccctact tccgcagcca cagtgcgcag attaggagcg 18780 ccacttcttt ttgtcacttg aaaaacatgt aaaaataatg tactagagac actttcaata 18840 aaggcaaatg cttttatttg tacactctcg ggtgattatt tacccccacc cttgccgtct 18900 gcgccgttta aaaatcaaag gggttctgcc gcgcatcgct atgcgccact ggcagggaca 18960 cgttgcgata ctggtgttta gtgctccact taaactcagg cacaaccatc cgcggcagct 19020 cggtgaagtt ttcactccac aggctgcgca ccatcaccaa cgcgtttagc aggtcgggcg 19080 ccgatatctt gaagtcgcag ttggggcctc cgccctgcgc gcgcgagttg cgatacacag 19140 ggttgcagca ctggaacact atcagcgccg ggtggtgcac gctggccagc acgctcttgt 19200 cggagatcag atccgcgtcc aggtcctccg cgttgctcag ggcgaacgga gtcaactttg 19260 gtagctgcct tcccaaaaag ggcgcgtgcc caggctttga gttgcactcg caccgtagtg 19320 gcatcaaaag gtgaccgtgc ccggtctggg cgttaggata cagcgcctgc ataaaagcct 19380 tgatctgctt aaaagccacc tgagcctttg cgccttcaga gaagaacatg ccgcaagact 19440 tgccggaaaa ctgattggcc ggacaggccg cgtcgtgcac gcagcacctt gcgtcggtgt 19500 tggagatctg caccacattt cggccccacc ggttcttcac gatcttggcc ttgctagact 19560 gctccttcag cgcgcgctgc ccgttttcgc tcgtcacatc catttcaatc acgtgctcct 19620 tatttatcat aatgcttccg tgtagacact taagctcgcc ttcgatctca gcgcagcggt 19680 gcagccacaa cgcgcagccc gtgggctcgt gatgcttgta ggtcacctct gcaaacgact 19740 gcaggtacgc ctgcaggaat cgccccatca tcgtcacaaa ggtcttgttg ctggtgaagg 19800 tcagctgcaa cccgcggtgc tcctcgttca gccaggtctt gcatacggcc gccagagctt 19860 ccacttggtc aggcagtagt ttgaagttcg cctttagatc gttatccacg tggtacttgt 19920 ccatcagcgc gcgcgcagcc tccatgccct tctcccacgc agacacgatc ggcacactca 19980 gcgggttcat caccgtaatt tcactttccg cttcgctggg ctcttcctct tcctcttgcg 20040 tccgcatacc acgcgccact gggtcgtctt cattcagccg ccgcactgtg cgcttacctc 20100 ctttgccatg cttgattagc accggtgggt tgctgaaacc caccatttgt agcgccacat 20160 cttctctttc ttcctcgctg tccacgatta cctctggtga tggcgggcgc tcgggcttgg 20220 gagaagggcg cttctttttc ttcttgggcg caatggccaa atccgccgcc gaggtcgatg 20280 gccgcgggct gggtgtgcgc ggcaccagcg cgtcttgtga tgagtcttcc tcgtcctcgg 20340 actcgatacg ccgcctcatc cgcttttttg ggggcgcccg gggaggcggc ggcgacgggg 20400 acggggacga cacgtcctcc atggttgggg gacgtcgcgc cgcaccgcgt ccgcgctcgg 20460 gggtggtttc gcgctgctcc tcttcccgac tggccatttc cttctcctat aggcagaaaa 20520 agatcatgga gtcagtcgag aagaaggaca gcctaaccgc cccctctgag ttcgccacca 20580 ccgcctccac cgatgccgcc aacgcgccta ccaccttccc cgtcgaggca cccccgcttg 20640 aggaggagga agtgattatc gagcaggacc caggttttgt aagcgaagac gacgaggacc 20700 gctcagtacc aacagaggat aaaaagcaag accaggacaa cgcagaggca aacgaggaac 20760 aagtcgggcg gggggacgaa aggcatggcg actacctaga tgtgggagac gacgtgctgt 20820 tgaagcatct gcagcgccag tgcgccatta tctgcgacgc gttgcaagag cgcagcgatg 20880 tgcccctcgc catagcggat gtcagccttg cctacgaacg ccacctattc tcaccgcgcg 20940 taccccccaa acgccaagaa aacggcacat gcgagcccaa cccgcgcctc aacttctacc 21000 ccgtatttgc cgtgccagag gtgcttgcca cctatcacat ctttttccaa aactgcaaga 21060 tacccctatc ctgccgtgcc aaccgcagcc gagcggacaa gcagctggcc ttgcggcagg 21120 gcgctgtcat acctgatatc gcctcgctca acgaagtgcc aaaaatcttt gagggtcttg 21180 gacgcgacga gaagcgcgcg gcaaacgctc tgcaacagga aaacagcgaa aatgaaagtc 21240 actctggagt gttggtggaa ctcgagggtg acaacgcgcg cctagccgta ctaaaacgca 21300 gcatcgaggt cacccacttt gcctacccgg cacttaacct accccccaag gtcatgagca 21360 cagtcatgag tgagctgatc gtgcgccgtg cgcagcccct ggagagggat gcaaatttgc 21420 aagaacaaac agaggagggc ctacccgcag ttggcgacga gcagctagcg cgctggcttc 21480 aaacgcgcga gcctgccgac ttggaggagc gacgcaaact aatgatggcc gcagtgctcg 21540 ttaccgtgga gcttgagtgc atgcagcggt tctttgctga cccggagatg cagcgcaagc 21600 tagaggaaac attgcactac acctttcgac agggctacgt acgccaggcc tgcaagatct 21660 ccaacgtgga gctctgcaac ctggtctcct accttggaat tttgcacgaa aaccgccttg 21720 ggcaaaacgt gcttcattcc acgctcaagg gcgaggcgcg ccgcgactac gtccgcgact 21780 gcgtttactt atttctatgc tacacctggc agacggccat gggcgtttgg cagcagtgct 21840 tggaggagtg caacctcaag gagctgcaga aactgctaaa gcaaaacttg aaggacctat 21900 ggacggcctt caacgagcgc tccgtggccg cgcacctggc ggacatcatt ttccccgaac 21960 gcctgcttaa aaccctgcaa cagggtctgc cagacttcac cagtcaaagc atgttgcaga 22020 actttaggaa ctttatccta gagcgctcag gaatcttgcc cgccacctgc tgtgcacttc 22080 ctagcgactt tgtgcccatt aagtaccgcg aatgccctcc gccgctttgg ggccactgct 22140 accttctgca gctagccaac taccttgcct accactctga cataatggaa gacgtgagcg 22200 gtgacggtct actggagtgt cactgtcgct gcaacctatg caccccgcac cgctccctgg 22260 tttgcaattc gcagctgctt aacgaaagtc aaattatcgg tacctttgag ctgcagggtc 22320 cctcgcctga cgaaaagtcc gcggctccgg ggttgaaact cactccgggg ctgtggacgt 22380 cggcttacct tcgcaaattt gtacctgagg actaccacgc ccacgagatt aggttctacg 22440 aagaccaatc ccgcccgcca aatgcggagc ttaccgcctg cgtcattacc cagggccaca 22500 ttcttggcca attgcaagcc atcaacaaag cccgccaaga gtttctgcta cgaaagggac 22560 ggggggttta cttggacccc cagtccggcg aggagctcaa cccaatcccc ccgccgccgc 22620 agccctatca gcagcagccg cgggcccttg cttcccagga tggcacccaa aaagaagctg 22680 cagctgccgc cgccacccac ggacgaggag gaatactggg acagtcaggc agaggaggtt 22740 ttggacgagg aggaggagga catgatggaa gactgggaga gcctagacga ggaagcttcc 22800 gaggtcgaag aggtgtcaga cgaaacaccg tcaccctcgg tcgcattccc ctcgccggcg 22860 ccccagaaat cggcaaccgg ttccagcatg gctacaacct ccgctcctca ggcgccgccg 22920 gcactgcccg ttcgccgacc caaccgtaga tgggacacca ctggaaccag ggccggtaag 22980 tccaagcagc cgccgccgtt agcccaagag caacaacagc gccaaggcta ccgctcatgg 23040 cgcgggcaca agaacgccat agttgcttgc ttgcaagact gtgggggcaa catctccttc 23100 gcccgccgct ttcttctcta ccatcacggc gtggccttcc cccgtaacat cctgcattac 23160 taccgtcatc tctacagccc atactgcacc ggcggcagcg gcagcggcag caacagcagc 23220 ggccacacag aagcaaaggc gaccggatag caagactctg acaaagccca agaaatccac 23280 agcggcggca gcagcaggag gaggagcgct gcgtctggcg cccaacgaac ccgtatcgac 23340 ccgcgagctt agaaacagga tttttcccac tctgtatgct atatttcaac agagcagggg 23400 ccaagaacaa gagctgaaaa taaaaaacag gtctctgcga tccctcaccc gcagctgcct 23460 gtatcacaaa agcgaagatc agcttcggcg cacgctggaa gacgcggagg ctctcttcag 23520 taaatactgc gcgctgactc ttaaggacta gtttcgcgcc ctttctcaaa tttaagcgcg 23580 aaaactacgt catctccagc ggccacaccc ggcgccagca cctgtcgtca gcgccattat 23640 gagcaaggaa attcccacgc cctacatgtg gagttaccag ccacaaatgg gacttgcggc 23700 tggagctgcc caagactact caacccgaat aaactacatg agcgcgggac cccacatgat 23760 atcccgggtc aacggaatcc gcgcccaccg aaaccgaatt ctcttggaac aggcggctat 23820 taccaccaca cctcgtaata accttaatcc ccgtagttgg cccgctgccc tggtgtacca 23880 ggaaagtccc gctcccacca ctgtggtact tcccagagac gcccaggccg aagttcagat 23940 gactaactca ggggcgcagc ttgcgggcgg ctttcgtcac agggtgcggt cgcccgggca 24000 gggtataact cacctgacaa tcagagggcg aggtattcag ctcaacgacg agtcggtgag 24060 ctcctcgctt ggtctccgtc cggacgggac atttcagatc ggcggcgccg gccgtccttc 24120 attcacgcct cgtcaggcaa tcctaactct gcagacctcg tcctctgagc cgcgctctgg 24180 aggcattgga actctgcaat ttattgagga gtttgtgcca tcggtctact ttaacccctt 24240 ctcgggacct cccggccact atccggatca atttattcct aactttgacg cggtaaagga 24300 ctcggcggac ggctacgact gaatgttaag tggagaggca gagcaactgc gcctgaaaca 24360 cctggtccac tgtcgccgcc acaagtgctt tgcccgcgac tccggtgagt tttgctactt 24420 tgaattgccc gaggatcata tcgagggccc ggcgcacggc gtccggctta ccgcccaggg 24480 agagcttgcc cgtagcctga ttcgggagtt tacccagcgc cccctgctag ttgagcggga 24540 caggggaccc tgtgttctca ctgtgatttg caactgtcct aaccttggat tacatcaaga 24600 tcctctagtt ataactagag tacccgggga tcttattccc tttaactaat aaaaaaaaat 24660 aataaagcat cacttactta aaatcagtta gcaaatttct gtccagttta ttcagcagca 24720 cctccttgcc ctcctcccag ctctggtatt gcagcttcct cctggctgca aactttctcc 24780 acaatctaaa tggaatgtca gtttcctcct gttcctgtcc atccgcaccc actatcttca 24840 tgttgttgca gatgaagcgc gcaagaccgt ctgaagatac cttcaacccc gtgtatccat 24900 atgacacgga aaccggtcct ccaactgtgc cttttcttac tcctcccttt gtatccccca 24960 atgggtttca agagagtccc cctggggtac tctctttgcg cctatccgaa cctctagtta 25020 cctccaatgg catgcttgcg ctcaaaatgg gcaacggcct ctctctggac gaggccggca 25080 accttacctc ccaaaatgta accactgtga gcccacctct caaaaaaacc aagtcaaaca 25140 taaacctgga aatatctgca cccctcacag ttacctcaga agccctaact gtggctgccg 25200 ccgcacctct aatggtcgcg ggcaacacac tcaccatgca atcacaggcc ccgctaaccg 25260 tgcacgactc caaacttagc attgccaccc aaggacccct cacagtgtca gaaggaaagc 25320 tagccctgca aacatcaggc cccctcacca ccaccgatag cagtaccctt actatcactg 25380 cctcaccccc tctaactact gccactggta gcttgggcat tgacttgaaa gagcccattt 25440 atacacaaaa tggaaaacta ggactaaagt acggggctcc tttgcatgta acagacgacc 25500 taaacacttt gaccgtagca actggtccag gtgtgactat taataatact tccttgcaaa 25560 ctaaagttac tggagccttg ggttttgatt cacaaggcaa tatgcaactt aatgtagcag 25620 gaggactaag gattgattct caaaacagac gccttatact tgatgttagt tatccgtttg 25680 atgctcaaaa ccaactaaat ctaagactag gacagggccc tctttttata aactcagccc 25740 acaacttgga tattaactac aacaaaggcc tttacttgtt tacagcttca aacaattcca 25800 aaaagcttga ggttaaccta agcactgcca aggggttgat gtttgacgct acagccatag 25860 ccattaatgc aggagatggg cttgaatttg gttcacctaa tgcaccaaac acaaatcccc 25920 tcaaaacaaa aattggccat ggcctagaat ttgattcaaa caaggctatg gttcctaaac 25980 taggaactgg ccttagtttt gacagcacag gtgccattac agtaggaaac aaaaataatg 26040 ataagctaac tttgtggacc acaccagctc catctcctaa ctgtagacta aatgcagaga 26100 aagatgctaa actcactttg gtcttaacaa aatgtggcag tcaaatactt gctacagttt 26160 cagttttggc tgttaaaggc agtttggctc caatatctgg aacagttcaa agtgctcatc 26220 ttattataag atttgacgaa aatggagtgc tactaaacaa ttccttcctg gacccagaat 26280 attggaactt tagaaatgga gatcttactg aaggcacagc ctatacaaac gctgttggat 26340 ttatgcctaa cctatcagct tatccaaaat ctcacggtaa aactgccaaa agtaacattg 26400 tcagtcaagt ttacttaaac ggagacaaaa ctaaacctgt aacactaacc attacactaa 26460 acggtacaca ggaaacagga gacacaactc caagtgcata ctctatgtca ttttcatggg 26520 actggtctgg ccacaactac attaatgaaa tatttgccac atcctcttac actttttcat 26580 acattgccca agaataaaga atcgtttgtg ttatgtttca acgtgtttat ttttcaattg 26640 cagaaaattt caagtcattt ttcattcagt agtatagccc caccaccaca tagcttatac 26700 agatcaccgt accttaatca aactcacaga accctagtat tcaacctgcc acctccctcc 26760 caacacacag agtacacagt cctttctccc cggctggcct taaaaagcat catatcatgg 26820 gtaacagaca tattcttagg tgttatattc cacacggttt cctgtcgagc caaacgctca 26880 tcagtgatat taataaactc cccgggcagc tcacttaagt tcatgtcgct gtccagctgc 26940 tgagccacag gctgctgtcc aacttgcggt tgcttaacgg gcggcgaagg agaagtccac 27000 gcctacatgg gggtagagtc ataatcgtgc atcaggatag ggcggtggtg ctgcagcagc 27060 gcgcgaataa actgctgccg ccgccgctcc gtcctgcagg aatacaacat ggcagtggtc 27120 tcctcagcga tgattcgcac cgcccgcagc ataaggcgcc ttgtcctccg ggcacagcag 27180 cgcaccctga tctcacttaa atcagcacag taactgcagc acagcaccac aatattgttc 27240 aaaatcccac agtgcaaggc gctgtatcca aagctcatgg cggggaccac agaacccacg 27300 tggccatcat accacaagcg caggtagatt aagtggcgac ccctcataaa cacgctggac 27360 ataaacatta cctcttttgg catgttgtaa ttcaccacct cccggtacca tataaacctc 27420 tgattaaaca tggcgccatc caccaccatc ctaaaccagc tggccaaaac ctgcccgccg 27480 gctatacact gcagggaacc gggactggaa caatgacagt ggagagccca ggactcgtaa 27540 ccatggatca tcatgctcgt catgatatca atgttggcac aacacaggca cacgtgcata 27600 cacttcctca ggattacaag ctcctcccgc gttagaacca tatcccaggg aacaacccat 27660 tcctgaatca gcgtaaatcc cacactgcag ggaagacctc gcacgtaact cacgttgtgc 27720 attgtcaaag tgttacattc gggcagcagc ggatgatcct ccagtatggt agcgcgggtt 27780 tctgtctcaa aaggaggtag acgatcccta ctgtacggag tgcgccgaga caaccgagat 27840 cgtgttggtc gtagtgtcat gccaaatgga acgccggacg tagtcatatt tcctgaagca 27900 aaaccaggtg cgggcgtgac aaacagatct gcgtctccgg tctcgccgct tagatcgctc 27960 tgtgtagtag ttgtagtata tccactctct caaagcatcc aggcgccccc tggcttcggg 28020 ttctatgtaa actccttcat gcgccgctgc cctgataaca tccaccaccg cagaataagc 28080 cacacccagc caacctacac attcgttctg cgagtcacac acgggaggag cgggaagagc 28140 tggaagaacc atgttttttt ttttattcca aaagattatc caaaacctca aaatgaagat 28200 ctattaagtg aacgcgctcc cctccggtgg cgtggtcaaa ctctacagcc aaagaacaga 28260 taatggcatt tgtaagatgt tgcacaatgg cttccaaaag gcaaacggcc ctcacgtcca 28320 agtggacgta aaggctaaac ccttcagggt gaatctcctc tataaacatt ccagcacctt 28380 caaccatgcc caaataattc tcatctcgcc accttctcaa tatatctcta agcaaatccc 28440 gaatattaag tccggccatt gtaaaaatct gctccagagc gccctccacc ttcagcctca 28500 agcagcgaat catgattgca aaaattcagg ttcctcacag acctgtataa gattcaaaag 28560 cggaacatta acaaaaatac cgcgatcccg taggtccctt cgcagggcca gctgaacata 28620 atcgtgcagg tctgcacgga ccagcgcggc cacttccccg ccaggaacct tgacaaaaga 28680 acccacactg attatgacac gcatactcgg agctatgcta accagcgtag ccccgatgta 28740 agctttcaat agcttgttgc atgggcggcg atataaaatg caaggtgctg ctcaaaaaat 28800 caggcaaagc ctcgcgcaaa aaagaaagca catcgtagtc atgctcatgc agataaaggc 28860 aggtaagctc cggaaccacc acagaaaaag acaccatttt tctctcaaac atgtctgcgg 28920 gtttctgcat aaacacaaaa taaaataaca aaaaaacatt taaacattag aagcctgtct 28980 tacaacagga aaaacaaccc ttataagcat aagacggact acggccatgc cggcgtgacc 29040 gtaaaaaaac tggtcaccgt gattaaaaag caccaccgac agctcctcgg tcatgtccgg 29100 agtcataatg taagactcgg taaacacatc aggttgattc atcggtcagt gctaaaaagc 29160 gaccgaaata gcccggggga atacataccc gcaggcgtag agacaacatt acagccccca 29220 taggaggtat aacaaaatta ataggagaga aaaacacata aacacctgaa aaaccctcct 29280 gcctaggcaa aatagcaccc