KR20220144837A - Htt 발현을 감소시키기 위한 방법 - Google Patents
Htt 발현을 감소시키기 위한 방법 Download PDFInfo
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- KR20220144837A KR20220144837A KR1020227032214A KR20227032214A KR20220144837A KR 20220144837 A KR20220144837 A KR 20220144837A KR 1020227032214 A KR1020227032214 A KR 1020227032214A KR 20227032214 A KR20227032214 A KR 20227032214A KR 20220144837 A KR20220144837 A KR 20220144837A
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Abstract
본원에서는 헌팅턴 질환의 개선, HTT RNA 감소, mHTT RNA 감소, HTT 단백질 감소 또는 mHTT 단백질 감소를 필요로 하는 인간 대상체에서 헌팅턴 질환의 개선, HTT RNA 감소, mHTT RNA 감소, HTT 단백질 감소 또는 mHTT 단백질을 감소시키기 위한 ISIS 443139를 투여하는 방법이 제공된다. 특정 경우에, 방법은 헌팅턴 질환의 적어도 하나의 증상을 개선시키기 위해 유용하다. 헌팅턴 질환의 이러한 증상에는 뇌 위축증, 근육 위축증, 신경 변성, 제어되지 않는 움직임, 연하곤란증, 말하기 어려움, 불안증 및 우울증이 포함되지만 이에 제한되지 않는다.
Description
서열 목록
본 출원은 전자 포맷의 서열 목록과 함께 출원된다. 서열 목록은 크기가 268 Kb이고 2021년 2월 18일자로 작성된 BIOL0380WOSEQ_ST25.txt 표제의 파일로서 제공된다. 서열 목록의 전자 포맷의 정보는 이의 전체가 본원에 참조로 인용된다.
분야
본원에서는 헌팅턴 질환의 개선, HTT RNA 감소, mHTT RNA 감소, HTT 단백질 감소 또는 mHTT 단백질 감소를 필요로 하는 인간 대상체에서 헌팅턴 질환의 개선, HTT RNA 감소, mHTT RNA 감소, HTT 단백질 감소 또는 mHTT 단백질 감소를 필요로 하는 인간 대상체에서 헌팅턴 질환을 개선시키거나, HTT RNA를 감소시키거나, mHTT RNA를 감소시키거나, HTT 단백질을 감소시키거나 mHTT 단백질을 감소시키기 위한 ISIS 443139를 투여하는 방법이 제공된다. 특정 경우에, 방법은 헌팅턴 질환의 적어도 하나의 증상을 개선시키기 위해 유용하다. 헌팅턴 질환의 이러한 증상에는 뇌 위축증, 근육 위축증, 신경 변성, 제어되지 않는 움직임, 연하곤란증, 말하기 어려움, 불안증 및 우울증이 포함되지만 이에 제한되지 않는다.
배경
헌팅턴 질환(HD)은 진행성 무도병, 정신과적 변화 및 지능 저하를 특징으로 하는 파괴적인 상염색체 우성 신경변성 질환이다. HD는 남성과 여성에게 동등하게 영향을 미치며 모든 인종에서 발생한다(참조: Gusella 및 MacDonald, Curr. Opin. Neurobiol. 1995 5:656-62). 선택적 세포 손실 및 원섬유 성상세포증은 HD 환자의 뇌, 특히 선조체의 미상과 피막 및 HD 환자의 대뇌 피질(참조: Vonsattel, J-P. et al., Neuropathol. Exp. Neurol. 1985, 44:559-577)에서, 및 보다 드물게는 해마(참조: Spargo, E. et al., J. Neurol. Neurosurg. Psychiatry 1993, 56:487-491) 및 시상하부(참조: Byers, R.K. et al., Neurology 1973, 23:561-569)에서 관찰된다. HD의 증상은 많은 뇌 영역에서 뉴런의 사멸로 인한 것이지만, 선조체에서, 특히 전체 구조를 결국 파괴하는 점진적인 세포 손실을 겪는 미상 핵에서 가장 분명하다.
HD는 헌팅틴 단백질(HTT 단백질)을 암호화하는 유전자인 IT15의 시토신-아데닌-구아닌(CAG) 트리뉴클레오타이드 반복 영역의 확장에 의해 유발된다. 결과적으로 확장된 CAG 반복 영역은 HTT 단백질에서 비정상적으로 긴 폴리글루타민(PolyQ) 관(tract)을 암호화하여 돌연변이체 HTT(mHTT) 단백질의 발현을 초래한다. 과도한 폴리글루타민 길이의 결과로서, mHTT 단백질은 CNS 뉴런의 세포질과 핵에서 응집체를 형성한다(참조: Davies et al., Cell 1997, 90:537-548). 이의 게놈 불안정성으로 인해, 확장된 CAG 반복 영역은 노화와 함께 및 감수분열 전달 동안에 추가로 확장하여 추가의 CAG 반복체를 포함할 수 있다. 27 내지 35개의 CAG 반복체를 갖는 개체는 전형적으로 HD가 발병하지 않지만 이들의 자녀는 HD가 발병할 위험이 있다. 35 내지 60개 CAG 반복체를 갖는 개체는 전형적으로 성인-발병 HD를 경험한다. 60개 초과의 CAG 반복체를 갖는 개체는 일반적으로 청소년(juvenile) HD가 발병하고, 20세 연령 전에 HD의 증상을 경험한다. 정상적인 수의 CAG 반복체 (<27)를 갖는 개체는 HD를 발병할 위험에 있는 것으로 고려되지 않는다.
개요
본원에서는 이를 필요로 하는 인간 대상체에서 헌팅턴 질환(HD)을 개선시키기 위한 방법, 및 HTT RNA 및/또는 HTT 단백질을 감소시키는 방법이 제공된다. 특정 구현예에서, HTT RNA는 mHTT RNA이다. 특정 구현예에서, HTT 단백질은 mHTT 단백질이다. 특정 구현예에서, 방법은 치료학적 유효량의 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함한다. 특정 구현예에서, 변형된 올리고뉴클레오타이드는 ISIS 443139이다. 특정 구현예에서, 치료학적 유효량은 약 40 mg 내지 약 200 mg의 범위 내에 있다. 특정 구현예에서, 치료학적 유효량은 약 120 mg이다. 특정 구현예에서, 치료학적 유효량은 약 4주 마다 1회 투여된다. 특정 구현예에서, 치료학적 유효량은 약 8주 마다 1회 투여된다. 특정 구현예에서, 치료학적 유효량은 약 16주 마다 1회 투여된다. 특정 구현에에서, 방법은 약 4주 마다 1회 약 120 mg의 ISIS 443139의 부하 용량을 투여하고 이어서 약 8주 마다 1회 또는 약 16주 마다 1회 120 mg의 ISIS 443139의 유지 용량을 투여하는 단계를 포함한다.
도 1a는 4주마다 변형된 올리고뉴클레오타이드 ISIS 443139로 처리된 인간 대상체의 다중 시점에서 기준선의 퍼센트로서 뇌척수액(CSF) mHTT 단백질 최저(trough) 농도의 평균 감소를 보여준다.
도 1b는 8주마다 변형된 올리고뉴클레오타이드 ISIS 443139로 처리된 인간 대상체의 다중 시점에서 기준선의 퍼센트로서 뇌척수액(CSF) mHTT 단백질 최저 농도의 평균 감소를 보여준다.
도 1b는 8주마다 변형된 올리고뉴클레오타이드 ISIS 443139로 처리된 인간 대상체의 다중 시점에서 기준선의 퍼센트로서 뇌척수액(CSF) mHTT 단백질 최저 농도의 평균 감소를 보여준다.
이전의 일반적인 기재 및 하기의 상세한 설명 둘다는 예시적이고 설명을 위한 것 뿐이며 제한적이지 않은 것으로 이해되어야 한다. 본원에서, 단수의 사용은 구체적을 달리 언급되지 않는 경우 복수를 포함한다. 본원에 사용된 바와 같이, "또는"의 사용은 달리 언급되지 않는 경우 "및/또는"을 의미한다. 또한, "포함하는" 및 "포함한다" 및 "포함된"과 같은 다른 형태의 사용은 제한적이지 않다. 또한, "요소" 또는 "성분"과 같은 용어는 달리 구체적으로 언급되지 않는 경우, 하나의 유닛을 포함하는 요소 및 성분 및 하나 초과의 서브유닛을 포함하는 요소 및 성분 둘다를 포함한다.
본원에 사용된 섹션 표제는 단지 구성 목적을 위한 것이고 기재된 주요 요지를 제한하는 것으로서 해석되지 말아야 한다. 특허, 특허 출원, 기사, 책 및 논문을 포함하되 이에 제한되지 않는 본 출원에서 인용된 모든 문서 또는 문서의 일부는 본원에서 논의된 문헌의 일부 및 이의 전문에 대해 참조로 명시적으로 인용된다.
정의
특정 정의가 제공되지 않는 경우, 본원에 기재된 분석 화학, 합성 유기 화학, 의약 및 약제학적 화학과 관련하여 사용되는 명명법, 절차 및 기술은 당업계에 널리 공지되고 일반적으로 사용된다. 허용되는 경우, 모든 특허, 출원, 공개된 출원 및 기타 간행물 및 본원 개시 내용 전반에 걸쳐 언급된 기타 데이터는 그 전체가 참조로 본원에 인용된다.
달리 지적되지 않는 경우, 하기의 용어는 하기의 의미를 갖는다:
본원에 사용된 바와 같이, "2'-데옥시리보뉴클레오시드"는 2'-H(H) 데옥시리보실 당 모이어티를 포함하는 뉴클레오시드를 의미한다. 특정 구현예에서, 2'-데옥시리보뉴클레오시드는 2'-β-D 데옥시리보뉴클레오시드이고 2'-β-D-데옥시리보실 당 모이어티를 포함하며, 이는 천연적으로 존재하는 데옥시리보핵산(DNA)에서 발견되는 바와 같이 β-D 배열을 갖는다. 특정 구현예에서, 2'-데옥시리보뉴클레오시드는 변형된 뉴클레오염기를 포함할 수 있거나 RNA 뉴클레오염기(우라실)를 포함할 수 있다.
본원에 사용된 바와 같은 "2'-MOE"는 리보실 당 모이어티의 2'-OH 그룹 대신 2'-OCH2CH2OCH3 그룹을 의미한다. "2'-MOE 당 모이어티"는 리보실 당 모이어티의 2'-OH 그룹 대신 2'-OCH2CH2OCH3 그룹을 갖는 당 모이어티이다. 달리 지적되지 않는 경우, 2'-MOE 당 모이어티는 β-D 배열로 있다. "MOE"는 O-메톡시에틸을 의미한다.
본원에 사용된 바와 같이, "2'-MOE 뉴클레오시드"는 2'-MOE 당 모이어티를 포함하는 뉴클레오시드를 의미한다.
본원에 사용된 바와 같이, "5-메틸 시토신"은 5 위치에 부착된 메틸 그룹으로 변형된 시토신을 의미한다. 5-메틸 시토신은 변형된 뉴클레오염기이다.
본원에 사용된 바와 같이, "약"은 제공된 값의 플러스 또는 마이너스 7%를 의미한다.
본원에 사용된 바와 같이, "투여하는"은 약제학적 제제를 인간 대상체에게 제공함을 의미한다.
본원에 사용된 바와 같이, 치료와 관련하여 "개선하다"는 치료의 부재하의 동일한 증상과 대비하여 적어도 하나의 증상에서의 개선을 의미한다. 특정 구현예에서, 개선은 증상의 중증도 또는 빈도의 감소, 또는 증상의 중증도 또는 빈도의 발병 지연 또는 진행의 둔화이다.
본원에 사용된 바와 같이, "CAG 반복체"는 다중 연속 트리뉴클레오타이드 유닛 중 하나를 의미하고, 여기서, 각각의 트리뉴클레오타이드 유닛은 5'에서 3'로 시토신(C), 아데닌(A), 및 구아닌(G)의 뉴클레오염기 서열을 갖는 3개의 연속 뉴클레오시드로 이루어진다.
본원에 사용된 바와 같이, "용량"은 투여되는 약제학적 제제의 양을 의미한다.
본원에 사용된 바와 같이, "HTT RNA"는 인간 유전자, IT15의 RNA 발현 생성물이다. "mHTT RNA"는 27개 이상의 연속 CAG 반복체를 함유하는 인간 유전자, IT15의 RNA 발현 생성물이다.
본원에 사용된 바와 같이, "HTT 단백질"은 HTT RNA의 단백질 발현 생성물이다. "mHTT 단백질"은 mHTT의 단백질 발현 생성물이다.
본원에 사용된 바와 같이, 용어 "뉴클레오시드간 연결"은 올리고뉴클레오타이드에서 연속 뉴클레오시드간의 공유 연결을 의미한다. 본원에 사용된 바와 같은 "변형된 뉴클레오시드간 연결"은 포스포디에스테르 뉴클레오시드간 연결 외의 임의의 뉴클레오시드간 연결을 의미한다. "포스포로티오에이트 뉴클레오시드간 연결"은 포스포디에스테르 뉴클레오시드간 연결의 비-가교 산소 원자 중 하나가 황 원자로 대체된 변형된 뉴클레오시드간 연결이다.
본원에 사용된 바와 같이 "IT15 유전자"는 HTT RNA를 암호화하는 게놈 서열을 지칭한다. 일반적으로, 인간은 동일하거나 상이한 뉴클레오염기 서열을 가질 수 있는 2개의 IT15 유전자를 갖는다.
본원에 사용된 바와 같은 "부하 용량"은 약제학적 제제의 정상 상태 농도가 달성되는 초기 투여 단계 동안 투여되는 약제학적 제제의 치료학적 유효량을 의미한다. "초기 부하 용량"은 투여된 첫 번째 부하 용량을 의미한다. "마지막 부하 용량"은 제1 유지 용량을 투여하기 전 가장 최근에 투여되는 부하 용량을 의미한다.
본원에 사용된 바와 같은 "유지 용량"은 약제학적 제제의 정상 상태 농도가 달성된 후 투여 단계 동안 투여되는 약제학적 제제의 치료학적 유효량을 의미한다.
본원에 사용된 바와 같은 "뉴클레오염기"는 비변형된 뉴클레오염기 또는 변형된 뉴클레오염기를 의미한다. "비변형된 뉴클레오염기"는 아데닌(A), 티민(T), 시토신(C), 우라실(U), 또는 구아닌(G)이다. "변형된 뉴클레오염기"는 적어도 하나의 비변형된 뉴클레오염기와 쌍을 형성할 수 있는 비변형된 A, T, C, U, 또는 G 이외의 다른 원자 그룹이다. "5-메틸 시토신"은 변형된 뉴클레오염기이다. 본원에 사용된 바와 같은 "뉴클레오염기 서열"은 임의의 당 또는 뉴클레오시드간 연결 변형과 무관한 표적 핵산 또는 올리고뉴클레오타이드에서 연속된 뉴클레오염기의 순서를 의미한다.
본원에 사용된 바와 같은 "뉴클레오시드"는 뉴클레오염기 및 당 모이어티를 포함하는 화합물을 의미한다. 뉴클레오염기 및 당 모이어티는 각각 독립적으로 변형되지 않거나 변형된다. 본원에 사용된 바와 같은 "변형된 뉴클레오시드"는 변형된 뉴클레오염기 및 변형된 당 모이어티를 포함하는 뉴클레오시드를 의미한다. "연결된 뉴클레오시드"는 연속 서열로 연결되는 뉴클레오시드이다(즉, 어떠한 추가의 뉴클레오시드는 연결되는 것들 사이에 제공되지 않는다). 본원에 사용된 바와 같은 "올리고뉴클레오타이드"는 뉴클레오시드간 연결을 통해 연결되어 있는 연결된 뉴클레오시드의 가닥을 의미하며, 여기서 각각의 뉴클레오시드 및 뉴클레오시드간 연결은 변형되거나 변형되지 않을 수 있다. 달리 지적되지 않는 경우, 올리고뉴클레오타이드는 8-50개의 연결된 뉴클레오시드로 이루어진다. 본원에 사용된 바와 같은 "변형된 올리고뉴클레오타이드"는 적어도 하나의 뉴클레오시드 또는 뉴클레오시드간 연결이 변형된 올리고뉴클레오타이드를 의미한다.
본원에 사용된 바와 같은 "약제학적으로 허용되는 담체 또는 희석제"는 인간 대상체에게 투여하는데 사용하기 위해 적합한 임의의 물질을 의미한다. 이러한 특정 담체는 약제학적 조성물이 예를 들어 인간 대상체에 의한 경구 섭취를 위한 정제, 환제, 당의정, 캡슐, 액체, 겔, 시럽, 슬러리, 현탁액 및 로젠지로서 제형화될 수 있게 한다. 특정 구현예에서, 약제학적으로 허용되는 담체 또는 희석제는 멸균수, 멸균 식염수, 멸균 완충액 또는 멸균 인공 뇌척수액이다.
본원에 사용된 바와 같이, "약제학적으로 허용되는 염"은 생리학적으로 및 약제학적으로 허용되는 화합물의 염을 의미한다. 약제학적으로 허용되는 염은 모 화합물의 목적하는 생물학적 활성을 보유하고 이에 목적하지 않는 독성 효과를 부여하지 않는다.
본원에 사용된 바와 같은 "칼륨 염"은 변형된 올리고뉴클레오타이드의 염을 의미하고, 여기서 염의 양이온은 칼륨이다.
본원에 사용된 바와 같은 "RNA"는 RNA 전사체를 의미하고 달리 명시되지 않는 경우 전구-mRNA 및 성숙한 mRNA를 포함한다.
본원에 사용된 바와 같은 "나트륨 염"은 변형된 올리고뉴클레오타이드의 염을 의미하고, 여기서 염의 양이온은 나트륨이다.
본원에 사용된 바와 같은 "대상체"는 인간 또는 비-인간 동물을 의미한다. 특정 구현예에서, 대상체는 인간 대상체이다. "이를 필요로 하는 대상체"는 본원에 개시된 변형된 올리고뉴클레오타이드의 투여가 이득이 되는 대상체이다. 특정 구현예에서, 이를 필요로 하는 대상체는 HD를 갖는다.
본원에 사용된 바와 같은 "당 모이어티"는 비변형된 당 모이어티 또는 변형된 당 모이어티를 의미한다. "비변형된 당 모이어티"는 RNA에서 발견되는 바와 같이 2'-OH(H) β-D 리보실 모이어티 ("비변형된 RNA 당 모이어티"), 또는 DNA에서 발견되는 바와 같이 2'-H(H) β-D 데옥시리보실 모이어티 ("비변형된 DNA 당 모이어티")를 의미한다. 변형되지 않은 당 모이어티는 1', 3' 및 4' 위치 각각에 하나의 수소, 3' 위치에 산소, 및 5' 위치에 2개의 수소를 갖는다. "변형된 당 모이어티" 또는 "변형된 당"은 변형된 푸라노실 당 모이어티 또는 당 대용물을 의미한다.
본원에 사용된 바와 같이, "증상"은 질환 또는 장애의 존재 또는 정도를 나타내는 임의의 신체적 특성 또는 시험 결과를 의미한다. 특정 구현예에서, 증상은 대상체 또는 대상체를 검사하거나 시험하는 의료 전문가에게 자명하다.
본원에 사용된 바와 같은 "치료학적 유효량"은 인간 대상체에게 치료학적 이득을 제공하는 약제학적 제제의 양을 의미한다. 예를 들어, 치료학적 유효량은 질환의 증상을 개선시킨다.
본원에 사용된 바와 같은 "최저 농도"는 인간 대상체가 후속 용량을 투여 받기 직전에 투여된 인간 대상체로부터 채취한 생물학적 샘플에서 분석물(예를 들어, mHTT)의 농도 또는 마지막 연구일에 분석물의 농도를 의미한다.
본원에 사용된 바와 같은 "주"는 7일을 의미한다.
특정 구현예
구현예 1. 헌팅턴 질환(HD) 개선을 필요로 하는 인간 대상체에서 헌팅턴 질환(HD)을 개선시키는 방법으로서, 상기 방법이 치료학적 유효량의 하기 화학 구조에 따른 변형된 올리고뉴클레오타이드 또는 이의 염을 인간 대상체에게 투여하는 단계를 포함하는, 방법:
(서열번호 4).
구현예 2. 구현예 1에 있어서, 상기 변형된 올리고뉴클레오타이드가 나트륨 염 또는 칼륨 염인, 방법.
구현예 3. HD 개선을 필요로 하는 인간 대상체에서 HD를 개선시키는 방법으로서, 상기 방법이 하기의 화학 구조에 따른 변형된 올리고뉴클레오타이드의 치료학적 유효량을 인간 대상체에게 투여하는 단계를 포함하는, 방법:
(서열번호 4).
구현예 4. HD 개선을 필요로 하는 인간 대상체에서 HD를 개선시키는 방법으로서, 상기 방법이 변형된 올리고뉴클레오타이드의 치료학적 유효량을 인간 대상체에게 투여하는 단계를 포함하고, 상기 변형된 올리고뉴클레오타이드가 mCes Teo mCeo Aeo Ges Tds Ads Ads mCds Ads Tds Tds Gds Ads mCds Aeo mCeo mCeo Aes mCe (서열번호 4)의 화학적 표기법(5'에서 3')을 갖고; 여기서,
A = 아데닌 뉴클레오염기,
mC = 5-메틸 시토신 뉴클레오염기,
G = 구아닌 뉴클레오염기,
T = 티민 뉴클레오염기,
e = 2'-MOE 당 모이어티,
d = 2'-β-D-데옥시리보실 당 모이어티,
s = 포스포로티오에이트 뉴클레오시드간 연결, 및
o = 포스포디에스테르 뉴클레오시드간 연결
인, 방법.
구현예 5. 구현예 1 내지 4 중 어느 하나에 있어서, HD의 적어도 하나의 증상이 개선되는, 방법.
구현예 6. 구현예 5에 있어서, 상기 적어도 하나의 증상이 뇌 위축증, 뇌 활동 감소증, 뇌 연결성 감소증, 근육 위축증, 신경 변성, 심부전, 내당능 손상, 체중 감소증, 골다공증, 고환 위축증, 전반적인 기능 손상, 운동 기능 손상, 인지 기능 손상, 일상 기능 손상, 주의력 손상, 시각 지각 처리 손상, 작업 기억 손상, 정신 운동 속도 손상, 언어 운동 아웃풋 손상, 독립성 정도 손상, 무감각증 손상, 학습 능력 손상, 정신 집중력 손상, 언어 손상, 우울증, 과민성, 분노, 운동능 손상, 자기 관리 손상, 통증, 불편함, 불안증, 자살 생각, 자살 행동 또는 이들의 조합을 포함하는, 방법.
구현예 7. HTT RNA 감소를 필요로 하는 인간 대상체에서 HTT RNA를 감소시키는 방법으로서, 상기 방법이 치료학적 유효량의 하기의 화학 구조에 따른 변형된 올리고뉴클레오타이드 또는 이의 염을 인간 대상체에게 투여하는 단계를 포함하는, 방법:
(서열번호 4).
구현예 8. 구현예 7에 있어서, 상기 변형된 올리고뉴클레오타이드가 나트륨 염 또는 칼륨 염인, 방법.
구현예 9. HTT RNA 감소를 필요로 하는 인간 대상체에서 HTT RNA를 감소시키는 방법으로서, 상기 방법이 하기의 화학 구조에 따른 변형된 올리고뉴클레오타이드의 치료학적 유효량을 인간 대상체에게 투여하는 단계를 포함하는, 방법:
(서열번호 4).