tcccgctcca gaacaacata cagcgcttca cagcggcagc 29340 ctaacagtca gccttaccag taaaaaagaa aacctattaa aaaaacacca ctcgacacgg 29400 caccagctca atcagtcaca gtgtaaaaaa gggccaagtg cagagcgagt atatatagga 29460 ctaaaaaatg acgtaacggt taaagtccac aaaaaacacc cagaaaaccg cacgcgaacc 29520 tacgcccaga aacgaaagcc aaaaaaccca caacttcctc aaatcgtcac ttccgttttc 29580 ccacgttacg taacttccca ttttaagaaa actacaattc ccaacacata caagttactc 29640 cgccctaaaa cctacgtcac ccgccccgtt cccacgcccc gcgccacgtc acaaactcca 29700 ccccctcatt atcatattgg cttcaatcca aaataaggta tattattgat gatgttaatt 29760 aacatgcatg gatccatatg cggtgtgaaa taccgcacag atgcgtaagg agaaaatacc 29820 gcatcaggcg ctcttccgct tcctcgctca ctgactcgct gcgctcggtc gttcggctgc 29880 ggcgagcggt atcagctcac tcaaaggcgg taatacggtt atccacagaa tcaggggata 29940 acgcaggaaa gaacatgtga gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg 30000 cgttgctggc gtttttccat aggctccgcc cccctgacga gcatcacaaa aatcgacgct 30060 caagtcagag gtggcgaaac ccgacaggac tataaagata ccaggcgttt ccccctggaa 30120 gctccctcgt gcgctctcct gttccgaccc tgccgcttac cggatacctg tccgcctttc 30180 tcccttcggg aagcgtggcg ctttctcata gctcacgctg taggtatctc agttcggtgt 30240 aggtcgttcg ctccaagctg ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg 30300 ccttatccgg taactatcgt cttgagtcca acccggtaag acacgactta tcgccactgg 30360 cagcagccac tggtaacagg attagcagag cgaggtatgt aggcggtgct acagagttct 30420 tgaagtggtg gcctaactac ggctacacta gaaggacagt atttggtatc tgcgctctgc 30480 tgaagccagt taccttcgga aaaagagttg gtagctcttg atccggcaaa caaaccaccg 30540 ctggtagcgg tggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc 30600 aagaagatcc tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt 30660 aagggatttt ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa 30720 aatgaagttt taaatcaatc taaagtatat atgagtaaac ttggtctgac agttaccaat 30780 gcttaatcag tgaggcacct atctcagcga tctgtctatt tcgttcatcc atagttgcct 30840 gactccccgt cgtgtagata actacgatac gggagggctt accatctggc cccagtgctg 30900 caatgatacc gcgagaccca cgctcaccgg ctccagattt atcagcaata aaccagccag 30960 ccggaagggc cgagcgcaga agtggtcctg caactttatc cgcctccatc cagtctatta 31020 attgttgccg ggaagctaga gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg 31080 ccattgctgc agccatgaga ttatcaaaaa ggatcttcac ctagatcctt ttcacgtaga 31140 aagccagtcc gcagaaacgg tgctgacccc ggatgaatgt cagctactgg gctatctgga 31200 caagggaaaa cgcaagcgca aagagaaagc aggtagcttg cagtgggctt acatggcgat 31260 agctagactg ggcggtttta tggacagcaa gcgaaccgga attgccagct ggggcgccct 31320 ctggtaaggt tgggaagccc tgcaaagtaa actggatggc tttctcgccg ccaaggatct 31380 gatggcgcag gggatcaagc tctgatcaag agacaggatg aggatcgttt cgcatgattg 31440 aacaagatgg attgcacgca ggttctccgg ccgcttgggt ggagaggcta ttcggctatg 31500 actgggcaca acagacaatc ggctgctctg atgccgccgt gttccggctg tcagcgcagg 31560 ggcgcccggt tctttttgtc aagaccgacc tgtccggtgc cctgaatgaa ctgcaagacg 31620 aggcagcgcg gctatcgtgg ctggccacga cgggcgttcc ttgcgcagct gtgctcgacg 31680 ttgtcactga agcgggaagg gactggctgc tattgggcga agtgccgggg caggatctcc 31740 tgtcatctca ccttgctcct gccgagaaag tatccatcat ggctgatgca atgcggcggc 31800 tgcatacgct tgatccggct acctgcccat tcgaccacca agcgaaacat cgcatcgagc 31860 gagcacgtac tcggatggaa gccggtcttg tcgatcagga tgatctggac gaagagcatc 31920 aggggctcgc gccagccgaa ctgttcgcca ggctcaaggc gagcatgccc gacggcgagg 31980 atctcgtcgt gacccatggc gatgcctgct tgccgaatat catggtggaa aatggccgct 32040 tttctggatt catcgactgt ggccggctgg gtgtggcgga ccgctatcag gacatagcgt 32100 tggctacccg tgatattgct gaagagcttg gcggcgaatg ggctgaccgc ttcctcgtgc 32160 tttacggtat cgccgctccc gattcgcagc gcatcgcctt ctatcgcctt cttgacgagt 32220 tcttctgaat tttgttaaaa tttttgttaa atcagctcat tttttaacca ataggccgaa 32280 atcggcaaca tcccttataa atcaaaagaa tagaccgcga tagggttgag tgttgttcca 32340 gtttggaaca agagtccact attaaagaac gtggactcca acgtcaaagg gcgaaaaacc 32400 gtctatcagg gcgatggccc actacgtgaa ccatcaccca aatcaagttt tttgcggtcg 32460 aggtgccgta aagctctaaa tcggaaccct aaagggagcc cccgatttag agcttgacgg 32520 ggaaagccgg cgaacgtggc gagaaaggaa gggaagaaag cgaaaggagc gggcgctagg 32580 gcgctggcaa gtgtagcggt cacgctgcgc gtaaccacca cacccgcgcg cttaatgcgc 32640 cgctacaggg cgcgtccatt cgccattcag gatcgaatta attcttaatt aacatcatca 32700 ataatatacc ttattttgga ttgaagccaa tatgataatg agggggtgga gtttgtgacg 32760 tggcgcgggg cgtgggaacg gggcgggtga cgtagtagtg tggcggaagt gtgatgttgc 32820 aagtgtggcg gaacacatgt aagcgacgga tgtggcaaaa gtgacgtttt tggtgtgcgc 32880 cggtgtacac aggaagtgac aattttcgcg cggttttagg cggatgttgt agtaaatttg 32940 ggcgtaaccg agtaagattt ggccattttc gcgggaaaac tgaataagag gaagtgaaat 33000 ctgaataatt ttgtgttact catagcgcgt aatactgcga tctatacatt gaatcaatat 33060 tggcaattag ccatattagt cattggttat atagcataaa tcaatattgg ctattggcca 33120 ttgcatacgt tgtatctata tcataatatg tacatttata ttggctcatg tccaatatga 33180 ccgccatgtt gacattgatt attgactagt ggcgcgccgt cgacgagctc tttggggagt 33240 cctaagaggg cagctggcaa tggacaccta gcagtccctt tgagacttat ttcagatgga 33300 gctgtagaaa gatgccatgg ctcacagtgc ctccctggga agggggcaga gggctgccca 33360 gtgaggcctc ttgcgagcag gaaatcacca gagacaagga aagaccagac cccaggatga 33420 cctcagttag gccttgcccg actgtcctca gagtcccatt ctctgtgtcc tggttctttt 33480 agaagatcat ggacctccag gtcatttcgt aaccggaatc tgcctgcggg gggttttgac 33540 aagctatggt atagtgtatg tgggggtact gacgaattgg aagatcatgg agaccccttc 33600 tcctcctcca tcattggtct gccacatccc tcccaggcga ctcacagcag agagaccttg 33660 gatgtatgta gggtgcttta aaactccagc tgagttacag tctctccttt ctgttttcac 33720 cttaaccttc cagggatgca aacccacgac aggtttagca gcagagtgga ggctggccat 33780 gaatctcaga gaaagtgctc actggaaagg ctggtttagc ccaggcctga tgtggaggca 33840 ctgagctgga cgttctagcg gggttgacac ccaacagttt acataggggg aggccacccc 33900 tcctgagcag tctcggtgac ttgaagagga agccgcttct tctgtaccaa cacagaagct 33960 ccagcgaacc cccagaatgc tggcagtgtg ggtgctatgt aaaagtattt acatagcttt 34020 gtagagtgag ccaagcccag tctgtttggg atgactcttc acagtgcctc gaatctgtca 34080 cacgtcttag taagcagagt cacagagttt ctgtcacatc atcctcctgc ctacagggaa 34140 gtaggccatg tccctgcccc ctactctgag cccagctgtg ggagccagcc ctgcccaatg 34200 ggctctctct gattggcttc tcactcactt ctaaactcca gtgagcaact tctctcggct 34260 cgttcaattg gcgtgaaggt ctgtgtcttg cagagaaggt tcttcacaac tgggataaag 34320 agatctttgc aaaaagcttc gaatcgcgaa aggccagcac gttcttcgcg ccgcgctcgc 34380 acagcctctg cagcactcgg gccaccagct ccttcaggca ggacacctgg cggaaggagg 34440 gggcggcggg gggcggccgt gcgtcccagg gcacgcacac caggcactgg gccaccagcg 34500 cgcggaaagc cgccgggtcc ccgcgctgca ccagccgcca gccctggggc cccaggcgcc 34560 gcacgaacgt ggccagcggc agcacctcgc ggtagtggct gcgcagcagg gagcgcacgg 34620 ctaggcagcg gggagcgcgc ggcatcgcgg gggtggccgg ggccagggct tcccaagctt 34680 cgttttgcgg caggaaaagt tatcaggcat gcacctggta gctagtcttt aaaccaatag 34740 attgcatcgg tttaaaaggc aagaccgtca aattgcggga aaggggtcaa cagccgttca 34800 gtaccaagtc tcaggggaaa ctttgagatg gccttgcaaa gggtatggta ataagctgac 34860 ggacatggtc ctaaccacgc agccaagtcc taagtcaaca gatcttctgt tgatatggat 34920 gcagttcaca gactaaatgt cggtcgggga agatgtattc ttctcataag atatagtcgg 34980 acctctcctt aatgggagct agcggatgaa gtgatgcaac actggagccg ctgggaacta 35040 atttgtatgc gaaagtatat tgattagttt tggagtactc gcgaaaacgc ccaccatggc 35100 ttcgtacccc tgccatcaac acgcgtctgc gttcgaccag gctgcgcgtt ctcgcggcca 35160 tagcaaccga cgtacggcgt tgcgccctcg ccggcagcaa gaagccacgg aagtccgcct 35220 ggagcagaaa atgcccacgc tactgcgggt ttatatagac ggtcctcacg ggatggggaa 35280 aaccaccacc acgcaactgc tggtggccct gggttcgcgc gacgatatcg tctacgtacc 35340 cgagccgatg acttactggc aggtgctggg ggcttccgag acaatcgcga acatctacac 35400 cacacaacac cgcctcgacc agggtgagat atcggccggg gacgcggcgg tggtaatgac 35460 aagcgcccag ataacaatgg gcatgcctta tgccgtgacc gacgccgttc tggctcctca 35520 tatcgggggg gaggctggga gctcacatgc cccgcccccg gccctcaccc tcatcttcga 35580 ccgccatccc atcgccgccc tcctgtgcta cccggccgcg cgatacctta tgggcagcat 35640 gaccccccag gccgtgctgg cgttcgtggc cctcatcccg ccgaccttgc ccggcacaaa 35700 catcgtgttg ggggcccttc cggaggacag acacatcgac cgcctggcca aacgccagcg 35760 ccccggcgag cggcttgacc tggctatgct ggccgcgatt cgccgcgttt acgggctgct 35820 tgccaatacg gtgcggtatc tgcagggcgg cgggtcgtgg tgggaggatt ggggacagct 35880 ttcggggacg gccgtgccgc cccagggtgc cgagccccag agcaacgcgg gcccacgacc 35940 ccatatcggg gacacgttat ttaccctgtt tcgggccccc gagttgctgg cccccaacgg 36000 cgacctgtat aacgtgtttg cctgggcctt ggacgtcttg gccaaacgcc tccgtcccat 36060 gcacgtcttt atcctggatt acgaccaatc gcccgccggc tgccgggacg ccctgctgca 36120 acttacctcc gggatggtcc agacccacgt caccacccca ggctccatac cgacgatctg 36180 cgacctggcg cgcacgtttg cccgggagat gggggaggct aactgaagcg gccgcaatca 36240 acctctggat tacaaaattt gtgaaagatt gactggtatt cttaactatg ttgctccttt 36300 tacgctatgt ggatacgctg ctttaatgcc tttgtatcat gctattgctt cccgtatggc 36360 tttcattttc tcctccttgt ataaatcctg gttgctgtct ctttatgagg agttgtggcc 36420 cgttgtcagg caacgtggcg tggtgtgcac tgtgtttgct gacgcaaccc ccactggttg 36480 gggcattgcc accacctgtc agctcctttc cgggactttc gctttccccc tccctattgc 36540 cacggcggaa ctcatcgccg cctgccttgc ccgctgctgg acaggggctc ggctgttggg 36600 cactgacaat tccgtggtgt tgtcggggaa atcatcgtcc tttccttggc tgctcgcctg 36660 tgttgccacc tggattctgc gcgggacgtc cttctgctac gtcccttcgg ccctcaatcc 36720 agcggacctt ccttcccgcg gcctgctgcc ggctctgcgg cctcttccgc gtcttcgcct 36780 tcgccctcag acgagtcgga tctccctttg ggccgcctcc ccgcgcggcc gcacctggta 36840 gctagtcttt aaaccaatag attgcatcgg tttaaaaggc aagaccgtca aattgcggga 36900 aaggggtcaa cagccgttca gtaccaagtc tcaggggaaa ctttgagatg gccttgcaaa 36960 gggtatggta ataagctgac ggacatggtc ctaaccacgc agccaagtcc taagtcaaca 37020 gatcttctgt tgatatggat gcagttcaca gactaaatgt cggtcgggga agatgtattc 37080 ttctcataag atatagtcgg acctctcctt aatgggagct agcggatgaa gtgatgcaac 37140 actggagccg ctgggaacta atttgtatgc gaaagtatat tgattagttt tggagtactc 37200 gcgaaaacgc ccaccatggc ttcgtacccc tgccatcaac acgcgtctgc gttcgaccag 37260 gctgcgcgtt ctcgcggcca tagcaaccga cgtacggcgt tgcgccctcg ccggcagcaa 37320 gaagccacgg aagtccgcct ggagcagaaa atgcccacgc tactgcgggt ttatatagac 37380 ggtcctcacg ggatggggaa aaccaccacc acgcaactgc tggtggccct gggttcgcgc 37440 gacgatatcg tctacgtacc cgagccgatg acttactggc aggtgctggg ggcttccgag 37500 acaatcgcga acatctacac cacacaacac cgcctcgacc agggtgagat atcggccggg 37560 gacgcggcgg tggtaatgac aagcgcccag ataacaatgg gcatgcctta tgccgtgacc 37620 gacgccgttc tggctcctca tatcgggggg gaggctggga gctcacatgc cccgcccccg 37680 gccctcaccc tcatcttcga ccgccatccc atcgccgccc tcctgtgcta cccggccgcg 37740 cgatacctta tgggcagcat gaccccccag gccgtgctgg cgttcgtggc cctcatcccg 37800 ccgaccttgc ccggcacaaa catcgtgttg ggggcccttc cggaggacag acacatcgac 37860 cgcctggcca aacgccagcg ccccggcgag cggcttgacc tggctatgct ggccgcgatt 37920 cgccgcgttt acgggctgct tgccaatacg gtgcggtatc tgcagggcgg cgggtcgtgg 37980 tgggaggatt ggggacagct ttcggggacg gccgtgccgc cccagggtgc cgagccccag 38040 agcaacgcgg gcccacgacc ccatatcggg gacacgttat ttaccctgtt tcgggccccc 38100 gagttgctgg cccccaacgg cgacctgtat aacgtgtttg cctgggcctt ggacgtcttg 38160 gccaaacgcc tccgtcccat gcacgtcttt atcctggatt acgaccaatc gcccgccggc 38220 tgccgggacg ccctgctgca acttacctcc gggatggtcc agacccacgt caccacccca 38280 ggctccatac cgacgatctg cgacctggcg cgcacgtttg cccgggagat gggggaggct 38340 aactgaagcg gccgcgggtg gcatccctgt gacccctccc cagtgcctct cctggccctg 38400 gaagttgcca ctccagtgcc caccagcctt gtcctaataa aattaagttg catcattttg 38460 tctgactagg tgtccttcta taatattatg gggtggaggg gggtggtatg gagcaagggg 38520 caagttggga agacaacctg tagggcctgc ggggtctatt gggaaccaag ctggagtgca 38580 gtggcacaat cttggctcac tgcaatctcc gcctcctggg ttcaagcgat tctcctgcct 38640 cagcctcccg agttgttggg attccaggca tgcatgacca ggctcagcta atttttgttt 38700 ttttggtaga gacggggttt caccatattg gccaggctgg tctccaactc ctaatctcag 38760 gtgatctacc caccttggcc tcccaaattg ctgggattac aggcgtgaac cactgctccc 38820 ttccctgtcc ttctgatttt aaaataacta taccagcagg aggacgtcca gacacagcat 38880 aggctacctg gccatgccca accggtggga catttgagtt gcttgcttgg cactgtcctc 38940 tcatgcgttg ggtccactca gtagatgcct gcaggctcag aggcacacag gagtttctgg 39000 gctcaccctg cccccttcca acccctcagt tcccatcctc cagcagctgt ttgtgtgctg 39060 cctctgaagt ccacactgaa caaacttcag cctactcatg tccctaaaat gggcaaacat 39120 tgcaagcagc aaacagcaaa cacacagccc tccctgcctg ctgaccttgg agctggggca 39180 gaggtcagag acctctctgg gcccatgcca cctccaacat ccactcgacc ccttggaatt 39240 tcggtggaga ggagcagagg ttgtcctggc gtggtttagg tagtgtgaga gggtccgggt 39300 tcaaaaccac ttgctgggtg gggagtcgtc agtaagtggc tatgccccga ccccgaagcc 39360 tgtttcccca tctgtacaat ggaaatgata aagacgccca tctgataggg tttttgtggc 39420 aaataaacat ttggtttttt tgttttgttt tgttttgttt tttgagatgg aggtttgctc 39480 tgtcgcccag gctggagtgc agtgacacaa tctcatctca ccacaacctt cccctgcctc 39540 agcctcccaa gtagctggga ttacaagcat gtgccaccac acctggctaa ttttctattt 39600 ttagtagaga cgggtttctc catgttggtc agcctcagcc tcccaagtaa ctgggattac 39660 aggcctgtgc caccacaccc ggctaatttt ttctattttt gacagggacg gggtttcacc 39720 atgttggtca ggctggtcta gaactcctga cctcaaatga tccacccacc taggcctccc 39780 aaagtgcaca gattacaggc gtgggccacc gcacctggcc aaatttttaa