구현예 10. HTT RNA 감소를 필요로 하는 인간 대상체에서 HTT RNA를 감소시키는 방법으로서, 상기 방법이 변형된 올리고뉴클레오타이드의 치료학적 유효량을 인간 대상체에게 투여하는 단계를 포함하고, 상기 변형된 올리고뉴클레오타이드가 mCes Teo mCeo Aeo Ges Tds Ads Ads mCds Ads Tds Tds Gds Ads mCds Aeo mCeo mCeo Aes mCe (서열번호 4)의 화학적 표기법(5'에서 3')을 갖고; 여기서,
A = 아데닌 뉴클레오염기,
mC = 5-메틸 시토신 뉴클레오염기,
G = 구아닌 뉴클레오염기,
T = 티민 뉴클레오염기,
e = 2'-MOE 당 모이어티,
d = 2'-β-D-데옥시리보실 당 모이어티,
s = 포스포로티오에이트 뉴클레오시드간 연결, 및
o = 포스포디에스테르 뉴클레오시드간 연결
인, 방법.
구현예 11. HTT 단백질 감소를 필요로 하는 인간 대상체에서 HTT 단백질을 감소시키는 방법으로서, 상기 방법이 치료학적 유효량의 하기의 화학 구조에 따른 변형된 올리고뉴클레오타이드 또는 이의 염을 인간 대상체에게 투여하는 단계를 포함하는, 방법:
(서열번호 4).
구현예 12. 구현예 11에 있어서, 상기 변형된 올리고뉴클레오타이드가 나트륨 염 또는 칼륨 염인, 방법.
구현예 13. HTT 단백질 감소를 필요로 하는 인간 대상체에서 HTT 단백질을 감소시키는 방법으로서, 상기 방법이 하기의 화학 구조에 따른 변형된 올리고뉴클레오타이드의 치료학적 유효량을 인간 대상체에게 투여하는 단계를 포함하는, 방법:
(서열번호 4).
구현예 14. HTT 단백질 감소를 필요로 하는 인간 대상체에서 HTT 단백질을 감소시키는 방법으로서, 상기 방법이 변형된 올리고뉴클레오타이드의 치료학적 유효량을 인간 대상체에게 투여하는 단계를 포함하고, 상기 변형된 올리고뉴클레오타이드가 mCes Teo mCeo Aeo Ges Tds Ads Ads mCds Ads Tds Tds Gds Ads mCds Aeo mCeo mCeo Aes mCe (서열번호 4)의 화학적 표기법(5'에서 3')을 갖고; 여기서,
A = 아데닌 뉴클레오염기,
mC = 5-메틸 시토신 뉴클레오염기,
G = 구아닌 뉴클레오염기,
T = 티민 뉴클레오염기,
e = 2'-MOE 당 모이어티,
d = 2'-β-D-데옥시리보실 당 모이어티,
s = 포스포로티오에이트 뉴클레오시드간 연결, 및
o = 포스포디에스테르 뉴클레오시드간 연결
인, 방법.
구현예 15. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 10 mg인, 방법.
구현예 16. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 30 mg인, 방법.
구현예 17. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 60 mg인, 방법.
구현예 18. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 90 mg인, 방법.
구현예 19. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 120 mg인, 방법.
구현예 20. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 약 10 mg인, 방법.
구현예 21. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 약 30 mg인, 방법.
구현예 22. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 약 60 mg인, 방법.
구현예 23. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 약 90 mg인, 방법.
구현예 24. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 약 120 mg인, 방법.
구현예 25. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 및 300 mg 중 어느 하나인, 방법.
구현예 26. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 약 5 mg, 약 10 mg, 약 15 mg, 약 20 mg, 약 25 mg, 약 30 mg, 약 35 mg, 약 40 mg, 약 45 mg, 약 50 mg, 약 55 mg, 약 60 mg, 약 65 mg, 약 70 mg, 약 75 mg, 약 80 mg, 약 85 mg, 약 90 mg, 약 95 mg, 약 100 mg, 약 105 mg, 약 110 mg, 약 115 mg, 약 120 mg, 약 125 mg, 약 130 mg, 약 135 mg, 약 140 mg, 약 145 mg, 약 150 mg, 약 155 mg, 약 160 mg, 약 165 mg, 약 170 mg, 약 175 mg, 약 180 mg, 약 185 mg, 약 190 mg, 약 195 mg, 약 200 mg, 약 205 mg, 약 210 mg, 약 215 mg, 약 220 mg, 약 225 mg, 약 230 mg, 약 235 mg, 약 240 mg, 약 245 mg, 약 250 mg, 약 255 mg, 약 260 mg, 약 265 mg, 약 270 mg, 약 275 mg, 약 280 mg, 약 285 mg, 약 290 mg, 약 295 mg, 및 약 300 mg 중 어느 하나인, 방법.
구현예 27. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 115.0 mg, 115.1 mg, 115.2 mg, 115.3 mg, 115.4 mg, 115.5 mg, 115.6 mg, 115.7 mg, 115.8 mg, 115.9 mg, 116.0 mg, 116.1 mg, 116.2 mg, 116.3 mg, 116.4 mg, 116.5 mg, 116.6 mg, 116.7 mg, 116.8 mg, 116.9 mg, 117.0 mg, 117.1 mg, 117.2 mg, 117.3 mg, 117.4 mg, 117.5 mg, 117.6 mg, 117.7 mg, 117.8 mg, 117.9 mg, 118.0 mg, 118.1 mg, 118.2 mg, 118.3 mg, 118.4 mg, 118.5 mg, 118.6 mg, 118.7 mg, 118.8 mg, 118.9 mg, 119.0 mg, 119.1 mg, 119.2 mg, 119.3 mg, 119.4 mg, 119.5 mg, 119.6 mg, 119.7 mg, 119.8 mg, 119.9 mg, 120.0 mg, 120.1 mg, 120.2 mg, 120.3 mg, 120.4 mg, 120.5 mg, 120.6 mg, 120.7 mg, 120.8 mg, 120.9 mg, 121.0 mg, 121.1 mg, 121.2 mg, 121.3 mg, 121.4 mg, 121.5 mg, 121.6 mg, 121.7 mg, 121.8 mg, 121.9 mg, 122.0 mg, 122.1 mg, 122.2 mg, 122.3 mg, 122.4 mg, 122.5 mg, 122.6 mg, 122.7 mg, 122.8 mg, 122.9 mg, 123.0 mg, 123.1 mg, 123.2 mg, 123.3 mg, 123.4 mg, 123.5 mg, 123.6 mg, 123.7 mg, 123.8 mg, 123.9 mg, 124.0 mg, 124.1 mg, 124.2 mg, 124.3 mg, 124.4 mg, 124.5 mg, 124.6 mg, 124.7 mg, 124.8 mg, 124.9 mg, 및 125.0 mg 중 어느 하나인, 방법.
구현예 28. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 약 115.0 mg, 약 115.1 mg, 약 115.2 mg, 약 115.3 mg, 약 115.4 mg, 약 115.5 mg, 약 115.6 mg, 약 115.7 mg, 약 115.8 mg, 약 115.9 mg, 약 116.0 mg, 약 116.1 mg, 약 116.2 mg, 약 116.3 mg, 약 116.4 mg, 약 116.5 mg, 약 116.6 mg, 약 116.7 mg, 약 116.8 mg, 약 116.9 mg, 약 117.0 mg, 약 117.1 mg, 약 117.2 mg, 약 117.3 mg, 약 117.4 mg, 약 117.5 mg, 약 117.6 mg, 약 117.7 mg, 약 117.8 mg, 약 117.9 mg, 약 118.0 mg, 약 118.1 mg, 약 118.2 mg, 약 118.3 mg, 118.4 mg, 약 118.5 mg, 약 118.6 mg, 약 118.7 mg, 약 118.8 mg, 약 118.9 mg, 약 119.0 mg, 약 119.1 mg, 약 119.2 mg, 약 119.3 mg, 약 119.4 mg, 약 119.5 mg, 약 119.6 mg, 약 119.7 mg, 약 119.8 mg, 약 119.9 mg, 약 120.0 mg, 약 120.1 mg, 약 120.2 mg, 약 120.3 mg, 120.4 mg, 약 120.5 mg, 약 120.6 mg, 약 120.7 mg, 약 120.8 mg, 약 120.9 mg, 약 121.0 mg, 약 121.1 mg, 약 121.2 mg, 약 121.3 mg, 약 121.4 mg, 약 121.5 mg, 약 121.6 mg, 약 121.7 mg, 약 121.8 mg, 약 121.9 mg, 약 122.0 mg, 약 122.1 mg, 약 122.2 mg, 약 122.3 mg, 122.4 mg, 약 122.5 mg, 약 122.6 mg, 약 122.7 mg, 약 122.8 mg, 약 122.9 mg, 약 123.0 mg, 약 123.1 mg, 약 123.2 mg, 약 123.3 mg, 약 123.4 mg, 약 123.5 mg, 약 123.6 mg, 약 123.7 mg, 약 123.8 mg, 약 123.9 mg, 약 124.0 mg, 약 124.1 mg, 약 124.2 mg, 약 124.3 mg, 124.4 mg, 약 124.5 mg, 약 124.6 mg, 약 124.7 mg, 약 124.8 mg, 약 124.9 mg, 및 약 125.0 mg 중 어느 하나인, 방법.