tttttttcta 39840 gagatagggt cttactgtgt tgcccaggct ggtgtcaaac tcctgggctc aagcagatcc 39900 tcctgcctca gcttcccaaa gtggtgggat tataggtgtg agccactgcg cccagtcagt 39960 agccccctct ttgcccctca ctgagcccta ctggatgttc ttggttgtgt gacagtttcc 40020 ccatctatta aacagaaacc cctatagcag aggggaggat gaggttggaa aatcaggagc 40080 attgttattc tattcttgtg ggatcgggga agcagacatc tgggtggatg tttggggaat 40140 gctgggctca gttgaggaag taggggggcc cctggggctt acagggactg gaagctctga 40200 gctggccaga gggatgttgc aatcctgcca gggtcttgtc tatgctgtcc ctttcacaac 40260 catcccccta ccgccaggct gacacgtggt tgtgggggca caaggccagc cgaactagag 40320 tctgaggctg ggctgaggac accctcccca tcagctgcca gggtcactgg cggtcaaagg 40380 cagctggtgg ggaaggaatt ggactccagc cctgggggac ggatgtggtg atggtgggaa 40440 gcaggcttgg tgccaggagg ggcatcagag ggtgaataag agcagataga gtgtttgggg 40500 gaggtagcca gccaaagggg gtgaggcccg gtggaaggga agaaggggca tacactcaga 40560 gctttgcagc tgaaggtttt aattttttga gatggggtct cactctgtct caccaggctg 40620 gagtgcagtg gcgcaatcac agctcactgc agacgcgtga attcctcgag tctagaggag 40680 catgcgcgtc ggcgcgcctt cgaaggcgaa agatcccaac gaaaagagag accacatggt 40740 ccttcttgag tttgtaacag ctgctgggat tacacatggc atggatgaac tgtacaactg 40800 aggatccccc gacctcgacc tctggctaat aaaggaaatt tattttcatt gcaatagtgt 40860 gttggaattt tttgtgtctc tcactcggaa ggacatatgg gagggcaaat catttggtcg 40920 agatccctcg gagatcggat ctgggcgtgg 40950 <210> 47 <211> 41134 <212> DNA <213> Artificial Sequence <220> <223> Ad-PEPCK SD/SA Ribozyme HSV-TK WPRE <400> 47 ttaagggtgg gaaagaatat ataaggtggg ggtcttatgt agttttgtat ctgttttgca 60 gcagccgccg ccgccatgag caccaactcg tttgatggaa gcattgtgag ctcatatttg 120 acaacgcgca tgcccccatg ggccggggtg cgtcagaatg tgatgggctc cagcattgat 180 ggtcgccccg tcctgcccgc aaactctact accttgacct acgagaccgt gtctggaacg 240 ccgttggaga ctgcagcctc cgccgccgct tcagccgctg cagccaccgc ccgcgggatt 300 gtgactgact ttgctttcct gagcccgctt gcaagcagtg cagcttcccg ttcatccgcc 360 cgcgatgaca agttgacggc tcttttggca caattggatt ctttgacccg ggaacttaat 420 gtcgtttctc agcagctgtt ggatctgcgc cagcaggttt ctgccctgaa ggcttcctcc 480 cctcccaatg cggtttaaaa cataaataaa aaaccagact ctgtttggat ttggatcaag 540 caagtgtctt gctgtcttta tttaggggtt ttgcgcgcgc ggtaggcccg ggaccagcgg 600 tctcggtcgt tgagggtcct gtgtattttt tccaggacgt ggtaaaggtg actctggatg 660 ttcagataca tgggcataag cccgtctctg gggtggaggt agcaccactg cagagcttca 720 tgctgcgggg tggtgttgta gatgatccag tcgtagcagg agcgctgggc gtggtgccta 780 aaaatgtctt tcagtagcaa gctgattgcc aggggcaggc ccttggtgta agtgtttaca 840 aagcggttaa gctgggatgg gtgcatacgt ggggatatga gatgcatctt ggactgtatt 900 tttaggttgg ctatgttccc agccatatcc ctccggggat tcatgttgtg cagaaccacc 960 agcacagtgt atccggtgca cttgggaaat ttgtcatgta gcttagaagg aaatgcgtgg 1020 aagaacttgg agacgccctt gtgacctcca agattttcca tgcattcgtc cataatgatg 1080 gcaatgggcc cacgggcggc ggcctgggcg aagatatttc tgggatcact aacgtcatag 1140 ttgtgttcca ggatgagatc gtcataggcc atttttacaa agcgcgggcg gagggtgcca 1200 gactgcggta taatggttcc atccggccca ggggcgtagt taccctcaca gatttgcatt 1260 tcccacgctt tgagttcaga tggggggatc atgtctacct gcggggcgat gaagaaaacg 1320 gtttccgggg taggggagat cagctgggaa gaaagcaggt tcctgagcag ctgcgactta 1380 ccgcagccgg tgggcccgta aatcacacct attaccgggt gcaactggta gttaagagag 1440 ctgcagctgc cgtcatccct gagcaggggg gccacttcgt taagcatgtc cctgactcgc 1500 atgttttccc tgaccaaatc cgccagaagg cgctcgccgc ccagcgatag cagttcttgc 1560 aaggaagcaa agtttttcaa cggtttgaga ccgtccgccg taggcatgct tttgagcgtt 1620 tgaccaagca gttccaggcg gtcccacagc tcggtcacct gctctacggc atctcgatcc 1680 agcatatctc ctcgtttcgc gggttggggc ggctttcgct gtacggcagt agtcggtgct 1740 cgtccagacg ggccagggtc atgtctttcc acgggcgcag ggtcctcgtc agcgtagtct 1800 gggtcacggt gaaggggtgc gctccgggct gcgcgctggc cagggtgcgc ttgaggctgg 1860 tcctgctggt gctgaagcgc tgccggtctt cgccctgcgc gtcggccagg tagcatttga 1920 ccatggtgtc atagtccagc ccctccgcgg cgtggccctt ggcgcgcagc ttgcccttgg 1980 aggaggcgcc gcacgagggg cagtgcagac ttttgagggc gtagagcttg ggcgcgagaa 2040 ataccgattc cggggagtag gcatccgcgc cgcaggcccc gcagacggtc tcgcattcca 2100 cgagccaggt gagctctggc cgttcggggt caaaaaccag gtttccccca tgctttttga 2160 tgcgtttctt acctctggtt tccatgagcc ggtgtccacg ctcggtgacg aaaaggctgt 2220 ccgtgtcccc gtatacagac ttgagaggcc tgtcctcgag cggtgttccg cggtcctcct 2280 cgtatagaaa ctcggaccac tctgagacaa aggctcgcgt ccaggccagc acgaaggagg 2340 ctaagtggga ggggtagcgg tcgttgtcca ctagggggtc cactcgctcc agggtgtgaa 2400 gacacatgtc gccctcttcg gcatcaagga aggtgattgg tttgtaggtg taggccacgt 2460 gaccgggtgt tcctgaaggg gggctataaa agggggtggg ggcgcgttcg tcctcactct 2520 cttccgcatc gctgtctgcg agggccagct gttggggtga gtactccctc tgaaaagcgg 2580 gcatgacttc tgcgctaaga ttgtcagttt ccaaaaacga ggaggatttg atattcacct 2640 ggcccgcggt gatgcctttg agggtggccg catccatctg gtcagaaaag acaatctttt 2700 tgttgtcaag cttggtggca aacgacccgt agagggcgtt ggacagcaac ttggcgatgg 2760 agcgcagggt ttggtttttg tcgcgatcgg cgcgctcctt ggccgcgatg tttagctgca 2820 cgtattcgcg cgcaacgcac cgccattcgg gaaagacggt ggtgcgctcg tcgggcacca 2880 ggtgcacgcg ccaaccgcgg ttgtgcaggg tgacaaggtc aacgctggtg gctacctctc 2940 cgcgtaggcg ctcgttggtc cagcagaggc ggccgccctt gcgcgagcag aatggcggta 3000 gggggtctag ctgcgtctcg tccggggggt ctgcgtccac ggtaaagacc ccgggcagca 3060 ggcgcgcgtc gaagtagtct atcttgcatc cttgcaagtc tagcgcctgc tgccatgcgc 3120 gggcggcaag cgcgcgctcg tatgggttga gtgggggacc ccatggcatg gggtgggtga 3180 gcgcggaggc gtacatgccg caaatgtcgt aaacgtagag gggctctctg agtattccaa 3240 gatatgtagg gtagcatctt ccaccgcgga tgctggcgcg cacgtaatcg tatagttcgt 3300 gcgagggagc gaggaggtcg ggaccgaggt tgctacgggc gggctgctct gctcggaaga 3360 ctatctgcct gaagatggca tgtgagttgg atgatatggt tggacgctgg aagacgttga 3420 agctggcgtc tgtgagacct accgcgtcac gcacgaagga ggcgtaggag tcgcgcagct 3480 tgttgaccag ctcggcggtg acctgcacgt ctagggcgca gtagtccagg gtttccttga 3540 tgatgtcata cttatcctgt cccttttttt tccacagctc gcggttgagg acaaactctt 3600 cgcggtcttt ccagtactct tggatcggaa acccgtcggc ctccgaacgg taagagccta 3660 gcatgtagaa ctggttgacg gcctggtagg cgcagcatcc cttttctacg ggtagcgcgt 3720 atgcctgcgc ggccttccgg agcgaggtgt gggtgagcgc aaaggtgtcc ctgaccatga 3780 ctttgaggta ctggtatttg aagtcagtgt cgtcgcatcc gccctgctcc cagagcaaaa 3840 agtccgtgcg ctttttggaa cgcggatttg gcagggcgaa ggtgacatcg ttgaagagta 3900 tctttcccgc gcgaggcata aagttgcgtg tgatgcggaa gggtcccggc acctcggaac 3960 ggttgttaat tacctgggcg gcgagcacga tctcgtcaaa gccgttgatg ttgtggccca 4020 caatgtaaag ttccaagaag cgcgggatgc ccttgatgga aggcaatttt ttaagttcct 4080 cgtaggtgag ctcttcaggg gagctgagcc cgtgctctga aagggcccag tctgcaagat 4140 gagggttgga agcgacgaat gagctccaca ggtcacgggc cattagcatt tgcaggtggt 4200 cgcgaaaggt cctaaactgg cgacctatgg ccattttttc tggggtgatg cagtagaagg 4260 taagcgggtc ttgttcccag cggtcccatc caaggttcgc ggctaggtct cgcgcggcag 4320 tcactagagg ctcatctccg ccgaacttca tgaccagcat gaagggcacg agctgcttcc 4380 caaaggcccc catccaagta taggtctcta catcgtaggt gacaaagaga cgctcggtgc 4440 gaggatgcga gccgatcggg aagaactgga tctcccgcca ccaattggag gagtggctat 4500 tgatgtggtg aaagtagaag tccctgcgac gggccgaaca ctcgtgctgg cttttgtaaa 4560 aacgtgcgca gtactggcag cggtgcacgg gctgtacatc ctgcacgagg ttgacctgac 4620 gaccgcgcac aaggaagcag agtgggaatt tgagcccctc gcctggcggg tttggctggt 4680 ggtcttctac ttcggctgct tgtccttgac cgtctggctg ctcgagggga gttacggtgg 4740 atcggaccac cacgccgcgc gagcccaaag tccagatgtc cgcgcgcggc ggtcggagct 4800 tgatgacaac atcgcgcaga tgggagctgt ccatggtctg gagctcccgc ggcgtcaggt 4860 caggcgggag ctcctgcagg tttacctcgc atagacgggt cagggcgcgg gctagatcca 4920 ggtgatacct aatttccagg ggctggttgg tggcggcgtc gatggcttgc aagaggccgc 4980 atccccgcgg cgcgactacg gtaccgcgcg gcgggcggtg ggccgcgggg gtgtccttgg 5040 atgatgcatc taaaagcggt gacgcgggcg agcccccgga ggtagggggg gctccggacc 5100 cgccgggaga gggggcaggg gcacgtcggc gccgcgcgcg ggcaggagct ggtgctgcgc 5160 gcgtaggttg ctggcgaacg cgacgacgcg gcggttgatc tcctgaatct ggcgcctctg 5220 cgtgaagacg acgggcccgg tgagcttgag cctgaaagag agttcgacag aatcaatttc 5280 ggtgtcgttg acggcggcct ggcgcaaaat ctcctgcacg tctcctgagt tgtcttgata 5340 ggcgatctcg gccatgaact gctcgatctc ttcctcctgg agatctccgc gtccggctcg 5400 ctccacggtg gcggcgaggt cgttggaaat gcgggccatg agctgcgaga aggcgttgag 5460 gcctccctcg ttccagacgc ggctgtagac cacgccccct tcggcatcgc gggcgcgcat 5520 gaccacctgc gcgagattga gctccacgtg ccgggcgaag acggcgtagt ttcgcaggcg 5580 ctgaaagagg tagttgaggg tggtggcggt gtgttctgcc acgaagaagt acataaccca 5640 gcgtcgcaac gtggattcgt tgatatcccc caaggcctca aggcgctcca tggcctcgta 5700 gaagtccacg gcgaagttga aaaactggga gttgcgcgcc gacacggtta actcctcctc 5760 cagaagacgg atgagctcgg cgacagtgtc gcgcacctcg cgctcaaagg ctacaggggc 5820 ctcttcttct tcttcaatct cctcttccat aagggcctcc ccttcttctt cttctggcgg 5880 cggtggggga ggggggacac ggcggcgacg acggcgcacc gggaggcggt cgacaaagcg 5940 ctcgatcatc tccccgcggc gacggcgcat ggtctcggtg acggcgcggc cgttctcgcg 6000 ggggcgcagt tggaagacgc cgcccgtcat gtcccggtta tgggttggcg gggggctgcc 6060 atgcggcagg gatacggcgc taacgatgca tctcaacaat tgttgtgtag gtactccgcc 6120 gccgagggac ctgagcgagt ccgcatcgac cggatcggaa aacctctcga gaaaggcgtc 6180 taaccagtca cagtcgcaag gtaggctgag caccgtggcg ggcggcagcg ggcggcggtc 6240 ggggttgttt ctggcggagg tgctgctgat gatgtaatta aagtaggcgg tcttgagacg 6300 gcggatggtc gacagaagca ccatgtcctt gggtccggcc tgctgaatgc gcaggcggtc 6360 ggccatgccc caggcttcgt tttgacatcg gcgcaggtct ttgtagtagt cttgcatgag 6420 cctttctacc ggcacttctt cttctccttc ctcttgtcct gcatctcttg catctatcgc 6480 tgcggcggcg gcggagtttg gccgtaggtg gcgccctctt cctcccatgc gtgtgacccc 6540 gaagcccctc atcggctgaa gcagggctag gtcggcgaca acgcgctcgg ctaatatggc 6600 ctgctgcacc tgcgtgaggg tagactggaa gtcatccatg tccacaaagc ggtggtatgc 6660 gcccgtgttg atggtgtaag tgcagttggc cataacggac cagttaacgg tctggtgacc 6720 cggctgcgag agctcggtgt acctgagacg cgagtaagcc ctcgagtcaa atacgtagtc 6780 gttgcaagtc cgcaccaggt actggtatcc caccaaaaag tgcggcggcg gctggcggta 6840 gaggggccag cgtagggtgg ccggggctcc gggggcgaga tcttccaaca taaggcgatg 6900 atatccgtag atgtacctgg acatccaggt gatgccggcg gcggtggtgg aggcgcgcgg 6960 aaagtcgcgg acgcggttcc agatgttgcg cagcggcaaa aagtgctcca tggtcgggac 7020 gctctggccg gtcaggcgcg cgcaatcgtt gacgctctac cgtgcaaaag gagagcctgt 7080 aagcgggcac tcttccgtgg tctggtggat aaattcgcaa gggtatcatg gcggacgacc 7140 ggggttcgag ccccgtatcc ggccgtccgc cgtgatccat gcggttaccg cccgcgtgtc 7200 gaacccaggt gtgcgacgtc agacaacggg ggagtgctcc ttttggcttc cttccaggcg 7260 cggcggctgc tgcgctagct tttttggcca ctggccgcgc gcagcgtaag cggttaggct 7320 ggaaagcgaa agcattaagt ggctcgctcc ctgtagccgg agggttattt tccaagggtt 7380 gagtcgcggg acccccggtt cgagtctcgg accggccgga ctgcggcgaa cgggggtttg 7440 cctccccgtc atgcaagacc ccgcttgcaa attcctccgg aaacagggac gagccccttt 7500 tttgcttttc ccagatgcat ccggtgctgc ggcagatgcg cccccctcct cagcagcggc 7560 aagagcaaga gcagcggcag acatgcaggg caccctcccc tcctcctacc gcgtcaggag 7620 gggcgacatc cgcggttgac gcggcagcag atggtgatta cgaacccccg cggcgccggg 7680 cccggcacta cctggacttg gaggagggcg agggcctggc gcggctagga gcgccctctc 7740 ctgagcggta cccaagggtg cagctgaagc gtgatacgcg tgaggcgtac gtgccgcggc 7800 agaacctgtt tcgcgaccgc gagggagagg agcccgagga gatgcgggat cgaaagttcc 7860 acgcagggcg cgagctgcgg catggcctga atcgcgagcg gttgctgcgc gaggaggact 7920 ttgagcccga cgcgcgaacc gggattagtc ccgcgcgcgc acacgtggcg gccgccgacc 7980 tggtaaccgc atacgagcag acggtgaacc aggagattaa ctttcaaaaa agctttaaca 8040 accacgtgcg tacgcttgtg gcgcgcgagg aggtggctat aggactgatg catctgtggg 8100 actttgtaag cgcgctggag caaaacccaa atagcaagcc gctcatggcg cagctgttcc 8160 ttatagtgca gcacagcagg gacaacgagg cattcaggga tgcgctgcta aacatagtag 8220 agcccgaggg ccgctggctg ctcgatttga taaacatcct gcagagcata gtggtgcagg 8280 agcgcagctt gagcctggct gacaaggtgg ccgccatcaa ctattccatg cttagcctgg 8340 gcaagtttta cgcccgcaag atataccata ccccttacgt tcccatagac aaggaggtaa 8400 agatcgaggg gttctacatg cgcatggcgc tgaaggtgct taccttgagc gacgacctgg 8460 gcgtttatcg caacgagcgc atccacaagg ccgtgagcgt gagccggcgg cgcgagctca 8520 gcgaccgcga gctgatgcac agcctgcaaa gggccctggc tggcacgggc agcggcgata 8580 gagaggccga gtcctacttt gacgcgggcg ctgacctgcg ctgggcccca agccgacgcg 8640 ccctggaggc agctggggcc ggacctgggc tggcggtggc acccgcgcgc gctggcaacg 8700 tcggcggcgt ggaggaatat gacgaggacg atgagtacga gccagaggac ggcgagtact 8760 aagcggtgat gtttctgatc agatgatgca agacgcaacg gacccggcgg tgcgggcggc 8820 gctgcagagc cagccgtccg gccttaactc cacggacgac tggcgccagg tcatggaccg 8880 catcatgtcg ctgactgcgc gcaatcctga cgcgttccgg cagcagccgc aggccaaccg 8940 gctctccgca attctggaag cggtggtccc ggcgcgcgca aaccccacgc acgagaaggt 9000 gctggcgatc gtaaacgcgc tggccgaaaa cagggccatc cggcccgacg aggccggcct 9060 ggtctacgac gcgctgcttc agcgcgtggc tcgttacaac agcggcaacg tgcagaccaa 9120 cctggaccgg ctggtggggg atgtgcgcga ggccgtggcg cagcgtgagc gcgcgcagca 9180 gcagggcaac ctgggctcca tggttgcact aaacgccttc ctgagtacac agcccgccaa 9240 cgtgccgcgg ggacaggagg actacaccaa ctttgtgagc gcactgcggc taatggtgac 9300 tgagacaccg caaagtgagg tgtaccagtc tgggccagac tattttttcc agaccagtag 9360 acaaggcctg cagaccgtaa acctgagcca ggctttcaaa aacttgcagg ggctgtgggg 9420 ggtgcgggct cccacaggcg accgcgcgac cgtgtctagc ttgctgacgc ccaactcgcg 9480 cctgttgctg