구현예 29. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 40 mg 내지 200 mg, 40 mg 내지 190 mg, 40 mg 내지 180 mg, 40 mg 내지 170 mg, 40 mg 내지 160 mg, 40 mg 내지 150 mg, 40 mg 내지 140 mg, 40 mg 내지 120 mg, 40 mg 내지 110 mg, 40 mg 내지 100 mg, 40 mg 내지 80 mg, 40 mg 내지 70 mg, 40 mg 내지 60 mg, 40 mg 내지 50 mg, 50 mg 내지 200 mg, 50 mg 내지 190 mg, 50 mg 내지 180 mg, 50 mg 내지 170 mg, 50 mg 내지 160 mg, 50 mg 내지 150 mg, 50 mg 내지 140 mg, 50 mg 내지 120 mg, 50 mg 내지 110 mg, 50 mg 내지 100 mg, 50 mg 내지 80 mg, 50 mg 내지 70 mg, 50 mg 내지 60 mg, 60 mg 내지 200 mg, 60 mg 내지 190 mg, 60 mg 내지 180 mg, 60 mg 내지 170 mg, 60 mg 내지 160 mg, 60 mg 내지 150 mg, 60 mg 내지 140 mg, 60 mg 내지 120 mg, 60 mg 내지 110 mg, 60 mg 내지 100 mg, 60 mg 내지 80 mg, 60 mg 내지 70 mg, 70 mg 내지 200 mg, 70 mg 내지 190 mg, 70 mg 내지 180 mg, 70 mg 내지 170 mg, 70 mg 내지 160 mg, 70 mg 내지 150 mg, 70 mg 내지 140 mg, 70 mg 내지 120 mg, 70 mg 내지 110 mg, 70 mg 내지 100 mg, 70 mg 내지 80 mg, 80 mg 내지 200 mg, 80 mg 내지 190 mg, 80 mg 내지 180 mg, 80 mg 내지 170 mg, 80 mg 내지 160 mg, 80 mg 내지 150 mg, 80 mg 내지 140 mg, 80 mg 내지 120 mg, 80 mg 내지 110 mg, 80 mg 내지 100 mg, 80 mg 내지 90 mg, 90 mg 내지 200 mg, 90 mg 내지 190 mg, 90 mg 내지 180 mg, 90 mg 내지 170 mg, 90 mg 내지 160 mg, 90 mg 내지 150 mg, 90 mg 내지 140 mg, 90 mg 내지 120 mg, 90 mg 내지 110 mg, 90 mg 내지 100 mg, 100 mg 내지 200 mg, 100 mg 내지 190 mg, 100 mg 내지 180 mg, 100 mg 내지 170 mg, 100 mg 내지 160 mg, 100 mg 내지 150 mg, 100 mg 내지 140 mg, 100 mg 내지 120 mg, 100 mg 내지 110 mg, 110 mg 내지 200 mg, 110 mg 내지 190 mg, 110 mg 내지 180 mg, 110 mg 내지 170 mg, 110 mg 내지 160 mg, 110 mg 내지 150 mg, 110 mg 내지 140 mg, 110 mg 내지 130 mg, 110 mg 내지 120 mg, 120 mg 내지 200 mg, 120 mg 내지 190 mg, 120 mg 내지 180 mg, 120 mg 내지 170 mg, 120 mg 내지 160 mg, 120 mg 내지 150 mg, 120 mg 내지 140 mg, 120 mg 내지 130 mg, 130 mg 내지 200 mg, 130 mg 내지 190 mg, 130 mg 내지 180 mg, 130 mg 내지 170 mg, 130 mg 내지 160 mg, 130 mg 내지 150 mg, 130 mg 내지 140 mg, 140 mg 내지 200 mg, 140 mg 내지 190 mg, 140 mg 내지 180 mg, 140 mg 내지 170 mg, 140 mg 내지 160 mg, 140 mg 내지 150 mg, 150 mg 내지 200 mg, 150 mg 내지 190 mg, 150 mg 내지 180 mg, 150 mg 내지 170 mg, 150 mg 내지 160 mg, 160 mg 내지 200 mg, 160 mg 내지 190 mg, 160 mg 내지 180 mg, 160 mg 내지 170 mg, 180 mg 내지 200 mg, 180 mg 내지 190 mg, 190 mg 내지 200 mg, 105 mg 내지 135 mg, 105 mg 내지 130 mg, 105 mg 내지 125 mg 105 mg 내지 120 mg, 110 mg 내지 135 mg, 110 mg 내지 130 mg, 110 mg 내지 125 mg, 110 mg 내지 120 mg, 115 mg 내지 135 mg, 115 mg 내지 130 mg, 115 mg 내지 125 mg, 115 mg 내지 120 mg, 115 mg 내지 125 mg, 115 mg 내지 120 mg, 120 mg 내지 135 mg, 120 mg 내지 125 mg, 125 mg 내지 140 mg, 125 mg 내지 130 mg, 130 mg 내지 135 mg, 135 mg 내지 140 mg, 120 mg 내지 129 mg, 120 mg 내지 128 mg, 120 mg 내지 127 mg, 120 mg 내지 86 mg, 120 mg 내지 124 mg, 120 mg 내지 123 mg, 120 mg 내지 122 mg, 120 mg 내지 121 mg, 121 mg 내지 130 mg, 122 mg 내지 129 mg, 122 mg 내지 128 mg, 122 mg 내지 127 mg, 122 mg 내지 126 mg, 122 mg 내지 125 mg, 122 mg 내지 124 mg, 122 mg 내지 123 mg, 123 mg 내지 130 mg, 123 mg 내지 129 mg, 123 mg 내지 128 mg, 123 mg 내지 127 mg, 123 mg 내지 126 mg, 123 mg 내지 125 mg, 123 mg 내지 124 mg, 124 mg 내지 130 mg, 124 mg 내지 129 mg, 124 mg 내지 128 mg, 124 mg 내지 127 mg, 124 mg 내지 126 mg, 124 mg 내지 125 mg, 125 mg 내지 129 mg, 125 mg 내지 128 mg, 125 mg 내지 127 mg, 125 mg 내지 126 mg, 126 mg 내지 130 mg, 126 mg 내지 129 mg, 126 mg 내지 128 mg, 126 mg 내지 127 mg, 127 mg 내지 130 mg, 127 mg 내지 129 mg, 127 mg 내지 128 mg, 128 mg 내지 130 mg, 128 mg 내지 129 mg, 및 129 mg 내지 130 mg 중 임의의 범위 내에 있는, 방법.
구현예 30. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 300 mg 미만, 295 mg 미만, 290 mg 미만, 285 mg 미만, 280 mg 미만, 275 mg 미만, 270 mg 미만, 265 mg 미만, 260 mg 미만, 255 mg 미만, 250 mg 미만, 245 mg 미만, 240 mg 미만, 235 mg 미만, 230 mg 미만, 225 mg 미만, 220 mg 미만, 215 mg 미만, 210 mg 미만, 205 mg 미만, 200 mg 미만, 195 mg 미만, 190 mg 미만, 185 mg 미만, 180 mg 미만, 175 mg 미만, 170 mg 미만, 165 mg 미만, 160 mg 미만, 150 mg 미만, 145 mg 미만, 140 mg 미만, 135 mg 미만, 130 mg 미만, 125 mg 미만, 120 mg 미만, 115 mg 미만, 110 mg 미만, 105 mg 미만, 100 mg 미만, 95 mg 미만, 90 mg 미만, 85 mg 미만, 80 mg 미만, 75 mg 미만, 70 mg 미만, 65 mg 미만, 60 mg 미만, 55 mg 미만, 50 mg 미만, 45 mg 미만, 40 mg 미만, 35 mg 미만, 30 mg 미만, 25 mg 미만, 20 mg 미만, 15 mg 미만, 10 mg 미만, 및 5 mg 미만 중 어느 하나인, 방법.
구현예 31. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 약 300 mg 미만, 약 295 mg 미만, 약 290 mg 미만, 약 285 mg 미만, 약 280 mg 미만, 약 275 mg 미만, 약 270 mg 미만, 약 265 mg 미만, 약 260 mg 미만, 약 255 mg 미만, 약 250 mg 미만, 약 245 mg 미만, 약 240 mg 미만, 약 235 mg 미만, 약 230 mg 미만, 약 225 mg 미만, 약 220 mg 미만, 약 215 mg 미만, 약 210 mg 미만, 약 205 mg 미만, 약 200 mg 미만, 약 195 mg 미만, 약 190 mg 미만, 약 185 mg 미만, 약 180 mg 미만, 약 175 mg 미만, 약 170 mg 미만, 약 165 mg 미만, 약 160 mg 미만, 약 150 mg 미만, 약 145 mg 미만, 약 140 mg 미만, 약 135 mg 미만, 약 130 mg 미만, 약 125 mg 미만, 약 120 mg 미만, 약 115 mg 미만, 약 110 mg 미만, 약 105 mg 미만, 약 100 mg 미만, 약 95 mg 미만, 약 90 mg 미만, 약 85 mg 미만, 약 80 mg 미만, 약 75 mg 미만, 약 70 mg 미만, 약 65 mg 미만, 약 60 mg 미만, 약 55 mg 미만, 약 50 mg 미만, 약 45 mg 미만, 약 40 mg 미만, 약 35 mg 미만, 약 30 mg 미만, 약 25 mg 미만, 약 20 mg 미만, 약 15 mg 미만, 약 10 mg 미만, 및 약 5 mg 미만 중 어느 하나인, 방법.
구현예 32. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 적어도 5 mg, 적어도 10 mg, 적어도 15 mg, 적어도 20 mg, 적어도 25 mg, 적어도 30 mg, 적어도 35 mg, 적어도 40 mg, 적어도 45 mg, 적어도 50 mg, 적어도 55 mg, 적어도 60 mg, 적어도 65 mg, 적어도 70 mg, 적어도 75 mg, 적어도 80 mg, 적어도 85 mg, 적어도 90 mg, 적어도 95 mg, 적어도 약 100 mg, 적어도 105 mg, 적어도 115 mg, 적어도 120 mg, 적어도 125 mg, 적어도 130 mg, 적어도 135 mg, 적어도 140 mg, 적어도 145 mg, 적어도 150 mg, 적어도 155 mg, 적어도 160 mg, 적어도 165 mg, 적어도 170 mg, 적어도 175 mg, 적어도 180 mg, 적어도 185, 적어도 190 mg, 적어도 195 mg, 및 적어도 200 mg 중 어느 하나인, 방법.
구현예 33. 구현예 1 내지 14 중 어느 하나에 있어서, 상기 치료학적 유효량이 적어도 약 5 mg, 적어도 약 10 mg, 적어도 약 15 mg, 적어도 약 20 mg, 적어도 약 25 mg, 적어도 약 30 mg, 적어도 약 35 mg, 적어도 약 40 mg, 적어도 약 45 mg, 적어도 약 50 mg, 적어도 약 55 mg, 적어도 약 60 mg, 적어도 약 65 mg, 적어도 약 70 mg, 적어도 약 75 mg, 적어도 약 80 mg, 적어도 약 85 mg, 적어도 약 90 mg, 적어도 약 95 mg, 적어도 약 100 mg, 적어도 약 105 mg, 적어도 약 115 mg, 적어도 약 120 mg, 적어도 약 125 mg, 적어도 약 130 mg, 적어도 약 135 mg, 적어도 약 140 mg, 적어도 약 145 mg, 적어도 약 150 mg, 적어도 약 155 mg, 적어도 약 160 mg, 적어도 약 165 mg, 적어도 약 170 mg, 적어도 약 175 mg, 적어도 약 180 mg, 적어도 약 185, 적어도 약 190 mg, 적어도 약 195 mg, 및 적어도 약 200 mg 중 어느 하나인, 방법.
구현예 34. 구현예 1 내지 33 중 어느 하나에 있어서, 4주 마다 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 35. 구현예 1 내지 33 중 어느 하나에 있어서, 8주 마다 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 36. 구현예 1 내지 33 중 어느 하나에 있어서, 12주 마다 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 37. 구현예 1 내지 33 중 어느 하나에 있어서, 16주 마다 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 38. 구현예 1 내지 33 중 어느 하나에 있어서, 20주 마다 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 39. 구현예 1 내지 33 중 어느 하나에 있어서, 4주 마다 약 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 40. 구현예 1 내지 33 중 어느 하나에 있어서, 8주 마다 약 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 41. 구현예 1 내지 33 중 어느 하나에 있어서, 12주 마다 약 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 42. 구현예 1 내지 33 중 어느 하나에 있어서, 16주 마다 약 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 43. 구현예 1 내지 33 중 어느 하나에 있어서, 20주 마다 약 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 44. 구현예 1 내지 33 중 어느 하나에 있어서, 1주 마다 1회, 2주 마다 1회, 3주 마다 1회, 4주 마다 1회, 5주 마다 1회, 6주 마다 1회, 7주 마다 1회, 8주 마다 1회, 9주 마다 1회, 10주 마다 1회, 11주 마다 1회, 12주 마다 1회, 13주 마다 1회, 14주 마다 1회, 15주 마다 1회, 16주 마다 1회, 17주 마다 1회, 18주 마다 1회, 19주 마다 1회, 및 20주 마다 1회로 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 45. 구현예 1 내지 33 중 어느 하나에 있어서, 약 1주 마다 1회, 약 2주 마다 1회, 약 3주 마다 1회, 약 4주 마다 1회, 약 5주 마다 1회, 약 6주 마다 1회, 약 7주 마다 1회, 약 8주 마다 1회, 약 9주 마다 1회, 약 10주 마다 1회, 약 11주 마다 1회, 약 12주 마다 1회, 약 13주 마다 1회, 약 14주 마다 1회, 약 15주 마다 1회, 약 16주 마다 1회, 약 17주 마다 1회, 약 18주 마다 1회, 약 19주 마다 1회, 및 약 20주 마다 1회로 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 46. 구현예 1 내지 33 중 어느 하나에 있어서, 상기 변형된 올리고뉴클레오타이드 120 mg의 초기 부하 용량을 인간 대상체에게 투여하는 단계를 포함하는, 방법.
구현예 47. 구현예 46에 있어서, 초기 부하 용량 4주 후 상기 변형된 올리고뉴클레오타이드 120 mg의 제2 부하 용량을 인간 대상체에게 투여하는 단계를 포함하는, 방법.
구현예 48. 구현예 47에 있어서, 제2 부하 용량 4주 후 상기 변형된 올리고뉴클레오타이드 120 mg의 유지 용량을 인간 대상체에게 투여하는 단계를 포함하는, 방법.
구현예 49. 구현예 47에 있어서, 제2 부하 용량 8주 후 상기 변형된 올리고뉴클레오타이드 120 mg의 유지 용량을 인간 대상체에게 투여하는 단계를 포함하는, 방법.
구현예 50. 구현예 47에 있어서, 제2 부하 용량 12주 후 상기 변형된 올리고뉴클레오타이드 120 mg의 유지 용량을 인간 대상체에게 투여하는 단계를 포함하는, 방법.
구현예 51. 구현예 47에 있어서, 제2 부하 용량 16주 후 상기 변형된 올리고뉴클레오타이드 120 mg의 유지 용량을 인간 대상체에게 투여하는 단계를 포함하는, 방법.
구현예 52. 구현예 7 내지 10 및 15 내지 51 중 어느 하나에 있어서, 상기 HTT RNA가 mHTT RNA인, 방법.
구현예 53. 구현예 11 내지 51 중 어느 하나에 있어서, 상기 HTT 단백질이 mHTT 단백질인, 방법.
구현예 54. HD 개선, HTT RNA 감소, HTT 단백질 감소, mHTT RNA 감소 또는 mHTT 단백질 감소를 필요로 하는 인간 대상체에서 HD 개선, HTT RNA 감소, HTT 단백질 감소, mHTT RNA 감소 또는 mHTT 단백질을 감소시키는 방법으로서, 상기 방법이 120 mg 또는 약 120 mg의 치료학적 유효량의 하기 화학 구조에 따른 변형된 올리고뉴클레오타이드 또는 이의 염을 인간 대상체에게 척수강내 투여하는 단계를 포함하는, 방법:
(서열번호 4).
구현예 55. 구현예 54에 있어서, 상기 변형된 올리고뉴클레오타이드가 나트륨 염 또는 칼륨 염인, 방법.
구현예 56. HD 개선, HTT RNA 감소, HTT 단백질 감소, mHTT RNA 감소 또는 mHTT 단백질 감소를 필요로 하는 인간 대상체에서 HD 개선, HTT RNA 감소, HTT 단백질 감소, mHTT RNA 감소 또는 mHTT 단백질을 감소시키는 방법으로서, 상기 방법이 하기의 화학 구조에 따른 변형된 올리고뉴클레오타이드의 120 mg 또는 약 120 mg의 치료학적 유효량을 인간 대상체에게 척수강내 투여하는 단계를 포함하는, 방법:
(서열번호 4).
구현예 57. HD 개선, HTT RNA 감소, HTT 단백질 감소, HTT mRNA 감소 또는 mHTT 단백질 감소를 필요로 하는 인간 대상체에서 HD를 개선시키거나, HTT RNA를 감소시키거나, HTT 단백질을 감소시키거나, HTT mRNA를 감소시키거나, mHTT 단백질을 감소시키는 방법으로서, 상기 방법이 변형된 올리고뉴클레오타이드의 120 mg 또는 약 120 mg의 치료학적 유효량을 인간 대상체에게 척수강내 투여하는 단계를 포함하고, 상기 변형된 올리고뉴클레오타이드가 mCes Teo mCeo Aeo Ges Tds Ads Ads mCds Ads Tds Tds Gds Ads mCds Aeo mCeo mCeo Aes mCe (서열번호 4)의 화학적 표기법(5'에서 3')을 갖고; 여기서,
A = 아데닌 뉴클레오염기,
mC = 5-메틸 시토신 뉴클레오염기,
G = 구아닌 뉴클레오염기,
T = 티민 뉴클레오염기,
e = 2'-MOE 당 모이어티,
d = 2'-β-D-데옥시리보실 당 모이어티,
s = 포스포로티오에이트 뉴클레오시드간 연결, 및
o = 포스포디에스테르 뉴클레오시드간 연결
인, 방법.
구현예 58. 구현예 54 내지 57 중 어느 하나에 있어서, 4주 마다 약 1회로 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 59. 구현예 54 내지 57 중 어느 하나에 있어서, 8주 마다 약 1회로 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 60. 구현예 54 내지 57 중 어느 하나에 있어서, 16주 마다 약 1회로 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
구현예 61. 구현예 54 내지 57 중 어느 하나에 있어서, 상기 인간 대상체에게 하기를 투여하는 단계를 포함하는 방법:
a) 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 초기 부하 용량,
b) 상기 초기 부하 용량 투여 약 4주 후에 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 제2 부하 용량;
c) 상기 제2 부하 용량 투여 약 8주 후에 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 제1 유지 용량;
d) 상기 제1 유지 용량 투여 약 8주 후에 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 제2 유지 용량.
구현예 62. 구현예 54 내지 57 중 어느 하나에 있어서, 상기 인간 대상체에게 하기를 투여하는 단계를 포함하는 방법:
a) 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 초기 부하 용량,
b) 상기 초기 부하 용량 투여 약 4주 후에 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 제2 부하 용량;
c) 상기 제2 부하 용량 투여 약 16주 후에 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 제1 유지 용량;
d) 상기 제1 유지 용량 투여 약 16주 후에 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 제2 유지 용량.
구현예 63. 구현예 54 내지 62 중 어느 하나에 있어서, HD의 적어도 하나의 증상이 개선되는, 방법.
구현예 64. 구현예 63에 있어서, 상기 적어도 하나의 증상이 뇌 위축증, 뇌 활동 감소증, 뇌 연결성 감소증, 근육 위축증, 신경 변성, 심부전, 내당능 손상, 체중 감소증, 골다공증, 고환 위축증, 전반적인 기능 손상, 운동 기능 손상, 인지 기능 손상, 일상 기능 손상, 주의력 손상, 시각 지각 처리 손상, 작업 기억 손상, 정신 운동 속도 손상, 언어 운동 아웃풋 손상, 독립성 정도 손상, 무감각증 손상, 학습 능력 손상, 정신 집중력 손상, 언어 손상, 우울증, 과민성, 분노, 운동능 손상, 자기 관리 손상, 통증, 불편함, 불안증, 자살 생각, 자살 행동 또는 이들의 조합을 포함하는, 방법.
구현예 65. 구현예 1 내지 64 중 어느 하나에 있어서, 상기 인간 대상체가 적어도 하나의 IT15 유전자에 돌연변이를 갖는, 방법.
구현예 66. 구현예 1 내지 65 중 어느 하나에 있어서, 상기 인간 대상체의 적어도 하나의 IT15 유전자에서 돌연변이를 동정하는 단계를 포함하는, 방법.
구현예 67. 구현예 65 또는 구현예 66에 있어서, 상기 적어도 하나의 IT15 유전자가 적어도 25, 적어도 26, 적어도 27, 적어도 28, 적어도 29, 적어도 30, 적어도 31, 적어도 32, 적어도 33, 적어도 34, 적어도 35, 적어도 36, 적어도 37, 적어도 38, 적어도 39, 적어도 40, 적어도 41, 적어도 42, 적어도 43, 적어도 44, 적어도 45, 적어도 46, 적어도 47, 적어도 48, 적어도 49, 적어도 50, 적어도 51, 적어도 52, 적어도 53, 적어도 54, 적어도 55, 적어도 56, 적어도 57, 적어도 58, 적어도 59, 또는 적어도 60개 연속 CAG 반복체 중 어느 하나를 갖는, 방법.
구현예 68. 구현예 65 또는 구현예 66에 있어서, 상기 적어도 하나의 IT15 유전자가 27 내지 35개 연속 CAG 반복체를 갖는, 방법.
구현예 69. 구현예 65 또는 구현예 66에 있어서, 상기 적어도 하나의 IT15 유전자가 35 내지 60개 연속 CAG 반복체를 갖는, 방법.
구현예 70. 구현예 65 또는 구현예 66에 있어서, 상기 적어도 하나의 IT15 유전자가 60개 초과의 연속 CAG 반복체를 갖는, 방법.
구현예 71. 구현예 1 내지 70 중 어느 하나에 있어서, 상기 변형된 올리고뉴클레오타이드가 상기 인간 대상체의 CNS에 투여되는, 방법.
구현예 72. 구현예 1 내지 71 중 어느 하나에 있어서, 상기 변형된 올리고뉴클레오타이드가 척수강내 투여에 의해 투여되는, 방법.
구현예 73. 구현예 1 내지 72 중 어느 하나에 있어서, 상기 변형된 올리고뉴클레오타이드가 볼러스 척수강내 투여에 의해 투여되는, 방법.
구현예 74. 구현예 1 내지 73 중 어느 하나에 있어서, HTT RNA가 감소되는, 방법.
구현예 75. 구현예 1 내지 74 중 어느 하나에 있어서, HTT 단백질이 감소되는, 방법.
구현예 76. 구현예 1 내지 75 중 어느 하나에 있어서, mHTT RNA가 감소되는, 방법.
구현예 77. 구현예 1 내지 76 중 어느 하나에 있어서, mHTT 단백질이 감소되는, 방법.
구현예 78. 구현예 1 내지 77 중 어느 하나에 있어서, 상기 인간 대상체 기원의 생물학적 샘플 중에 mHTT RNA의 양을 검출하는 단계를 포함하는, 방법.
구현예 79. 구현예 1 내지 78 중 어느 하나에 있어서, 상기 인간 대상체 기원의 생물학적 샘플 중에 mHTT 단백질의 양을 검출하는 단계를 포함하는, 방법.
구현예 80. 구현예 1 내지 79 중 어느 하나에 있어서, 상기 생물학적 샘플이 뇌척수액을 포함하는, 방법.
구현예 81. 구현예 78 내지 80 중 어느 하나에 있어서, 상기 검출이 투여 전에 수행되는, 방법.
구현예 82. 구현예 78 내지 80 중 어느 하나에 있어서, 상기 검출이 투여 후에 수행되는, 방법.
구현예 83. 구현예 78 내지 80 중 어느 하나에 있어서, 상기 검출이 투여 전 및 후에 수행되는, 방법.
구현예 84. 구현예 78 내지 83 중 어느 하나에 있어서, HTT RNA, HTT 단백질, mHTT RNA, mHTT 단백질 또는 이의 조합의 양을 검출한 후 투여되는 초기 부하 용량, 부하 용량, 유지 용량 또는 치료학적 유효량을 조정하는 단계를 포함하는, 방법.
구현예 85. 구현예 1 내지 84 중 어느 하나에 있어서, 상기 대상체에 대해 뇌파도(EEG) 또는 자기공명영상(MRI)을 수행함으로써 대상체의 뇌 활동, 뇌 크기, 또는 이들의 조합을 분석하는 단계를 포함하는, 방법.
구현예 86. 구현예 85에 있어서, 상기 EEG 또는 MRI가 투여 전, 투여 후 또는 이의 조합으로 수행되는, 방법.
구현예 87. 구현예 86에 있어서, EEG 또는 MRI를 수행한 후 치료학적 유효량을 결정하거나 조정하는 단계를 포함하는, 방법.
구현예 88. 구현예 87에 있어서, 투여 후 EEG 또는 MRI를 수행하는 단계 및 EEG 또는 MRI를 수행한 후 투여 빈도를 조정하는 단계를 포함하는, 방법.
구현예 89. 구현예 85 내지 88 중 어느 하나에 있어서, EEG 또는 MRI가 투여 1, 2, 4, 6, 8, 12 또는 24시간 이내에 수행되는, 방법.
구현예 90. 구현예 85 내지 89 중 어느 하나에 있어서, 투여 전 EEG를 수행하는 단계 및 투여 후 분석하는 단계, 제1 EEG로부터 제2 EEG까지의 EEG 신호 전력에서 4 Hz 미만의 증가를 검출하는 단계, 및 이어서 변형된 올리고뉴클레오타이드의 치료학적 유효량을 투여하는 빈도를 증가시키는 단계를 포함하는, 방법.
구현예 91. 구현예 90에 있어서, 약 4주 마다 1회 부하 용량을 투여하는 단계 및 제1 EEG를 기록하기 전 약 8주 또는 16주 마다 1회 유지 용량을 투여하는 단계 및 약 8주 미만 마다 또는 약 16주 미만 마다 유지 용량을 투여하는 단계를 포함하는, 방법.
구현예 92. 구현예 85 내지 91 중 어느 하나에 있어서, 투여 전 제1 EEG를 기록하는 단계, 및 투여 후 제2 EEG를 기록하는 단계, 제1 EEG에서 제2 EEG까지 EEG 신호 전력에서 4 Hz 미만의 증가를 검출하는 단계, 및 이어서 치료학적 유효량 초과인 변형된 올리고뉴클레오타이드의 용량을 투여하는 단계를 포함하는, 방법.
구현예 93. 구현예 92에 있어서, 상기 용량이 치료학적 유효량의 적어도 약 10%, 적어도 약 20%, 적어도 약 30%, 적어도 약 40%, 적어도 약 50%, 적어도 약 60%, 적어도 약 70%, 적어도 약 90%, 또는 적어도 약 100% 초과인, 방법.