ctgctaatag cgcccttcac ggacagtggc agcgtgtccc gggacacata 9540 cctaggtcac ttgctgacac tgtaccgcga ggccataggt caggcgcatg tggacgagca 9600 tactttccag gagattacaa gtgtcagccg cgcgctgggg caggaggaca cgggcagcct 9660 ggaggcaacc ctaaactacc tgctgaccaa ccggcggcag aagatcccct cgttgcacag 9720 tttaaacagc gaggaggagc gcattttgcg ctacgtgcag cagagcgtga gccttaacct 9780 gatgcgcgac ggggtaacgc ccagcgtggc gctggacatg accgcgcgca acatggaacc 9840 gggcatgtat gcctcaaacc ggccgtttat caaccgccta atggactact tgcatcgcgc 9900 ggccgccgtg aaccccgagt atttcaccaa tgccatcttg aacccgcact ggctaccgcc 9960 ccctggtttc tacaccgggg gattcgaggt gcccgagggt aacgatggat tcctctggga 10020 cgacatagac gacagcgtgt tttccccgca accgcagacc ctgctagagt tgcaacagcg 10080 cgagcaggca gaggcggcgc tgcgaaagga aagcttccgc aggccaagca gcttgtccga 10140 tctaggcgct gcggccccgc ggtcagatgc tagtagccca tttccaagct tgatagggtc 10200 tcttaccagc actcgcacca cccgcccgcg cctgctgggc gaggaggagt acctaaacaa 10260 ctcgctgctg cagccgcagc gcgaaaaaaa cctgcctccg gcatttccca acaacgggat 10320 agagagccta gtggacaaga tgagtagatg gaagacgtac gcgcaggagc acagggacgt 10380 gccaggcccg cgcccgccca cccgtcgtca aaggcacgac cgtcagcggg gtctggtgtg 10440 ggaggacgat gactcggcag acgacagcag cgtcctggat ttgggaggga gtggcaaccc 10500 gtttgcgcac cttcgcccca ggctggggag aatgttttaa aaaaaaaaaa gcatgatgca 10560 aaataaaaaa ctcaccaagg ccatggcacc gagcgttggt tttcttgtat tccccttagt 10620 atgcggcgcg cggcgatgta tgaggaaggt cctcctccct cctacgagag tgtggtgagc 10680 gcggcgccag tggcggcggc gctgggttct cccttcgatg ctcccctgga cccgccgttt 10740 gtgcctccgc ggtacctgcg gcctaccggg gggagaaaca gcatccgtta ctctgagttg 10800 gcacccctat tcgacaccac ccgtgtgtac ctggtggaca acaagtcaac ggatgtggca 10860 tccctgaact accagaacga ccacagcaac tttctgacca cggtcattca aaacaatgac 10920 tacagcccgg gggaggcaag cacacagacc atcaatcttg acgaccggtc gcactggggc 10980 ggcgacctga aaaccatcct gcataccaac atgccaaatg tgaacgagtt catgtttacc 11040 aataagttta aggcgcgggt gatggtgtcg cgcttgccta ctaaggacaa tcaggtggag 11100 ctgaaatacg agtgggtgga gttcacgctg cccgagggca actactccga gaccatgacc 11160 atagacctta tgaacaacgc gatcgtggag cactacttga aagtgggcag acagaacggg 11220 gttctggaaa gcgacatcgg ggtaaagttt gacacccgca acttcagact ggggtttgac 11280 cccgtcactg gtcttgtcat gcctggggta tatacaaacg aagccttcca tccagacatc 11340 attttgctgc caggatgcgg ggtggacttc acccacagcc gcctgagcaa cttgttgggc 11400 atccgcaagc ggcaaccctt ccaggagggc tttaggatca cctacgatga tctggagggt 11460 ggtaacattc ccgcactgtt ggatgtggac gcctaccagg cgagcttgaa agatgacacc 11520 gaacagggcg ggggtggcgc aggcggcagc aacagcagtg gcagcggcgc ggaagagaac 11580 tccaacgcgg cagccgcggc aatgcagccg gtggaggaca tgaacgatca tgccattcgc 11640 ggcgacacct ttgccacacg ggctgaggag aagcgcgctg aggccgaagc agcggccgaa 11700 gctgccgccc ccgctgcgca acccgaggtc gagaagcctc agaagaaacc ggtgatcaaa 11760 cccctgacag aggacagcaa gaaacgcagt tacaacctaa taagcaatga cagcaccttc 11820 acccagtacc gcagctggta ccttgcatac aactacggcg accctcagac cggaatccgc 11880 tcatggaccc tgctttgcac tcctgacgta acctgcggct cggagcaggt ctactggtcg 11940 ttgccagaca tgatgcaaga ccccgtgacc ttccgctcca cgcgccagat cagcaacttt 12000 ccggtggtgg gcgccgagct gttgcccgtg cactccaaga gcttctacaa cgaccaggcc 12060 gtctactccc aactcatccg ccagtttacc tctctgaccc acgtgttcaa tcgctttccc 12120 gagaaccaga ttttggcgcg cccgccagcc cccaccatca ccaccgtcag tgaaaacgtt 12180 cctgctctca cagatcacgg gacgctaccg ctgcgcaaca gcatcggagg agtccagcga 12240 gtgaccatta ctgacgccag acgccgcacc tgcccctacg tttacaaggc cctgggcata 12300 gtctcgccgc gcgtcctatc gagccgcact ttttgagcaa gcatgtccat ccttatatcg 12360 cccagcaata acacaggctg gggcctgcgc ttcccaagca agatgtttgg cggggccaag 12420 aagcgctccg accaacaccc agtgcgcgtg cgcgggcact accgcgcgcc ctggggcgcg 12480 cacaaacgcg gccgcactgg gcgcaccacc gtcgatgacg ccatcgacgc ggtggtggag 12540 gaggcgcgca actacacgcc cacgccgcca ccagtgtcca cagtggacgc ggccattcag 12600 accgtggtgc gcggagcccg gcgctatgct aaaatgaaga gacggcggag gcgcgtagca 12660 cgtcgccacc gccgccgacc cggcactgcc gcccaacgcg cggcggcggc cctgcttaac 12720 cgcgcacgtc gcaccggccg acgggcggcc atgcgggccg ctcgaaggct ggccgcgggt 12780 attgtcactg tgccccccag gtccaggcga cgagcggccg ccgcagcagc cgcggccatt 12840 agtgctatga ctcagggtcg caggggcaac gtgtattggg tgcgcgactc ggttagcggc 12900 ctgcgcgtgc ccgtgcgcac ccgccccccg cgcaactaga ttgcaagaaa aaactactta 12960 gactcgtact gttgtatgta tccagcggcg gcggcgcgca acgaagctat gtccaagcgc 13020 aaaatcaaag aagagatgct ccaggtcatc gcgccggaga tctatggccc cccgaagaag 13080 gaagagcagg attacaagcc ccgaaagcta aagcgggtca aaaagaaaaa gaaagatgat 13140 gatgatgaac ttgacgacga ggtggaactg ctgcacgcta ccgcgcccag gcgacgggta 13200 cagtggaaag gtcgacgcgt aaaacgtgtt ttgcgacccg gcaccaccgt agtctttacg 13260 cccggtgagc gctccacccg cacctacaag cgcgtgtatg atgaggtgta cggcgacgag 13320 gacctgcttg agcaggccaa cgagcgcctc ggggagtttg cctacggaaa gcggcataag 13380 gacatgctgg cgttgccgct ggacgagggc aacccaacac ctagcctaaa gcccgtaaca 13440 ctgcagcagg tgctgcccgc gcttgcaccg tccgaagaaa agcgcggcct aaagcgcgag 13500 tctggtgact tggcacccac cgtgcagctg atggtaccca agcgccagcg actggaagat 13560 gtcttggaaa aaatgaccgt ggaacctggg ctggagcccg aggtccgcgt gcggccaatc 13620 aagcaggtgg cgccgggact gggcgtgcag accgtggacg ttcagatacc cactaccagt 13680 agcaccagta ttgccaccgc cacagagggc atggagacac aaacgtcccc ggttgcctca 13740 gcggtggcgg atgccgcggt gcaggcggtc gctgcggccg cgtccaagac ctctacggag 13800 gtgcaaacgg acccgtggat gtttcgcgtt tcagcccccc ggcgcccgcg cggttcgagg 13860 aagtacggcg ccgccagcgc gctactgccc gaatatgccc tacatccttc cattgcgcct 13920 acccccggct atcgtggcta cacctaccgc cccagaagac gagcaactac ccgacgccga 13980 accaccactg gaacccgccg ccgccgtcgc cgtcgccagc ccgtgctggc cccgatttcc 14040 gtgcgcaggg tggctcgcga aggaggcagg accctggtgc tgccaacagc gcgctaccac 14100 cccagcatcg tttaaaagcc ggtctttgtg gttcttgcag atatggccct cacctgccgc 14160 ctccgtttcc cggtgccggg attccgagga agaatgcacc gtaggagggg catggccggc 14220 cacggcctga cgggcggcat gcgtcgtgcg caccaccggc ggcggcgcgc gtcgcaccgt 14280 cgcatgcgcg gcggtatcct gcccctcctt attccactga tcgccgcggc gattggcgcc 14340 gtgcccggaa ttgcatccgt ggccttgcag gcgcagagac actgattaaa aacaagttgc 14400 atgtggaaaa atcaaaataa aaagtctgga ctctcacgct cgcttggtcc tgtaactatt 14460 ttgtagaatg gaagacatca actttgcgtc tctggccccg cgacacggct cgcgcccgtt 14520 catgggaaac tggcaagata tcggcaccag caatatgagc ggtggcgcct tcagctgggg 14580 ctcgctgtgg agcggcatta aaaatttcgg ttccaccgtt aagaactatg gcagcaaggc 14640 ctggaacagc agcacaggcc agatgctgag ggataagttg aaagagcaaa atttccaaca 14700 aaaggtggta gatggcctgg cctctggcat tagcggggtg gtggacctgg ccaaccaggc 14760 agtgcaaaat aagattaaca gtaagcttga tccccgccct cccgtagagg agcctccacc 14820 ggccgtggag acagtgtctc cagaggggcg tggcgaaaag cgtccgcgcc ccgacaggga 14880 agaaactctg gtgacgcaaa tagacgagcc tccctcgtac gaggaggcac taaagcaagg 14940 cctgcccacc acccgtccca tcgcgcccat ggctaccgga gtgctgggcc agcacacacc 15000 cgtaacgctg gacctgcctc cccccgccga cacccagcag aaacctgtgc tgccaggccc 15060 gaccgccgtt gttgtaaccc gtcctagccg cgcgtccctg cgccgcgccg ccagcggtcc 15120 gcgatcgttg cggcccgtag ccagtggcaa ctggcaaagc acactgaaca gcatcgtggg 15180 tctgggggtg caatccctga agcgccgacg atgcttctga atagctaacg tgtcgtatgt 15240 gtgtcatgta tgcgtccatg tcgccgccag aggagctgct gagccgccgc gcgcccgctt 15300 tccaagatgg ctaccccttc gatgatgccg cagtggtctt acatgcacat ctcgggccag 15360 gacgcctcgg agtacctgag ccccgggctg gtgcagtttg cccgcgccac cgagacgtac 15420 ttcagcctga ataacaagtt tagaaacccc acggtggcgc ctacgcacga cgtgaccaca 15480 gaccggtccc agcgtttgac gctgcggttc atccctgtgg accgtgagga tactgcgtac 15540 tcgtacaagg cgcggttcac cctagctgtg ggtgataacc gtgtgctgga catggcttcc 15600 acgtactttg acatccgcgg cgtgctggac aggggcccta cttttaagcc ctactctggc 15660 actgcctaca acgccctggc tcccaagggt gccccaaatc cttgcgaatg ggatgaagct 15720 gctactgctc ttgaaataaa cctagaagaa gaggacgatg acaacgaaga cgaagtagac 15780 gagcaagctg agcagcaaaa aactcacgta tttgggcagg cgccttattc tggtataaat 15840 attacaaagg agggtattca aataggtgtc gaaggtcaaa cacctaaata tgccgataaa 15900 acatttcaac ctgaacctca aataggagaa tctcagtggt acgaaactga aattaatcat 15960 gcagctggga gagtccttaa aaagactacc ccaatgaaac catgttacgg ttcatatgca 16020 aaacccacaa atgaaaatgg agggcaaggc attcttgtaa agcaacaaaa tggaaagcta 16080 gaaagtcaag tggaaatgca atttttctca actactgagg cgaccgcagg caatggtgat 16140 aacttgactc ctaaagtggt attgtacagt gaagatgtag atatagaaac cccagacact 16200 catatttctt acatgcccac tattaaggaa ggtaactcac gagaactaat gggccaacaa 16260 tctatgccca acaggcctaa ttacattgct tttagggaca attttattgg tctaatgtat 16320 tacaacagca cgggtaatat gggtgttctg gcgggccaag catcgcagtt gaatgctgtt 16380 gtagatttgc aagacagaaa cacagagctt tcataccagc ttttgcttga ttccattggt 16440 gatagaacca ggtacttttc tatgtggaat caggctgttg acagctatga tccagatgtt 16500 agaattattg aaaatcatgg aactgaagat gaacttccaa attactgctt tccactggga 16560 ggtgtgatta atacagagac tcttaccaag gtaaaaccta aaacaggtca ggaaaatgga 16620 tgggaaaaag atgctacaga attttcagat aaaaatgaaa taagagttgg aaataatttt 16680 gccatggaaa tcaatctaaa tgccaacctg tggagaaatt tcctgtactc caacatagcg 16740 ctgtatttgc ccgacaagct aaagtacagt ccttccaacg taaaaatttc tgataaccca 16800 aacacctacg actacatgaa caagcgagtg gtggctcccg ggttagtgga ctgctacatt 16860 aaccttggag cacgctggtc ccttgactat atggacaacg tcaacccatt taaccaccac 16920 cgcaatgctg gcctgcgcta ccgctcaatg ttgctgggca atggtcgcta tgtgcccttc 16980 cacatccagg tgcctcagaa gttctttgcc attaaaaacc tccttctcct gccgggctca 17040 tacacctacg agtggaactt caggaaggat gttaacatgg ttctgcagag ctccctagga 17100 aatgacctaa gggttgacgg agccagcatt aagtttgata gcatttgcct ttacgccacc 17160 ttcttcccca tggcccacaa caccgcctcc acgcttgagg ccatgcttag aaacgacacc 17220 aacgaccagt cctttaacga ctatctctcc gccgccaaca tgctctaccc tatacccgcc 17280 aacgctacca acgtgcccat atccatcccc tcccgcaact gggcggcttt ccgcggctgg 17340 gccttcacgc gccttaagac taaggaaacc ccatcactgg gctcgggcta cgacccttat 17400 tacacctact ctggctctat accctaccta gatggaacct tttacctcaa ccacaccttt 17460 aagaaggtgg ccattacctt tgactcttct gtcagctggc ctggcaatga ccgcctgctt 17520 acccccaacg agtttgaaat taagcgctca gttgacgggg agggttacaa cgttgcccag 17580 tgtaacatga ccaaagactg gttcctggta caaatgctag ctaactacaa cattggctac 17640 cagggcttct atatcccaga gagctacaag gaccgcatgt actccttctt tagaaacttc 17700 cagcccatga gccgtcaggt ggtggatgat actaaataca aggactacca acaggtgggc 17760 atcctacacc aacacaacaa ctctggattt gttggctacc ttgcccccac catgcgcgaa 17820 ggacaggcct accctgctaa cttcccctat ccgcttatag gcaagaccgc agttgacagc 17880 attacccaga aaaagtttct ttgcgatcgc accctttggc gcatcccatt ctccagtaac 17940 tttatgtcca tgggcgcact cacagacctg ggccaaaacc ttctctacgc caactccgcc 18000 cacgcgctag acatgacttt tgaggtggat cccatggacg agcccaccct tctttatgtt 18060 ttgtttgaag tctttgacgt ggtccgtgtg caccggccgc accgcggcgt catcgaaacc 18120 gtgtacctgc gcacgccctt ctcggccggc aacgccacaa cataaagaag caagcaacat 18180 caacaacagc tgccgccatg ggctccagtg agcaggaact gaaagccatt gtcaaagatc 18240 ttggttgtgg gccatatttt ttgggcacct atgacaagcg ctttccaggc tttgtttctc 18300 cacacaagct cgcctgcgcc atagtcaata cggccggtcg cgagactggg ggcgtacact 18360 ggatggcctt tgcctggaac ccgcactcaa aaacatgcta cctctttgag ccctttggct 18420 tttctgacca gcgactcaag caggtttacc agtttgagta cgagtcactc ctgcgccgta 18480 gcgccattgc ttcttccccc gaccgctgta taacgctgga aaagtccacc caaagcgtac 18540 aggggcccaa ctcggccgcc tgtggactat tctgctgcat gtttctccac gcctttgcca 18600 actggcccca aactcccatg gatcacaacc ccaccatgaa ccttattacc ggggtaccca 18660 actccatgct caacagtccc caggtacagc ccaccctgcg tcgcaaccag gaacagctct 18720 acagcttcct ggagcgccac tcgccctact tccgcagcca cagtgcgcag attaggagcg 18780 ccacttcttt ttgtcacttg aaaaacatgt aaaaataatg tactagagac actttcaata 18840 aaggcaaatg cttttatttg tacactctcg ggtgattatt tacccccacc cttgccgtct 18900 gcgccgttta aaaatcaaag gggttctgcc gcgcatcgct atgcgccact ggcagggaca 18960 cgttgcgata ctggtgttta gtgctccact taaactcagg cacaaccatc cgcggcagct 19020 cggtgaagtt ttcactccac aggctgcgca ccatcaccaa cgcgtttagc aggtcgggcg 19080 ccgatatctt gaagtcgcag ttggggcctc cgccctgcgc gcgcgagttg cgatacacag 19140 ggttgcagca ctggaacact atcagcgccg ggtggtgcac gctggccagc acgctcttgt 19200 cggagatcag atccgcgtcc aggtcctccg cgttgctcag ggcgaacgga gtcaactttg 19260 gtagctgcct tcccaaaaag ggcgcgtgcc caggctttga gttgcactcg caccgtagtg 19320 gcatcaaaag gtgaccgtgc ccggtctggg cgttaggata cagcgcctgc ataaaagcct 19380 tgatctgctt aaaagccacc tgagcctttg cgccttcaga gaagaacatg ccgcaagact 19440 tgccggaaaa ctgattggcc ggacaggccg cgtcgtgcac gcagcacctt gcgtcggtgt 19500 tggagatctg caccacattt cggccccacc ggttcttcac gatcttggcc ttgctagact 19560 gctccttcag cgcgcgctgc ccgttttcgc tcgtcacatc catttcaatc acgtgctcct 19620 tatttatcat aatgcttccg tgtagacact taagctcgcc ttcgatctca gcgcagcggt 19680 gcagccacaa cgcgcagccc gtgggctcgt gatgcttgta ggtcacctct gcaaacgact 19740 gcaggtacgc ctgcaggaat cgccccatca tcgtcacaaa ggtcttgttg ctggtgaagg 19800 tcagctgcaa cccgcggtgc tcctcgttca gccaggtctt gcatacggcc gccagagctt 19860 ccacttggtc aggcagtagt ttgaagttcg cctttagatc gttatccacg tggtacttgt 19920 ccatcagcgc gcgcgcagcc tccatgccct tctcccacgc agacacgatc ggcacactca 19980 gcgggttcat caccgtaatt tcactttccg cttcgctggg ctcttcctct tcctcttgcg 20040 tccgcatacc