구현예 94. 구현예 85 내지 93 중 어느 하나에 있어서, 상기 치료학적 유효량이 약 120 mg 또는 120 mg인, 방법.
I.
HTT
특정 구현예에서, 본원에서는 대상체의 세포 또는 생물학적 유체에서 HTT RNA 및/또는 HTT 단백질을 감소시키는 방법이 기재된다. 특정 구현예에서, HTT RNA는 mHTT RNA이다. 특정 구현예에서, HTT 단백질은 mHTT 단백질이다. HTT RNA는 인간 염색체 4의 짧은 (p) 아암 상에 위치한 인간 IT15 유전자에 의해 암호화되어 있다. HTT 단백질은 HTT RNA의 단백질 발현 생성물이다. HTT 단백질은 다른 세포 유형에 비해 뉴런에서 높게 발현된다. 인간 IT15 유전자에 대한 대표적인 뉴클레오염기 서열은 서열번호 1로서 본원에 언급된, 뉴클레오타이드 3072001에서 3247000까지 절단된 GENBANK 승인 번호 NC_000004.12로 제공된다. 인간 HTT RNA에 대한 대표적인 뉴클레오염기 서열은 서열번호 2로서 본원에 언급된, GENBANK 승인 번호 NM_002111.6으로 제공된다. 인간 HTT 단백질에 대한 대표적인 단백질 서열은 서열번호 3으로서 본원에 언급된, GENBANK 승인 번호 NP 002102.4로 제공된다.
II.
ISIS 443139
특정 구현예에서, 본원에서는 변형된 올리고뉴클레오타이드, ISIS 443139를 이를 필요로 하는 대상체에게 투여하는 방법이 기재되어 있다. 특정 구현예에서, ISIS 443139는 (5'에서 3') CTCAGTAACATTGACACCAC(본원에 서열번호 4로 인용됨)의 서열을 갖는 5-10-5 MOE 갭머(gapmer)로서 특징분석되고, 여기서 각각의 뉴클레오시드 1-5 및 16-20(5'에서 3')은 2'-MOE 뉴클레오시드이고, 각각의 뉴클레오시드 6-15는 2'-β-D 데옥시리보뉴클레오시드이고, 여기서 뉴클레오시드 2에서 3, 3에서 4, 4에서 5, 16에서 17, 17에서 18, 및 18에서 19 사이의 뉴클레오시드간 연결은 포스포디에스테르 뉴클레오시드간 연결 및 뉴클레오시드 1에서 2, 5에서 6, 6에서 7, 7에서 8, 8에서 9, 9에서 10, 10에서 11, 11에서 12, 12에서 13, 13에서 14, 14에서 15, 15에서 16, 및 19에서 20 사이의 뉴클레오시드간 연결은 포스포로티오에이트 뉴클레오시드간 연결이고, 여기서 각각의 시토신은 5-메틸 시토신이다.
특정 구현예에서, ISIS 443139는 하기의 화학적 표기법(5'에서 3')으로 나타낸다: mCes Teo mCeo Aeo Ges Tds Ads Ads mCds Ads Tds Tds Gds Ads mCds Aeo mCeo mCeo Aes mCe (서열번호 4); 여기서,
A = 아데닌 뉴클레오염기,
mC = 5-메틸 시토신 뉴클레오염기,
G = 구아닌 뉴클레오염기,
T = 티민 뉴클레오염기,
e = 2'-MOE 당 모이어티,
d = 2'-β-D-데옥시리보실 당 모이어티,
s = 포스포로티오에이트 뉴클레오시드간 연결, 및
o = 포스포디에스테르 뉴클레오시드간 연결.
특정 구현예에서, ISIS 443139는 하기의 화학 구조로 나타낸다:
(서열번호 4).
구조 1. ISIS 443139
특정 구현예에서, ISIS 443139의 나트륨 염은 하기의 화학 구조로 나타낸다:
(서열번호 4).
구조 2. ISIS 443139의 나트륨 염
III.
특정 약제학적 조성물
특정 구현예에서, 본원에서는 변형된 올리고뉴클레오타이드 ISIS 443139를 포함하는 약제학적 조성물을 대상체에게 투여하는 방법이 기재된다. 특정 구현예에서, 약제학적 조성물은 약제학적으로 허용되는 희석제 또는 담체를 포함한다. 특정 구현예에서, 약제학적 조성물은 멸균 식염수 및 변형된 올리고뉴클레오타이드 ISIS 443139를 포함하거나 이들로 필수적으로 이루어진다. 특정 구현예에서, 멸균 식염수는 약제학적 등급의 식염수이다. 특정 구현예에서, 약제학적 조성물은 멸균수 및 변형된 올리고뉴클레오타이드 ISIS 443139를 포함하거나 이들로 필수적으로 이루어진다. 특정 구현예에서, 멸균수는 약제학적 등급의 물이다. 특정 구현예에서, 약제학적 조성물은 인공 뇌척수액(aCSF) 및 변형된 올리고뉴클레오타이드 ISIS 443139를 포함하거나 이들로 필수적으로 이루어진다. 특정 구현예에서, 인공 뇌척수액은 약제학적 등급이다.
특정 구현예에서, 약제학적 조성물은 하나 이상의 부형제 및 변형된 올리고뉴클레오타이드 ISIS 443139를 포함한다. 특정 구현예에서, 부형제는 물, 염 용액, 알콜, 폴리에틸렌 글리콜, 겔라틴, 락토스, 아밀라제, 마그네슘 스테아레이트, 활석, 규산, 점성 파라핀, 히드록시메틸셀룰로스, 및 폴리비닐피롤리돈으로부터 선택된다.
특정 구현예에서, 변형된 올리고뉴클레오타이드 ISIS 443139를 포함하는 약제학적 조성물은 변형된 올리고뉴클레오타이드 ISIS 443139의 임의의 약제학적으로 허용되는 염, 변형된 올리고뉴클레오타이드 ISIS 443139의 에스테르, 또는 상기 에스테르의 염을 포함한다. 특정 구현예에서, 변형된 올리고뉴클레오타이드 ISIS 443139를 포함하는 약제학적 조성물은 인간 대상체에 투여시 생물학적 활성 대사산물 또는 이의 잔기를 (직접적으로 또는 간접적으로) 제공할 수 있다. 따라서, 예를 들어, 본원 개시내용은 또한 변형된 올리고뉴클레오타이드 ISIS 443139의 약제학적으로 허용되는 염, 변형된 올리고뉴클레오타이드 ISIS 443139의 프로드럭, 이러한 프로드럭의 약제학적으로 허용되는 염, 및 기타 생등가물에 관한 것이다. 적합한 약제학적으로 허용되는 염은 나트륨 및 칼륨 염을 포함하지만, 이들에 제한되지 않는다.
특정 구현예에서, 약제학적 조성물은 하나 이상의 지질 모이어티 및 변형된 올리고뉴클레오타이드 ISIS 443139를 포함한다. 특정 구현예에서, 지질 모이어티는 특정 세포 또는 조직으로의 ISIS 443139의 분포를 증가시키기 위해 사용된다. 특정 상기 방법에서, 상기 변형된 올리고뉴클레오타이드 ISIS 443139는 양이온성 지질 및 중성 지질의 혼합물로 이루어진 미리 형성된 리포좀 또는 지질복합체로 도입된다. 특정 방법에서, 단일- 또는 다중-양이온 지질과의 DNA 복합체는 중성 지질의 존재 없이 형성된다.
특정 구현예에서, 본원에 기재된 약제학적 조성물은 전달 시스템을 포함한다. 전달 시스템의 예는 리포좀 및 에멀젼을 포함하지만 이에 제한되지 않는다. 특정 전달 시스템은 소수성 화합물을 포함하는 것을 포함하는 약제학적 조성물을 제조하기 위해 유용하다. 특정 구현예에서, 특정 유기 용매, 예를 들어, 디메틸설폭사이드가 사용된다.
특정 구현예에서, 약제학적 조성물은 본원에 기재된 변형된 올리고뉴클레오타이드를 특정 조직 또는 세포 유형에 전달하도록 디자인된 하나 이상의 조직-특이적 전달 분자를 포함한다. 예를 들어, 특정 구현예에서, 약제학적 조성물은 조직-특이적 항체로 코팅된 리포좀을 포함한다.
특정 구현예에서, 약제학적 조성물은 조용매 시스템을 포함한다. 이러한 특정 조용매 시스템은 예를 들어 벤질 알코올, 비극성 계면활성제, 수혼화성 유기 중합체, 및 수성상을 포함한다. 특정 구현예에서, 상기 조용매 시스템은 소수성 화합물에 대해 사용된다. 이러한 조용매 시스템의 비제한적인 예는 VPD 조용매 시스템이고, 이는 3% w/v의 벤질 알코올, 8% w/v의 비극성 계면활성제 Polysorbate 80™ 및 65 % w/v의 폴리에틸렌 글리콜 300의 용액이다. 이러한 조용매 시스템의 비율은 용해도 및 독성 특성을 크게 변경하지 않고 상당히 다양할 수 있다. 또한 조용매 성분의 정체는 다양할 수 있다: 예를 들어 Polysorbate 80™ 대신 다른 계면활성제가 사용될 수 있고; 폴리에틸렌 글리콜의 분획 크기는 다양할 수 있으며; 다른 생체적합성 중합체는 폴리에틸렌 글리콜, 예를 들어 폴리비닐 피롤리돈을 대체할 수 있고; 기타 당 또는 폴리사카라이드가 덱스트로스를 대체할 수 있다.
특정 구현예에서, 약제학적 조성물은 경구 투여용으로 제조된다. 특정 구현예에서, 약제학적 조성물은 협측 투여용으로 제조된다. 특정 구현예에서, 약제학적 조성물은 주사 (예를 들어, 정맥내, 피하, 근육내, 척수강내(IT), 뇌실내(ICV))에 의한 투여용으로 제조된다. 이러한 특정 구현예에서, 약제학적 조성물은 담체를 포함하고 aCSF, 물과 같은 수용액, 또는 행크스 용액, 링거 용액, 또는 생리 식염수 완충제와 같은 생리학적 상용성 완충제로 제형화된다. 특정 구현예에서, 다른 성분이 포함된다(예를 들어, 용해도를 보조하거나 보존제로 작용하는 성분). 특정 구현예에서, 주사가능한 현탁액은 적절한 액체 담체, 현탁제 등을 사용하여 제조된다. 특정 주사용 약제학적 조성물은 단위 투여 형태, 예를 들어 앰푸울 또는 다중 용량 컨테이너로 제공된다. 주사용 특정 약제학적 조성물은 유성 또는 수성 비히클 중의 현탁액, 용액 또는 에멀젼이고, 현탁제, 안정화제 및/또는 분산제와 같은 제형화 제제를 함유할 수 있다. 주사용 약제학적 조성물에 사용하기에 적합한 특정 용매는 친지성 용매 및 지방 오일, 예를 들어 참기름, 합성 지방산 에스테르, 예를 들어 에틸 올레에이트 또는 트리글리세리드, 및 리포좀을 포함하지만 이에 제한되지 않는다.
특정 조건하에서, 변형된 올리고뉴클레오타이드 ISIS 443139는 산으로서 작용한다. ISIS 443139가 양성자화된(유리산) 형태로 도시되거나 설명될 수 있거나 이온화되고 양이온(염) 형태와 결합될 수 있지만 ISIS 443139의 수용액은 이러한 형태 사이에서 평형 상태로 존재한다. 예를 들어, 수용액에서 ISIS 443139의 포스페이트 연결은 유리산, 음이온 및 염 형태 사이에서 평형 상태로 존재한다. 달리 특정되지 않는 경우, 용어 "ISIS 443139"는 모든 상기 형태를 포함하도록 의도된다. 더욱이 ISIS 443139에는 이러한 연결이 여러 개 있고, 이의 각각은 평형 상태로 있다. 따라서 ISIS 443139는 여러 위치에서 모두 평형 상태에 있는 앙상블 형태로 용액 중에 존재한다. 용어 "ISIS 443139"는 모든 상기 형태를 포함하는 것으로 의도된다. 그려진 구조는 필수적으로 단일 형태를 도시한다. 그럼에도 불구하고, 달리 지적되지 않는 경우, 상기 도면은 또한 상응하는 형태를 포함하는 것으로 의도된다. 본원에서, ISIS 443139의 유리산 다음에 용어 "또는 이의 염"을 나타내는 구조는 양이온과 연합하여 완전히 또는 부분적으로 양성자화/탈양성자화될 수 있는 모든 상기 형태를 명시적으로 포함한다. 특정 경우에서, 하나 이상의 특정 양이온이 확인된다.