acgcgccact gggtcgtctt cattcagccg ccgcactgtg cgcttacctc 20100 ctttgccatg cttgattagc accggtgggt tgctgaaacc caccatttgt agcgccacat 20160 cttctctttc ttcctcgctg tccacgatta cctctggtga tggcgggcgc tcgggcttgg 20220 gagaagggcg cttctttttc ttcttgggcg caatggccaa atccgccgcc gaggtcgatg 20280 gccgcgggct gggtgtgcgc ggcaccagcg cgtcttgtga tgagtcttcc tcgtcctcgg 20340 actcgatacg ccgcctcatc cgcttttttg ggggcgcccg gggaggcggc ggcgacgggg 20400 acggggacga cacgtcctcc atggttgggg gacgtcgcgc cgcaccgcgt ccgcgctcgg 20460 gggtggtttc gcgctgctcc tcttcccgac tggccatttc cttctcctat aggcagaaaa 20520 agatcatgga gtcagtcgag aagaaggaca gcctaaccgc cccctctgag ttcgccacca 20580 ccgcctccac cgatgccgcc aacgcgccta ccaccttccc cgtcgaggca cccccgcttg 20640 aggaggagga agtgattatc gagcaggacc caggttttgt aagcgaagac gacgaggacc 20700 gctcagtacc aacagaggat aaaaagcaag accaggacaa cgcagaggca aacgaggaac 20760 aagtcgggcg gggggacgaa aggcatggcg actacctaga tgtgggagac gacgtgctgt 20820 tgaagcatct gcagcgccag tgcgccatta tctgcgacgc gttgcaagag cgcagcgatg 20880 tgcccctcgc catagcggat gtcagccttg cctacgaacg ccacctattc tcaccgcgcg 20940 taccccccaa acgccaagaa aacggcacat gcgagcccaa cccgcgcctc aacttctacc 21000 ccgtatttgc cgtgccagag gtgcttgcca cctatcacat ctttttccaa aactgcaaga 21060 tacccctatc ctgccgtgcc aaccgcagcc gagcggacaa gcagctggcc ttgcggcagg 21120 gcgctgtcat acctgatatc gcctcgctca acgaagtgcc aaaaatcttt gagggtcttg 21180 gacgcgacga gaagcgcgcg gcaaacgctc tgcaacagga aaacagcgaa aatgaaagtc 21240 actctggagt gttggtggaa ctcgagggtg acaacgcgcg cctagccgta ctaaaacgca 21300 gcatcgaggt cacccacttt gcctacccgg cacttaacct accccccaag gtcatgagca 21360 cagtcatgag tgagctgatc gtgcgccgtg cgcagcccct ggagagggat gcaaatttgc 21420 aagaacaaac agaggagggc ctacccgcag ttggcgacga gcagctagcg cgctggcttc 21480 aaacgcgcga gcctgccgac ttggaggagc gacgcaaact aatgatggcc gcagtgctcg 21540 ttaccgtgga gcttgagtgc atgcagcggt tctttgctga cccggagatg cagcgcaagc 21600 tagaggaaac attgcactac acctttcgac agggctacgt acgccaggcc tgcaagatct 21660 ccaacgtgga gctctgcaac ctggtctcct accttggaat tttgcacgaa aaccgccttg 21720 ggcaaaacgt gcttcattcc acgctcaagg gcgaggcgcg ccgcgactac gtccgcgact 21780 gcgtttactt atttctatgc tacacctggc agacggccat gggcgtttgg cagcagtgct 21840 tggaggagtg caacctcaag gagctgcaga aactgctaaa gcaaaacttg aaggacctat 21900 ggacggcctt caacgagcgc tccgtggccg cgcacctggc ggacatcatt ttccccgaac 21960 gcctgcttaa aaccctgcaa cagggtctgc cagacttcac cagtcaaagc atgttgcaga 22020 actttaggaa ctttatccta gagcgctcag gaatcttgcc cgccacctgc tgtgcacttc 22080 ctagcgactt tgtgcccatt aagtaccgcg aatgccctcc gccgctttgg ggccactgct 22140 accttctgca gctagccaac taccttgcct accactctga cataatggaa gacgtgagcg 22200 gtgacggtct actggagtgt cactgtcgct gcaacctatg caccccgcac cgctccctgg 22260 tttgcaattc gcagctgctt aacgaaagtc aaattatcgg tacctttgag ctgcagggtc 22320 cctcgcctga cgaaaagtcc gcggctccgg ggttgaaact cactccgggg ctgtggacgt 22380 cggcttacct tcgcaaattt gtacctgagg actaccacgc ccacgagatt aggttctacg 22440 aagaccaatc ccgcccgcca aatgcggagc ttaccgcctg cgtcattacc cagggccaca 22500 ttcttggcca attgcaagcc atcaacaaag cccgccaaga gtttctgcta cgaaagggac 22560 ggggggttta cttggacccc cagtccggcg aggagctcaa cccaatcccc ccgccgccgc 22620 agccctatca gcagcagccg cgggcccttg cttcccagga tggcacccaa aaagaagctg 22680 cagctgccgc cgccacccac ggacgaggag gaatactggg acagtcaggc agaggaggtt 22740 ttggacgagg aggaggagga catgatggaa gactgggaga gcctagacga ggaagcttcc 22800 gaggtcgaag aggtgtcaga cgaaacaccg tcaccctcgg tcgcattccc ctcgccggcg 22860 ccccagaaat cggcaaccgg ttccagcatg gctacaacct ccgctcctca ggcgccgccg 22920 gcactgcccg ttcgccgacc caaccgtaga tgggacacca ctggaaccag ggccggtaag 22980 tccaagcagc cgccgccgtt agcccaagag caacaacagc gccaaggcta ccgctcatgg 23040 cgcgggcaca agaacgccat agttgcttgc ttgcaagact gtgggggcaa catctccttc 23100 gcccgccgct ttcttctcta ccatcacggc gtggccttcc cccgtaacat cctgcattac 23160 taccgtcatc tctacagccc atactgcacc ggcggcagcg gcagcggcag caacagcagc 23220 ggccacacag aagcaaaggc gaccggatag caagactctg acaaagccca agaaatccac 23280 agcggcggca gcagcaggag gaggagcgct gcgtctggcg cccaacgaac ccgtatcgac 23340 ccgcgagctt agaaacagga tttttcccac tctgtatgct atatttcaac agagcagggg 23400 ccaagaacaa gagctgaaaa taaaaaacag gtctctgcga tccctcaccc gcagctgcct 23460 gtatcacaaa agcgaagatc agcttcggcg cacgctggaa gacgcggagg ctctcttcag 23520 taaatactgc gcgctgactc ttaaggacta gtttcgcgcc ctttctcaaa tttaagcgcg 23580 aaaactacgt catctccagc ggccacaccc ggcgccagca cctgtcgtca gcgccattat 23640 gagcaaggaa attcccacgc cctacatgtg gagttaccag ccacaaatgg gacttgcggc 23700 tggagctgcc caagactact caacccgaat aaactacatg agcgcgggac cccacatgat 23760 atcccgggtc aacggaatcc gcgcccaccg aaaccgaatt ctcttggaac aggcggctat 23820 taccaccaca cctcgtaata accttaatcc ccgtagttgg cccgctgccc tggtgtacca 23880 ggaaagtccc gctcccacca ctgtggtact tcccagagac gcccaggccg aagttcagat 23940 gactaactca ggggcgcagc ttgcgggcgg ctttcgtcac agggtgcggt cgcccgggca 24000 gggtataact cacctgacaa tcagagggcg aggtattcag ctcaacgacg agtcggtgag 24060 ctcctcgctt ggtctccgtc cggacgggac atttcagatc ggcggcgccg gccgtccttc 24120 attcacgcct cgtcaggcaa tcctaactct gcagacctcg tcctctgagc cgcgctctgg 24180 aggcattgga actctgcaat ttattgagga gtttgtgcca tcggtctact ttaacccctt 24240 ctcgggacct cccggccact atccggatca atttattcct aactttgacg cggtaaagga 24300 ctcggcggac ggctacgact gaatgttaag tggagaggca gagcaactgc gcctgaaaca 24360 cctggtccac tgtcgccgcc acaagtgctt tgcccgcgac tccggtgagt tttgctactt 24420 tgaattgccc gaggatcata tcgagggccc ggcgcacggc gtccggctta ccgcccaggg 24480 agagcttgcc cgtagcctga ttcgggagtt tacccagcgc cccctgctag ttgagcggga 24540 caggggaccc tgtgttctca ctgtgatttg caactgtcct aaccttggat tacatcaaga 24600 tcctctagtt ataactagag tacccgggga tcttattccc tttaactaat aaaaaaaaat 24660 aataaagcat cacttactta aaatcagtta gcaaatttct gtccagttta ttcagcagca 24720 cctccttgcc ctcctcccag ctctggtatt gcagcttcct cctggctgca aactttctcc 24780 acaatctaaa tggaatgtca gtttcctcct gttcctgtcc atccgcaccc actatcttca 24840 tgttgttgca gatgaagcgc gcaagaccgt ctgaagatac cttcaacccc gtgtatccat 24900 atgacacgga aaccggtcct ccaactgtgc cttttcttac tcctcccttt gtatccccca 24960 atgggtttca agagagtccc cctggggtac tctctttgcg cctatccgaa cctctagtta 25020 cctccaatgg catgcttgcg ctcaaaatgg gcaacggcct ctctctggac gaggccggca 25080 accttacctc ccaaaatgta accactgtga gcccacctct caaaaaaacc aagtcaaaca 25140 taaacctgga aatatctgca cccctcacag ttacctcaga agccctaact gtggctgccg 25200 ccgcacctct aatggtcgcg ggcaacacac tcaccatgca atcacaggcc ccgctaaccg 25260 tgcacgactc caaacttagc attgccaccc aaggacccct cacagtgtca gaaggaaagc 25320 tagccctgca aacatcaggc cccctcacca ccaccgatag cagtaccctt actatcactg 25380 cctcaccccc tctaactact gccactggta gcttgggcat tgacttgaaa gagcccattt 25440 atacacaaaa tggaaaacta ggactaaagt acggggctcc tttgcatgta acagacgacc 25500 taaacacttt gaccgtagca actggtccag gtgtgactat taataatact tccttgcaaa 25560 ctaaagttac tggagccttg ggttttgatt cacaaggcaa tatgcaactt aatgtagcag 25620 gaggactaag gattgattct caaaacagac gccttatact tgatgttagt tatccgtttg 25680 atgctcaaaa ccaactaaat ctaagactag gacagggccc tctttttata aactcagccc 25740 acaacttgga tattaactac aacaaaggcc tttacttgtt tacagcttca aacaattcca 25800 aaaagcttga ggttaaccta agcactgcca aggggttgat gtttgacgct acagccatag 25860 ccattaatgc aggagatggg cttgaatttg gttcacctaa tgcaccaaac acaaatcccc 25920 tcaaaacaaa aattggccat ggcctagaat ttgattcaaa caaggctatg gttcctaaac 25980 taggaactgg ccttagtttt gacagcacag gtgccattac agtaggaaac aaaaataatg 26040 ataagctaac tttgtggacc acaccagctc catctcctaa ctgtagacta aatgcagaga 26100 aagatgctaa actcactttg gtcttaacaa aatgtggcag tcaaatactt gctacagttt 26160 cagttttggc tgttaaaggc agtttggctc caatatctgg aacagttcaa agtgctcatc 26220 ttattataag atttgacgaa aatggagtgc tactaaacaa ttccttcctg gacccagaat 26280 attggaactt tagaaatgga gatcttactg aaggcacagc ctatacaaac gctgttggat 26340 ttatgcctaa cctatcagct tatccaaaat ctcacggtaa aactgccaaa agtaacattg 26400 tcagtcaagt ttacttaaac ggagacaaaa ctaaacctgt aacactaacc attacactaa 26460 acggtacaca ggaaacagga gacacaactc caagtgcata ctctatgtca ttttcatggg 26520 actggtctgg ccacaactac attaatgaaa tatttgccac atcctcttac actttttcat 26580 acattgccca agaataaaga atcgtttgtg ttatgtttca acgtgtttat ttttcaattg 26640 cagaaaattt caagtcattt ttcattcagt agtatagccc caccaccaca tagcttatac 26700 agatcaccgt accttaatca aactcacaga accctagtat tcaacctgcc acctccctcc 26760 caacacacag agtacacagt cctttctccc cggctggcct taaaaagcat catatcatgg 26820 gtaacagaca tattcttagg tgttatattc cacacggttt cctgtcgagc caaacgctca 26880 tcagtgatat taataaactc cccgggcagc tcacttaagt tcatgtcgct gtccagctgc 26940 tgagccacag gctgctgtcc aacttgcggt tgcttaacgg gcggcgaagg agaagtccac 27000 gcctacatgg gggtagagtc ataatcgtgc atcaggatag ggcggtggtg ctgcagcagc 27060 gcgcgaataa actgctgccg ccgccgctcc gtcctgcagg aatacaacat ggcagtggtc 27120 tcctcagcga tgattcgcac cgcccgcagc ataaggcgcc ttgtcctccg ggcacagcag 27180 cgcaccctga tctcacttaa atcagcacag taactgcagc acagcaccac aatattgttc 27240 aaaatcccac agtgcaaggc gctgtatcca aagctcatgg cggggaccac agaacccacg 27300 tggccatcat accacaagcg caggtagatt aagtggcgac ccctcataaa cacgctggac 27360 ataaacatta cctcttttgg catgttgtaa ttcaccacct cccggtacca tataaacctc 27420 tgattaaaca tggcgccatc caccaccatc ctaaaccagc tggccaaaac ctgcccgccg 27480 gctatacact gcagggaacc gggactggaa caatgacagt ggagagccca ggactcgtaa 27540 ccatggatca tcatgctcgt catgatatca atgttggcac aacacaggca cacgtgcata 27600 cacttcctca ggattacaag ctcctcccgc gttagaacca tatcccaggg aacaacccat 27660 tcctgaatca gcgtaaatcc cacactgcag ggaagacctc gcacgtaact cacgttgtgc 27720 attgtcaaag tgttacattc gggcagcagc ggatgatcct ccagtatggt agcgcgggtt 27780 tctgtctcaa aaggaggtag acgatcccta ctgtacggag tgcgccgaga caaccgagat 27840 cgtgttggtc gtagtgtcat gccaaatgga acgccggacg tagtcatatt tcctgaagca 27900 aaaccaggtg cgggcgtgac aaacagatct gcgtctccgg tctcgccgct tagatcgctc 27960 tgtgtagtag ttgtagtata tccactctct caaagcatcc aggcgccccc tggcttcggg 28020 ttctatgtaa actccttcat gcgccgctgc cctgataaca tccaccaccg cagaataagc 28080 cacacccagc caacctacac attcgttctg cgagtcacac acgggaggag cgggaagagc 28140 tggaagaacc atgttttttt ttttattcca aaagattatc caaaacctca aaatgaagat 28200 ctattaagtg aacgcgctcc cctccggtgg cgtggtcaaa ctctacagcc aaagaacaga 28260 taatggcatt tgtaagatgt tgcacaatgg cttccaaaag gcaaacggcc ctcacgtcca 28320 agtggacgta aaggctaaac ccttcagggt gaatctcctc tataaacatt ccagcacctt 28380 caaccatgcc caaataattc tcatctcgcc accttctcaa tatatctcta agcaaatccc 28440 gaatattaag tccggccatt gtaaaaatct gctccagagc gccctccacc ttcagcctca 28500 agcagcgaat catgattgca aaaattcagg ttcctcacag acctgtataa gattcaaaag 28560 cggaacatta acaaaaatac cgcgatcccg taggtccctt cgcagggcca gctgaacata 28620 atcgtgcagg tctgcacgga ccagcgcggc cacttccccg ccaggaacct tgacaaaaga 28680 acccacactg attatgacac gcatactcgg agctatgcta accagcgtag ccccgatgta 28740 agctttcaat agcttgttgc atgggcggcg atataaaatg caaggtgctg ctcaaaaaat 28800 caggcaaagc ctcgcgcaaa aaagaaagca catcgtagtc atgctcatgc agataaaggc 28860 aggtaagctc cggaaccacc acagaaaaag acaccatttt tctctcaaac atgtctgcgg 28920 gtttctgcat aaacacaaaa taaaataaca aaaaaacatt taaacattag aagcctgtct 28980 tacaacagga aaaacaaccc ttataagcat aagacggact acggccatgc cggcgtgacc 29040 gtaaaaaaac tggtcaccgt gattaaaaag caccaccgac agctcctcgg tcatgtccgg 29100 agtcataatg taagactcgg taaacacatc aggttgattc atcggtcagt gctaaaaagc 29160 gaccgaaata gcccggggga atacataccc gcaggcgtag agacaacatt acagccccca 29220 taggaggtat aacaaaatta ataggagaga aaaacacata aacacctgaa aaaccctcct 29280 gcctaggcaa aatagcaccc tcccgctcca gaacaacata cagcgcttca cagcggcagc 29340 ctaacagtca gccttaccag taaaaaagaa aacctattaa aaaaacacca ctcgacacgg 29400 caccagctca atcagtcaca gtgtaaaaaa gggccaagtg cagagcgagt atatatagga 29460 ctaaaaaatg acgtaacggt taaagtccac aaaaaacacc cagaaaaccg cacgcgaacc 29520 tacgcccaga aacgaaagcc aaaaaaccca caacttcctc aaatcgtcac ttccgttttc 29580 ccacgttacg taacttccca ttttaagaaa actacaattc ccaacacata caagttactc 29640 cgccctaaaa cctacgtcac ccgccccgtt cccacgcccc gcgccacgtc acaaactcca 29700 ccccctcatt atcatattgg cttcaatcca aaataaggta tattattgat gatgttaatt 29760 aacatgcatg gatccatatg cggtgtgaaa taccgcacag atgcgtaagg agaaaatacc 29820 gcatcaggcg ctcttccgct tcctcgctca ctgactcgct gcgctcggtc gttcggctgc 29880 ggcgagcggt atcagctcac tcaaaggcgg taatacggtt atccacagaa tcaggggata 29940 acgcaggaaa gaacatgtga gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg 30000 cgttgctggc gtttttccat aggctccgcc cccctgacga gcatcacaaa aatcgacgct 30060 caagtcagag gtggcgaaac ccgacaggac tataaagata ccaggcgttt ccccctggaa 30120 gctccctcgt gcgctctcct gttccgaccc tgccgcttac cggatacctg tccgcctttc 30180 tcccttcggg aagcgtggcg ctttctcata gctcacgctg taggtatctc agttcggtgt 30240 aggtcgttcg ctccaagctg ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg 30300 ccttatccgg taactatcgt cttgagtcca acccggtaag acacgactta tcgccactgg 30360 cagcagccac tggtaacagg attagcagag cgaggtatgt aggcggtgct acagagttct 30420 tgaagtggtg gcctaactac ggctacacta gaaggacagt atttggtatc tgcgctctgc 30480 tgaagccagt taccttcgga aaaagagttg gtagctcttg atccggcaaa caaaccaccg 30540 ctggtagcgg tggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc 30600 aagaagatcc tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt 30660 aagggatttt ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa 30720 aatgaagttt taaatcaatc taaagtatat atgagtaaac ttggtctgac agttaccaat 30780 gcttaatcag tgaggcacct atctcagcga tctgtctatt tcgttcatcc atagttgcct 30840 gactccccgt cgtgtagata actacgatac gggagggctt accatctggc cccagtgctg 30900 caatgatacc gcgagaccca cgctcaccgg ctccagattt atcagcaata aaccagccag 30960 ccggaagggc cgagcgcaga agtggtcctg caactttatc cgcctccatc cagtctatta 31020 attgttgccg ggaagctaga gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg 31080 ccattgctgc agccatgaga ttatcaaaaa ggatcttcac ctagatcctt ttcacgtaga 31140 aagccagtcc gcagaaacgg tgctgacccc ggatgaatgt cagctactgg gctatctgga 31200 caagggaaaa cgcaagcgca aagagaaagc aggtagcttg cagtgggctt acatggcgat 31260 agctagactg ggcggtttta tggacagcaa gcgaaccgga attgccagct ggggcgccct 31320 ctggtaaggt tgggaagccc tgcaaagtaa actggatggc tttctcgccg ccaaggatct 31380 gatggcgcag gggatcaagc tctgatcaag agacaggatg aggatcgttt cgcatgattg 31440 aacaagatgg attgcacgca ggttctccgg ccgcttgggt ggagaggcta ttcggctatg 31500 actgggcaca acagacaatc ggctgctctg atgccgccgt gttccggctg tcagcgcagg 31560 ggcgcccggt tctttttgtc aagaccgacc tgtccggtgc cctgaatgaa ctgcaagacg 31620 aggcagcgcg gctatcgtgg ctggccacga cgggcgttcc ttgcgcagct gtgctcgacg 31680 ttgtcactga agcgggaagg gactggctgc tattgggcga agtgccgggg caggatctcc 31740 tgtcatctca ccttgctcct gccgagaaag tatccatcat ggctgatgca atgcggcggc 31800 tgcatacgct tgatccggct acctgcccat tcgaccacca agcgaaacat cgcatcgagc 31860 gagcacgtac tcggatggaa gccggtcttg tcgatcagga tgatctggac gaagagcatc 31920 aggggctcgc gccagccgaa ctgttcgcca ggctcaaggc gagcatgccc gacggcgagg 31980 atctcgtcgt gacccatggc gatgcctgct tgccgaatat catggtggaa aatggccgct 32040 tttctggatt catcgactgt ggccggctgg gtgtggcgga ccgctatcag gacatagcgt 32100 tggctacccg tgatattgct gaagagcttg gcggcgaatg ggctgaccgc ttcctcgtgc 32160 tttacggtat cgccgctccc gattcgcagc gcatcgcctt ctatcgcctt cttgacgagt 32220 tcttctgaat tttgttaaaa tttttgttaa atcagctcat tttttaacca ataggccgaa 32280 atcggcaaca tcccttataa atcaaaagaa tagaccgcga tagggttgag tgttgttcca 32340 gtttggaaca agagtccact attaaagaac gtggactcca acgtcaaagg gcgaaaaacc 32400 gtctatcagg gcgatggccc actacgtgaa ccatcaccca aatcaagttt tttgcggtcg 32460 aggtgccgta aagctctaaa tcggaaccct aaagggagcc cccgatttag agcttgacgg 32520 ggaaagccgg cgaacgtggc gagaaaggaa gggaagaaag cgaaaggagc gggcgctagg 32580 gcgctggcaa gtgtagcggt cacgctgcgc gtaaccacca cacccgcgcg cttaatgcgc 32640 cgctacaggg cgcgtccatt cgccattcag gatcgaatta attcttaatt aacatcatca 32700 ataatatacc ttattttgga ttgaagccaa tatgataatg agggggtgga gtttgtgacg 32760 tggcgcgggg cgtgggaacg gggcgggtga cgtagtagtg tggcggaagt gtgatgttgc 32820 aagtgtggcg gaacacatgt aagcgacgga tgtggcaaaa gtgacgtttt tggtgtgcgc 32880 cggtgtacac aggaagtgac aattttcgcg cggttttagg cggatgttgt agtaaatttg 32940 ggcgtaaccg agtaagattt ggccattttc gcgggaaaac tgaataagag gaagtgaaat 33000 ctgaataatt ttgtgttact catagcgcgt aatactgcga tctatacatt gaatcaatat 33060 tggcaattag ccatattagt cattggttat atagcataaa tcaatattgg ctattggcca 33120 ttgcatacgt tgtatctata tcataatatg tacatttata ttggctcatg tccaatatga 33180 ccgccatgtt gacattgatt attgactagt ggcgcgccgt cgacgagctc tttggggagt 33240 cctaagaggg cagctggcaa tggacaccta gcagtccctt tgagacttat ttcagatgga 33300 gctgtagaaa gatgccatgg ctcacagtgc ctccctggga agggggcaga gggctgccca 33360 gtgaggcctc ttgcgagcag gaaatcacca gagacaagga aagaccagac cccaggatga 33420 cctcagttag gccttgcccg actgtcctca gagtcccatt ctctgtgtcc tggttctttt 33480 agaagatcat ggacctccag gtcatttcgt aaccggaatc tgcctgcggg gggttttgac 33540 aagctatggt atagtgtatg tgggggtact gacgaattgg aagatcatgg agaccccttc 33600 tcctcctcca tcattggtct gccacatccc tcccaggcga ctcacagcag agagaccttg 33660 gatgtatgta gggtgcttta aaactccagc tgagttacag tctctccttt ctgttttcac 33720 cttaaccttc cagggatgca aacccacgac aggtttagca gcagagtgga ggctggccat 33780 gaatctcaga gaaagtgctc actggaaagg ctggtttagc ccaggcctga tgtggaggca 33840 ctgagctgga cgttctagcg gggttgacac ccaacagttt acataggggg aggccacccc 33900 tcctgagcag tctcggtgac ttgaagagga agccgcttct tctgtaccaa cacagaagct 33960 ccagcgaacc cccagaatgc tggcagtgtg ggtgctatgt aaaagtattt acatagcttt 34020 gtagagtgag ccaagcccag tctgtttggg atgactcttc acagtgcctc gaatctgtca 34080 cacgtcttag taagcagagt cacagagttt ctgtcacatc atcctcctgc ctacagggaa 34140 gtaggccatg tccctgcccc ctactctgag cccagctgtg ggagccagcc ctgcccaatg 34200 ggctctctct gattggcttc tcactcactt ctaaactcca gtgagcaact tctctcggct 34260 cgttcaattg gcgtgaaggt ctgtgtcttg cagagaaggt tcttcacaac tgggataaag 34320 agatctgaac tgaaaaacca gaaagttaac tggtaagttt agtctttttg tcttttattt 34380 caggtcccgg atccggtggt ggtgcaaatc aaagaactgc tcctcagtgg atgttgcctt 34440 tacttctagg cctgtacgga agtgttactt ctgctctaaa agctgcggaa ttgtacccag 34500 gcctaggctt ttgcaaaaag cttcgaatcg cgaaaggcca gcacgttctt cgcgccgcgc 34560 tcgcacagcc tctgcagcac tcgggccacc agctccttca ggcaggacac ctggcggaag 34620 gagggggcgg cggggggcgg ccgtgcgtcc cagggcacgc acaccaggca ctgggccacc 34680 agcgcgcgga aagccgccgg gtccccgcgc tgcaccagcc gccagccctg gggccccagg 34740 cgccgcacga acgtggccag cggcagcacc tcgcggtagt ggctgcgcag cagggagcgc 34800 acggctaggc agcggggagc gcgcggcatc gcgggggtgg ccggggccag ggcttcccaa 34860 gcttcgtttt gcggcaggaa aagttatcag gcatgcacct ggtagctagt ctttaaacca 34920 atagattgca tcggtttaaa aggcaagacc gtcaaattgc gggaaagggg tcaacagccg 34980 ttcagtacca agtctcaggg gaaactttga gatggccttg caaagggtat ggtaataagc 35040 tgacggacat ggtcctaacc acgcagccaa gtcctaagtc aacagatctt ctgttgatat 35100 ggatgcagtt cacagactaa atgtcggtcg gggaagatgt attcttctca taagatatag 35160 tcggacctct ccttaatggg agctagcgga tgaagtgatg caacactgga gccgctggga 35220 actaatttgt atgcgaaagt atattgatta gttttggagt actcgcgaaa acgcccacca 35280 tggcttcgta cccctgccat caacacgcgt ctgcgttcga ccaggctgcg cgttctcgcg 35340 gccatagcaa ccgacgtacg gcgttgcgcc ctcgccggca gcaagaagcc acggaagtcc 35400 gcctggagca gaaaatgccc acgctactgc gggtttatat agacggtcct cacgggatgg 35460 ggaaaaccac caccacgcaa ctgctggtgg ccctgggttc gcgcgacgat atcgtctacg 35520 tacccgagcc gatgacttac tggcaggtgc tgggggcttc cgagacaatc gcgaacatct 35580 acaccacaca acaccgcctc gaccagggtg agatatcggc cggggacgcg gcggtggtaa 35640 tgacaagcgc ccagataaca atgggcatgc cttatgccgt gaccgacgcc gttctggctc 35700 ctcatatcgg gggggaggct gggagctcac atgccccgcc cccggccctc accctcatct 35760 tcgaccgcca tcccatcgcc gccctcctgt gctacccggc cgcgcgatac cttatgggca 35820 gcatgacccc ccaggccgtg ctggcgttcg tggccctcat cccgccgacc ttgcccggca 35880 caaacatcgt gttgggggcc cttccggagg acagacacat cgaccgcctg gccaaacgcc 35940 agcgccccgg cgagcggctt gacctggcta tgctggccgc gattcgccgc gtttacgggc 36000 tgcttgccaa tacggtgcgg tatctgcagg gcggcgggtc gtggtgggag gattggggac 36060 agctttcggg gacggccgtg ccgccccagg gtgccgagcc ccagagcaac gcgggcccac 36120 gaccccatat cggggacacg ttatttaccc tgtttcgggc ccccgagttg ctggccccca 36180 acggcgacct gtataacgtg tttgcctggg ccttggacgt cttggccaaa cgcctccgtc 36240 ccatgcacgt ctttatcctg gattacgacc aatcgcccgc cggctgccgg gacgccctgc 36300 tgcaacttac ctccgggatg gtccagaccc acgtcaccac cccaggctcc ataccgacga 36360 tctgcgacct ggcgcgcacg tttgcccggg agatggggga ggctaactga agcggccgca 36420 atcaacctct ggattacaaa atttgtgaaa gattgactgg tattcttaac tatgttgctc 36480 cttttacgct atgtggatac gctgctttaa tgcctttgta tcatgctatt gcttcccgta 36540 tggctttcat tttctcctcc ttgtataaat cctggttgct gtctctttat gaggagttgt 36600 ggcccgttgt caggcaacgt ggcgtggtgt gcactgtgtt tgctgacgca acccccactg 36660 gttggggcat tgccaccacc tgtcagctcc tttccgggac tttcgctttc cccctcccta 36720 ttgccacggc ggaactcatc gccgcctgcc ttgcccgctg ctggacaggg gctcggctgt 36780 tgggcactga caattccgtg gtgttgtcgg ggaaatcatc gtcctttcct tggctgctcg 36840 cctgtgttgc cacctggatt ctgcgcggga cgtccttctg ctacgtccct tcggccctca 36900 atccagcgga ccttccttcc cgcggcctgc tgccggctct gcggcctctt ccgcgtcttc 36960 gccttcgccc tcagacgagt cggatctccc tttgggccgc ctccccgcgc ggccgcacct 37020 ggtagctagt ctttaaacca atagattgca tcggtttaaa aggcaagacc gtcaaattgc 37080 gggaaagggg tcaacagccg ttcagtacca agtctcaggg gaaactttga gatggccttg 37140 caaagggtat ggtaataagc tgacggacat ggtcctaacc acgcagccaa gtcctaagtc 37200 aacagatctt ctgttgatat ggatgcagtt cacagactaa atgtcggtcg gggaagatgt 37260 attcttctca taagatatag tcggacctct ccttaatggg agctagcgga tgaagtgatg 37320 caacactgga gccgctggga actaatttgt atgcgaaagt atattgatta gttttggagt 37380 actcgcgaaa acgcccacca tggcttcgta cccctgccat caacacgcgt ctgcgttcga 37440 ccaggctgcg cgttctcgcg gccatagcaa ccgacgtacg gcgttgcgcc ctcgccggca 37500 gcaagaagcc acggaagtcc gcctggagca gaaaatgccc acgctactgc gggtttatat 37560 agacggtcct cacgggatgg ggaaaaccac caccacgcaa ctgctggtgg ccctgggttc 37620 gcgcgacgat atcgtctacg tacccgagcc gatgacttac tggcaggtgc tgggggcttc 37680 cgagacaatc gcgaacatct acaccacaca acaccgcctc gaccagggtg agatatcggc 37740 cggggacgcg gcggtggtaa tgacaagcgc ccagataaca atgggcatgc cttatgccgt 37800 gaccgacgcc gttctggctc ctcatatcgg gggggaggct gggagctcac atgccccgcc 37860 cccggccctc accctcatct tcgaccgcca tcccatcgcc gccctcctgt gctacccggc 37920 cgcgcgatac cttatgggca gcatgacccc ccaggccgtg ctggcgttcg tggccctcat 37980 cccgccgacc ttgcccggca caaacatcgt gttgggggcc cttccggagg acagacacat 38040 cgaccgcctg gccaaacgcc agcgccccgg cgagcggctt gacctggcta tgctggccgc 38100 gattcgccgc gtttacgggc tgcttgccaa tacggtgcgg tatctgcagg gcggcgggtc 38160 gtggtgggag gattggggac agctttcggg gacggccgtg ccgccccagg gtgccgagcc 38220 ccagagcaac gcgggcccac gaccccatat cggggacacg ttatttaccc tgtttcgggc 38280 ccccgagttg ctggccccca acggcgacct gtataacgtg tttgcctggg ccttggacgt 38340 cttggccaaa cgcctccgtc ccatgcacgt ctttatcctg gattacgacc aatcgcccgc 38400 cggctgccgg gacgccctgc tgcaacttac ctccgggatg gtccagaccc acgtcaccac 38460 cccaggctcc ataccgacga tctgcgacct ggcgcgcacg tttgcccggg agatggggga 38520 ggctaactga agcggccgcg ggtggcatcc ctgtgacccc tccccagtgc ctctcctggc 38580 cctggaagtt gccactccag tgcccaccag ccttgtccta ataaaattaa gttgcatcat 38640 tttgtctgac taggtgtcct tctataatat tatggggtgg aggggggtgg tatggagcaa 38700 ggggcaagtt gggaagacaa cctgtagggc ctgcggggtc tattgggaac caagctggag 38760 tgcagtggca caatcttggc tcactgcaat ctccgcctcc tgggttcaag cgattctcct 38820 gcctcagcct cccgagttgt tgggattcca ggcatgcatg accaggctca gctaattttt 38880 gtttttttgg tagagacggg gtttcaccat attggccagg ctggtctcca actcctaatc 38940 tcaggtgatc tacccacctt ggcctcccaa attgctggga ttacaggcgt gaaccactgc 39000 tcccttccct gtccttctga ttttaaaata actataccag caggaggacg tccagacaca 39060 gcataggcta cctggccatg cccaaccggt gggacatttg agttgcttgc ttggcactgt 39120 cctctcatgc gttgggtcca ctcagtagat gcctgcaggc tcagaggcac acaggagttt 39180 ctgggctcac cctgccccct tccaacccct cagttcccat cctccagcag ctgtttgtgt 39240 gctgcctctg aagtccacac tgaacaaact tcagcctact catgtcccta aaatgggcaa 39300 acattgcaag cagcaaacag caaacacaca gccctccctg cctgctgacc ttggagctgg 39360 ggcagaggtc agagacctct ctgggcccat gccacctcca acatccactc gaccccttgg 39420 aatttcggtg gagaggagca gaggttgtcc tggcgtggtt taggtagtgt gagagggtcc 39480 gggttcaaaa ccacttgctg ggtggggagt cgtcagtaag tggctatgcc ccgaccccga 39540 agcctgtttc cccatctgta caatggaaat gataaagacg cccatctgat agggtttttg 39600 tggcaaataa acatttggtt tttttgtttt gttttgtttt gttttttgag atggaggttt 39660 gctctgtcgc ccaggctgga gtgcagtgac acaatctcat ctcaccacaa ccttcccctg 39720 cctcagcctc ccaagtagct gggattacaa gcatgtgcca ccacacctgg ctaattttct 39780 atttttagta gagacgggtt tctccatgtt ggtcagcctc agcctcccaa gtaactggga 39840 ttacaggcct gtgccaccac acccggctaa ttttttctat ttttgacagg gacggggttt 39900 caccatgttg gtcaggctgg tctagaactc ctgacctcaa atgatccacc cacctaggcc 39960 tcccaaagtg cacagattac aggcgtgggc caccgcacct ggccaaattt ttaatttttt 40020 tctagagata gggtcttact gtgttgccca ggctggtgtc aaactcctgg gctcaagcag 40080 atcctcctgc ctcagcttcc caaagtggtg ggattatagg tgtgagccac tgcgcccagt 40140 cagtagcccc ctctttgccc ctcactgagc cctactggat gttcttggtt gtgtgacagt 40200 ttccccatct attaaacaga aacccctata gcagagggga ggatgaggtt ggaaaatcag 40260 gagcattgtt attctattct tgtgggatcg gggaagcaga catctgggtg gatgtttggg 40320 gaatgctggg ctcagttgag gaagtagggg ggcccctggg gcttacaggg actggaagct 40380 ctgagctggc cagagggatg ttgcaatcct gccagggtct tgtctatgct gtccctttca 40440 caaccatccc cctaccgcca ggctgacacg tggttgtggg ggcacaaggc cagccgaact 40500 agagtctgag gctgggctga ggacaccctc cccatcagct gccagggtca ctggcggtca 40560 aaggcagctg gtggggaagg aattggactc cagccctggg ggacggatgt ggtgatggtg 40620 ggaagcaggc ttggtgccag gaggggcatc agagggtgaa taagagcaga tagagtgttt 40680 gggggaggta gccagccaaa gggggtgagg cccggtggaa gggaagaagg ggcatacact 40740 cagagctttg cagctgaagg ttttaatttt ttgagatggg gtctcactct gtctcaccag 40800 gctggagtgc agtggcgcaa tcacagctca ctgcagacgc gtgaattcct cgagtctaga 40860 ggagcatgcg cgtcggcgcg ccttcgaagg cgaaagatcc caacgaaaag agagaccaca 40920 tggtccttct tgagtttgta acagctgctg ggattacaca tggcatggat gaactgtaca 40980 actgaggatc ccccgacctc gacctctggc taataaagga aatttatttt cattgcaata 41040 gtgtgttgga attttttgtg tctctcactc ggaaggacat atgggagggc aaatcatttg 41100 gtcgagatcc ctcggagatc ggatctgggc gtgg 41134