특정 구현예에서, ISIS 443139는 나트륨과의 수용액 중에 있다. 특정 구현예에서, ISIS 443139는 칼륨과의 수용액 중에 있다. 특정 구현예에서, ISIS 443139는 PBS 중에 있다. 특정 구현예에서, ISIS 443139는 물 중에 있다. 이러한 특정 구현예에서, 용액의 pH는 목적하는 pH를 달성하기 위해 NaOH 및/또는 HCl로 조정된다.
본원에서, 특정한 구체적인 용량이 기재된다. 명확성을 위해 밀리그램 단위의 ISIS 443139 용량은 ISIS 443139의 유리산 형태의 질량을 지적한다. 상기된 바와 같이, 수용액에서 유리산은 음이온 및 염 형태와 평형 상태로 있다. 그러나 용량 계산을 위해 ISIS 443139는 무용매, 나트륨-아세테이트 부재, 무수, 유리산으로 존재하는 것으로 추정된다. 예를 들어, ISIS 443139가 나트륨을 포함하는 용액(예를 들어 식염수)에 있는 경우, ISIS 443139는 부분적으로 또는 완전히 탈양성자화되고 Na+ 이온과 연합될 수 있다. 그러나 양성자의 질량은 그럼에도 불구하고 용량의 무게에 대해 계산되고 Na+ 이온의 질량은 용량의 무게로 계산되지 않는다. 따라서, 예를 들어 ISIS 443139 120 mg의 용량은 무게가 120 mg인 완전히 양성자화된 분자의 수와 균등하다. 이는 무용매, 나트륨-아세테이트 부재, 무수 나트륨화 ISIS 443139 127 mg에 균등하다.
IV.
특정 투여량
특정 구현예에서, 본원에서는 치료학적 유효량의 변형된 올리고뉴클레오타이드 ISIS 443139를 대상체에게 투여하는 방법이 기재된다. 특정 구현예에서, 치료학적 유효량은 10 mg이다. 특정 구현예에서, 치료학적 유효량은 30 mg이다. 특정 구현예에서, 치료학적 유효량은 60 mg이다. 특정 구현예에서, 치료학적 유효량은 90 mg이다. 특정 구현예에서, 치료학적 유효량은 120 mg이다.
특정 구현예에서, 치료학적 유효량은 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 및 300 mg 중 어느 하나이다.
특정 구현예에서, 치료학적 유효량은 약 5 mg, 약 10 mg, 약 15 mg, 약 20 mg, 약 25 mg, 약 30 mg, 약 35 mg, 약 40 mg, 약 45 mg, 약 50 mg, 약 55 mg, 약 60 mg, 약 65 mg, 약 70 mg, 약 75 mg, 약 80 mg, 약 85 mg, 약 90 mg, 약 95 mg, 약 100 mg, 약 105 mg, 약 110 mg, 약 115 mg, 약 120 mg, 약 125 mg, 약 130 mg, 약 135 mg, 약 140 mg, 약 145 mg, 약 150 mg, 약 155 mg, 약 160 mg, 약 165 mg, 약 170 mg, 약 175 mg, 약 180 mg, 약 185 mg, 약 190 mg, 약 195 mg, 약 200 mg, 약 205 mg, 약 210 mg, 약 215 mg, 약 220 mg, 약 225 mg, 약 230 mg, 약 235 mg, 약 240 mg, 약 245 mg, 약 250 mg, 약 255 mg, 약 260 mg, 약 265 mg, 약 270 mg, 약 275 mg, 약 280 mg, 약 285 mg, 약 290 mg, 약 295 mg, 및 약 300 mg 중 어느 하나이다.
특정 구현예에서, 치료학적 유효량은 115.0 mg, 115.1 mg, 115.2 mg, 115.3 mg, 115.4 mg, 115.5 mg, 115.6 mg, 115.7 mg, 115.8 mg, 115.9 mg, 116.0 mg, 116.1 mg, 116.2 mg, 116.3 mg, 116.4 mg, 116.5 mg, 116.6 mg, 116.7 mg, 116.8 mg, 116.9 mg, 117.0 mg, 117.1 mg, 117.2 mg, 117.3 mg, 117.4 mg, 117.5 mg, 117.6 mg, 117.7 mg, 117.8 mg, 117.9 mg, 118.0 mg, 118.1 mg, 118.2 mg, 118.3 mg, 118.4 mg, 118.5 mg, 118.6 mg, 118.7 mg, 118.8 mg, 118.9 mg, 119.0 mg, 119.1 mg, 119.2 mg, 119.3 mg, 119.4 mg, 119.5 mg, 119.6 mg, 119.7 mg, 119.8 mg, 119.9 mg, 120.0 mg, 120.1 mg, 120.2 mg, 120.3 mg, 120.4 mg, 120.5 mg, 120.6 mg, 120.7 mg, 120.8 mg, 120.9 mg, 121.0 mg, 121.1 mg, 121.2 mg, 121.3 mg, 121.4 mg, 121.5 mg, 121.6 mg, 121.7 mg, 121.8 mg, 121.9 mg, 122.0 mg, 122.1 mg, 122.2 mg, 122.3 mg, 122.4 mg, 122.5 mg, 122.6 mg, 122.7 mg, 122.8 mg, 122.9 mg, 123.0 mg, 123.1 mg, 123.2 mg, 123.3 mg, 123.4 mg, 123.5 mg, 123.6 mg, 123.7 mg, 123.8 mg, 123.9 mg, 124.0 mg, 124.1 mg, 124.2 mg, 124.3 mg, 124.4 mg, 124.5 mg, 124.6 mg, 124.7 mg, 124.8 mg, 124.9 mg, 및 125.0 mg 중 어느 하나이다.
특정 구현예에서, 상기 치료학적 유효량은 약 115.0 mg, 약 115.1 mg, 약 115.2 mg, 약 115.3 mg, 약 115.4 mg, 약 115.5 mg, 약 115.6 mg, 약 115.7 mg, 약 115.8 mg, 약 115.9 mg, 약 116.0 mg, 약 116.1 mg, 약 116.2 mg, 약 116.3 mg, 약 116.4 mg, 약 116.5 mg, 약 116.6 mg, 약 116.7 mg, 약 116.8 mg, 약 116.9 mg, 약 117.0 mg, 약 117.1 mg, 약 117.2 mg, 약 117.3 mg, 약 117.4 mg, 약 117.5 mg, 약 117.6 mg, 약 117.7 mg, 약 117.8 mg, 약 117.9 mg, 약 118.0 mg, 약 118.1 mg, 약 118.2 mg, 약 118.3 mg, 118.4 mg, 약 118.5 mg, 약 118.6 mg, 약 118.7 mg, 약 118.8 mg, 약 118.9 mg, 약 119.0 mg, 약 119.1 mg, 약 119.2 mg, 약 119.3 mg, 약 119.4 mg, 약 119.5 mg, 약 119.6 mg, 약 119.7 mg, 약 119.8 mg, 약 119.9 mg, 약 120.0 mg, 약 120.1 mg, 약 120.2 mg, 약 120.3 mg, 120.4 mg, 약 120.5 mg, 약 120.6 mg, 약 120.7 mg, 약 120.8 mg, 약 120.9 mg, 약 121.0 mg, 약 121.1 mg, 약 121.2 mg, 약 121.3 mg, 약 121.4 mg, 약 121.5 mg, 약 121.6 mg, 약 121.7 mg, 약 121.8 mg, 약 121.9 mg, 약 122.0 mg, 약 122.1 mg, 약 122.2 mg, 약 122.3 mg, 122.4 mg, 약 122.5 mg, 약 122.6 mg, 약 122.7 mg, 약 122.8 mg, 약 122.9 mg, 약 123.0 mg, 약 123.1 mg, 약 123.2 mg, 약 123.3 mg, 약 123.4 mg, 약 123.5 mg, 약 123.6 mg, 약 123.7 mg, 약 123.8 mg, 약 123.9 mg, 약 124.0 mg, 약 124.1 mg, 약 124.2 mg, 약 124.3 mg, 124.4 mg, 약 124.5 mg, 약 124.6 mg, 약 124.7 mg, 약 124.8 mg, 약 124.9 mg, 및 약 125.0 mg 중 어느 하나이다.
특정 구현예에서, 상기 치료학적 유효량은 40 mg 내지 200 mg, 40 mg 내지 190 mg, 40 mg 내지 180 mg, 40 mg 내지 170 mg, 40 mg 내지 160 mg, 40 mg 내지 150 mg, 40 mg 내지 140 mg, 40 mg 내지 120 mg, 40 mg 내지 110 mg, 40 mg 내지 100 mg, 40 mg 내지 80 mg, 40 mg 내지 70 mg, 40 mg 내지 60 mg, 40 mg 내지 50 mg, 50 mg 내지 200 mg, 50 mg 내지 190 mg, 50 mg 내지 180 mg, 50 mg 내지 170 mg, 50 mg 내지 160 mg, 50 mg 내지 150 mg, 50 mg 내지 140 mg, 50 mg 내지 120 mg, 50 mg 내지 110 mg, 50 mg 내지 100 mg, 50 mg 내지 80 mg, 50 mg 내지 70 mg, 50 mg 내지 60 mg, 60 mg 내지 200 mg, 60 mg 내지 190 mg, 60 mg 내지 180 mg, 60 mg 내지 170 mg, 60 mg 내지 160 mg, 60 mg 내지 150 mg, 60 mg 내지 140 mg, 60 mg 내지 120 mg, 60 mg 내지 110 mg, 60 mg 내지 100 mg, 60 mg 내지 80 mg, 60 mg 내지 70 mg, 70 mg 내지 200 mg, 70 mg 내지 190 mg, 70 mg 내지 180 mg, 70 mg 내지 170 mg, 70 mg 내지 160 mg, 70 mg 내지 150 mg, 70 mg 내지 140 mg, 70 mg 내지 120 mg, 70 mg 내지 110 mg, 70 mg 내지 100 mg, 70 mg 내지 80 mg, 80 mg 내지 200 mg, 80 mg 내지 190 mg, 80 mg 내지 180 mg, 80 mg 내지 170 mg, 80 mg 내지 160 mg, 80 mg 내지 150 mg, 80 mg 내지 140 mg, 80 mg 내지 120 mg, 80 mg 내지 110 mg, 80 mg 내지 100 mg, 80 mg 내지 90 mg, 90 mg 내지 200 mg, 90 mg 내지 190 mg, 90 mg 내지 180 mg, 90 mg 내지 170 mg, 90 mg 내지 160 mg, 90 mg 내지 150 mg, 90 mg 내지 140 mg, 90 mg 내지 120 mg, 90 mg 내지 110 mg, 90 mg 내지 100 mg, 100 mg 내지 200 mg, 100 mg 내지 190 mg, 100 mg 내지 180 mg, 100 mg 내지 170 mg, 100 mg 내지 160 mg, 100 mg 내지 150 mg, 100 mg 내지 140 mg, 100 mg 내지 120 mg, 100 mg 내지 110 mg, 110 mg 내지 200 mg, 110 mg 내지 190 mg, 110 mg 내지 180 mg, 110 mg 내지 170 mg, 110 mg 내지 160 mg, 110 mg 내지 150 mg, 110 mg 내지 140 mg, 110 mg 내지 130 mg, 110 mg 내지 120 mg, 120 mg 내지 200 mg, 120 mg 내지 190 mg, 120 mg 내지 180 mg, 120 mg 내지 170 mg, 120 mg 내지 160 mg, 120 mg 내지 150 mg, 120 mg 내지 140 mg, 120 mg 내지 130 mg, 130 mg 내지 200 mg, 130 mg 내지 190 mg, 130 mg 내지 180 mg, 130 mg 내지 170 mg, 130 mg 내지 160 mg, 130 mg 내지 150 mg, 130 mg 내지 140 mg, 140 mg 내지 200 mg, 140 mg 내지 190 mg, 140 mg 내지 180 mg, 140 mg 내지 170 mg, 140 mg 내지 160 mg, 140 mg 내지 150 mg, 150 mg 내지 200 mg, 150 mg 내지 190 mg, 150 mg 내지 180 mg, 150 mg 내지 170 mg, 150 mg 내지 160 mg, 160 mg 내지 200 mg, 160 mg 내지 190 mg, 160 mg 내지 180 mg, 160 mg 내지 170 mg, 180 mg 내지 200 mg, 180 mg 내지 190 mg, 190 mg 내지 200 mg, 105 mg 내지 135 mg, 105 mg 내지 130 mg, 105 mg 내지 125 mg 105 mg 내지 120 mg, 110 mg 내지 135 mg, 110 mg 내지 130 mg, 110 mg 내지 125 mg, 110 mg 내지 120 mg, 115 mg 내지 135 mg, 115 mg 내지 130 mg, 115 mg 내지 125 mg, 115 mg 내지 120 mg, 115 mg 내지 125 mg, 115 mg 내지 120 mg, 120 mg 내지 135 mg, 120 mg 내지 125 mg, 125 mg 내지 140 mg, 125 mg 내지 130 mg, 130 mg 내지 135 mg, 135 mg 내지 140 mg, 120 mg 내지 129 mg, 120 mg 내지 128 mg, 120 mg 내지 127 mg, 120 mg 내지 86 mg, 120 mg 내지 124 mg, 120 mg 내지 123 mg, 120 mg 내지 122 mg, 120 mg 내지 121 mg, 121 mg 내지 130 mg, 122 mg 내지 129 mg, 122 mg 내지 128 mg, 122 mg 내지 127 mg, 122 mg 내지 126 mg, 122 mg 내지 125 mg, 122 mg 내지 124 mg, 122 mg 내지 123 mg, 123 mg 내지 130 mg, 123 mg 내지 129 mg, 123 mg 내지 128 mg, 123 mg 내지 127 mg, 123 mg 내지 126 mg, 123 mg 내지 125 mg, 123 mg 내지 124 mg, 124 mg 내지 130 mg, 124 mg 내지 129 mg, 124 mg 내지 128 mg, 124 mg 내지 127 mg, 124 mg 내지 126 mg, 124 mg 내지 125 mg, 125 mg 내지 129 mg, 125 mg 내지 128 mg, 125 mg 내지 127 mg, 125 mg 내지 126 mg, 126 mg 내지 130 mg, 126 mg 내지 129 mg, 126 mg 내지 128 mg, 126 mg 내지 127 mg, 127 mg 내지 130 mg, 127 mg 내지 129 mg, 127 mg 내지 128 mg, 128 mg 내지 130 mg, 128 mg 내지 129 mg, 및 129 mg 내지 130 mg 중 어느 하나이다.