Claims (16)

1. (i) 조직 특이적 프로모터; 및
   (ii) 암특이적 유전자를 표적으로 하는 트랜스-스플라이싱 라이보자임 및 상기 라이보자임의 3' 엑손에 연결된 목적 유전자를 포함하는, 라이보자임-목적 유전자 발현 카세트를 포함하며,
   상기 발현카세트는 라이보자임-목적 유전자 발현 카세트의 5' 말단에 스플라이싱 공여/스플라이싱 수여 서열(splicing donor/splicing acceptor sequence, SD/SA sequence)이 연결되고, 3' 말단에 WPRE(Woodchuck hepatitis virus Posttranscriptional Regulatory Element)가 연결된 것을 특징으로 하는, 재조합 아데노바이러스.
   
2. 제1항에 있어서,
   상기 트랜스-스플라이싱 라이보자임은 서열번호 5의 핵산 서열로 이루어진 Rib21 라이보자임인 것인 재조합 아데노바이러스.
   
3. 제1항에 있어서,
   상기 암특이적 유전자는 hTERT(human Telomerase Reverse Transcriptase) mRNA, AFP(alphafetoprotein) mRNA, CEA(carcinoembryonic antigen) mRNA, PSA(Prostate-specific antigen) mRNA, 또는 CKAP2(Cytoskeleton-associated protein 2) mRNA인 것인 재조합 아데노바이러스.
   
4. 제1항에 있어서,
   상기 조직 특이적 프로모터는 간세포 특이적 프로모터인 PEPCK (phosphoenolpyruvate carboxykinase) 프로모터, 아포리포프로테인 E(apolipoprotein E) 프로모터, 혈청 알부민 프로모터, 간암 특이적 AFP(alphafetoprotein) 프로모터, 대장암 특이적 CEA(carcinoembryonic antigen) 프로모터, 또는 전립선암 특이적 PSA(Prostate-specific antigen) 프로모터인 것인, 재조합 아데노바이러스.
   
5. 제1항에 있어서,
   상기 아데노바이러스는 E1 및 E3 영역이 결실된 것인, 재조합 아데노바이러스.
   
6. 제1항에 있어서,
   상기 목적 유전자는 치료용 유전자 또는 리포터 유전자인, 재조합 아데노바이러스.
   
7. 제6항에 있어서,
   상기 치료용 유전자는 약제감수성 유전자, 세포사멸 유전자, 세포증식 억제 유전자, 세포독성 유전자, 종양 억제인자 유전자, 항원성 유전자, 사이토카인 유전자 및 항신생 혈관 생성 유전자로 이루어진 군에서 선택된 1종 이상의 유전자인, 재조합 아데노바이러스.
   
8. 제7항에 있어서,
   상기 약제감수성 유전자는 HSVtk(Human Simplex Virus thymidine kinase) 유전자인 것인, 재조합 아데노바이러스.
   
9. 제8항에 있어서,
   상기 HSVtk 유전자는 서열번호 6의 아미노산 서열을 가지는 것인, 재조합 아데노바이러스.
   
10. 제6항에 있어서,
    상기 리포터 유전자는 루시퍼라제(luciferase), 녹색 형광 단백질 (GFP), 변형된 녹색 형광 단백질(modified green fluorescent protein; mGFP), 증강된 녹색 형광 단백질 (enhanced green fluorescent protein; EGFP), 적색 형광 단백질 (RFP), 변형된 적색 형광 단백질 (mRFP), 증강된 적색 형광 단백질 (ERFP), 청색 형광 단백질 (BFP), 증강된 청색 형광 단백질 (EBFP), 황색 형광 단백질 (YFP), 증강된 황색 형광 단백질(EYFP), 남색 형광 단백질 (CFP) 및 증강된 남색 형광 단백질 (ECFP)로 이루어지는 군에서 선택된 것인, 재조합 아데노바이러스.
    
11. 제1항에 있어서,
    복제불가능하며 간에 선택적으로 작용하는 것이 특징인, 재조합 아데노바이러스.
    
12. 제1항 내지 제11항 중 어느 한 항의 재조합 아데노바이러스가 도입된 숙주세포.
    
13. 제1항 내지 제11항 중 어느 한 항의 재조합 아데노바이러스를 유효성분으로 포함하는 암 예방 또는 치료용 약학 조성물.
    
14. 제13항에 있어서,
    상기 암은 간암 또는 간 내로 전이된 암인 것인 약학 조성물.
    
15. 제13항에 있어서,
    약학적으로 허용가능한 담체, 부형제 또는 희석제를 추가로 포함하는 것인 약학 조성물.
    
16. 제1항 내지 제11항 중 어느 한 항의 재조합 아데노바이러스를 치료를 필요로 하는 개체에 약학적으로 유효한 양으로 투여하는 단계를 포함하는 인간을 제외한 동물의 암을 치료하는 방법.

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