특정 구현예에서, 상기 치료학적 유효량은 300 mg 미만, 295 mg 미만, 290 mg 미만, 285 mg 미만, 280 mg 미만, 275 mg 미만, 270 mg 미만, 265 mg 미만, 260 mg 미만, 255 mg 미만, 250 mg 미만, 245 mg 미만, 240 mg 미만, 235 mg 미만, 230 mg 미만, 225 mg 미만, 220 mg 미만, 215 mg 미만, 210 mg 미만, 205 mg 미만, 200 mg 미만, 195 mg 미만, 190 mg 미만, 185 mg 미만, 180 mg 미만, 175 mg 미만, 170 mg 미만, 165 mg 미만, 160 mg 미만, 150 mg 미만, 145 mg 미만, 140 mg 미만, 135 mg 미만, 130 mg 미만, 125 mg 미만, 120 mg 미만, 115 mg 미만, 110 mg 미만, 105 mg 미만, 100 mg 미만, 95 mg 미만, 90 mg 미만, 85 mg 미만, 80 mg 미만, 75 mg 미만, 70 mg 미만, 65 mg 미만, 60 mg 미만, 55 mg 미만, 50 mg 미만, 45 mg 미만, 40 mg 미만, 35 mg 미만, 30 mg 미만, 25 mg 미만, 20 mg 미만, 15 mg 미만, 10 mg 미만, 및 5 mg 미만 중 어느 하나이다.
특정 구현예에서, 상기 치료학적 유효량은 약 300 mg 미만, 약 295 mg 미만, 약 290 mg 미만, 약 285 mg 미만, 약 280 mg 미만, 약 275 mg 미만, 약 270 mg 미만, 약 265 mg 미만, 약 260 mg 미만, 약 255 mg 미만, 약 250 mg 미만, 약 245 mg 미만, 약 240 mg 미만, 약 235 mg 미만, 약 230 mg 미만, 약 225 mg 미만, 약 220 mg 미만, 약 215 mg 미만, 약 210 mg 미만, 약 205 mg 미만, 약 200 mg 미만, 약 195 mg 미만, 약 190 mg 미만, 약 185 mg 미만, 약 180 mg 미만, 약 175 mg 미만, 약 170 mg 미만, 약 165 mg 미만, 약 160 mg 미만, 약 150 mg 미만, 약 145 mg 미만, 약 140 mg 미만, 약 135 mg 미만, 약 130 mg 미만, 약 125 mg 미만, 약 120 mg 미만, 약 115 mg 미만, 약 110 mg 미만, 약 105 mg 미만, 약 100 mg 미만, 약 95 mg 미만, 약 90 mg 미만, 약 85 mg 미만, 약 80 mg 미만, 약 75 mg 미만, 약 70 mg 미만, 약 65 mg 미만, 약 60 mg 미만, 약 55 mg 미만, 약 50 mg 미만, 약 45 mg 미만, 약 40 mg 미만, 약 35 mg 미만, 약 30 mg 미만, 약 25 mg 미만, 약 20 mg 미만, 약 15 mg 미만, 약 10 mg 미만, 및 약 5 mg 미만 중 어느 하나이다.
특정 구현예에서, 상기 치료학적 유효량은 적어도 5 mg, 적어도 10 mg, 적어도 15 mg, 적어도 20 mg, 적어도 25 mg, 적어도 30 mg, 적어도 35 mg, 적어도 40 mg, 적어도 45 mg, 적어도 50 mg, 적어도 55 mg, 적어도 60 mg, 적어도 65 mg, 적어도 70 mg, 적어도 75 mg, 적어도 80 mg, 적어도 85 mg, 적어도 90 mg, 적어도 95 mg, 적어도 100 mg, 적어도 105 mg, 적어도 115 mg, 적어도 120 mg, 적어도 125 mg, 적어도 130 mg, 적어도 135 mg, 적어도 140 mg, 적어도 145 mg, 적어도 150 mg, 적어도 155 mg, 적어도 160 mg, 적어도 165 mg, 적어도 170 mg, 적어도 175 mg, 적어도 180 mg, 적어도 185, 적어도 190 mg, 적어도 195 mg, 및 적어도 200 mg 중 어느 하나이다.
특정 구현예에서, 상기 치료학적 유효량은 적어도 약 5 mg, 적어도 약 10 mg, 적어도 약 15 mg, 적어도 약 20 mg, 적어도 약 25 mg, 적어도 약 30 mg, 적어도 약 35 mg, 적어도 약 40 mg, 적어도 약 45 mg, 적어도 약 50 mg, 적어도 약 55 mg, 적어도 약 60 mg, 적어도 약 65 mg, 적어도 약 70 mg, 적어도 약 75 mg, 적어도 약 80 mg, 적어도 약 85 mg, 적어도 약 90 mg, 적어도 약 95 mg, 적어도 약 100 mg, 적어도 약 105 mg, 적어도 약 115 mg, 적어도 약 120 mg, 적어도 약 125 mg, 적어도 약 130 mg, 적어도 약 135 mg, 적어도 약 140 mg, 적어도 약 145 mg, 적어도 약 150 mg, 적어도 약 155 mg, 적어도 약 160 mg, 적어도 약 165 mg, 적어도 약 170 mg, 적어도 약 175 mg, 적어도 약 180 mg, 적어도 약 185, 적어도 약 190 mg, 적어도 약 195 mg, 및 적어도 약 200 mg 중 어느 하나이다.
V.
특정 투여 요법
특정 구현예에서, 본원에서는 치료학적 유효량의 변형된 올리고뉴클레오타이드 ISIS 443139를 대상체에게 1회 이상 투여하는 방법이 기재된다. 특정 구현예에서, 방법은 치료학적 유효량을 적어도 1, 2, 3, 4, 5, 6, 7, 8, 9 또는 10회 투여함을 포함한다. 특정 구현예에서, 방법은 4주 마다 1회 치료학적 유효량을 투여함을 포함한다. 특정 구현예에서, 방법은 8주 마다 1회 치료학적 유효량을 투여함을 포함한다. 특정 구현예에서, 방법은 16주 마다 1회 치료학적 유효량을 투여함을 포함한다.
특정 구현예에서, 방법은 치료학적 유효량을 약 1주 마다, 약 2주 마다, 약 3주 마다, 약 4주 마다, 약 5주 마다, 약 6주 마다, 약 7주 마다, 약 8주 마다, 약 9주 마다, 약 10주 마다, 약 11주 마다, 약 12주 마다, 약 13주 마다, 약 14주 마다, 약 15주 마다, 약 16주 마다, 약 17주 마다, 약 18주 마다, 약 19주 마다, 또는 약 20주 마다 투여함을 포함한다.
특정 구현예에서, 방법은 치료학적 유효량을 적어도 약 1개월, 적어도 약 2개월, 적어도 약 3개월, 적어도 약 4개월, 적어도 약 5개월, 적어도 약 6개월, 적어도 약 7개월, 적어도 약 8개월, 적어도 약 9개월, 적어도 약 10개월, 적어도 약 11개월, 또는 적어도 약 12개월 동안 투여함을 포함한다.
부하 및 유지 용량
특정 구현예에서, 치료학적 유효량은 부하 용량 및/또는 유지 용량으로서 투여된다. 특정 구현예에서, 방법은 부하 용량 또는 용량들을 투여하고 후속적으로 유지 용량 또는 용량들을 투여하는 것을 포함한다. 특정 구현예에서, 방법은 부하 용량을 약 4주마다 1회 투여하고, 후속적으로 유지 용량을 약 8주마다 1회 투여하는 것을 포함한다. 특정 구현예에서, 방법은 부하 용량을 약 4주마다 1회 투여하고, 후속적으로 유지 용량을 약 16주마다 1회 투여하는 것을 포함한다.
특정 구현예에서, 방법은 적어도 2개의 부하 용량, 적어도 3개의 부하 용량, 적어도 4개의 부하 용량, 적어도 5개의 부하 용량, 또는 적어도 6개의 부하 용량을 투여하는 것을 포함한다. 특정 구현예에서, 방법은 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 또는 16개의 부하 용량을 투여함을 포함한다. 특정 구현예에서, 방법은 부하 용량 또는 용량들을 약 1주마다, 약 2주마다, 약 3주마다, 약 4주마다, 약 5주마다, 약 6주마다, 약 7주마다, 약 8주마다, 약 9주마다, 약 10주마다, 약 11주마다, 또는 약 12주마다 투여하는 것을 포함한다. 특정 구현예에서, 방법은 초기 부하 용량을 투여하고, 상기 초기 부하 용량을 투여한 후 약 1주, 약 2주, 약 3주, 약 4주, 약 5주, 약 6주, 약 7주, 약 8주, 약 9주, 약 10주, 약 11주, 또는 약 12주에 제2 부하 용량을 투여함을 포함한다.
특정 구현예에서, 방법은 적어도 2개의 유지 용량, 적어도 3개의 유지 용량, 적어도 4개의 유지 용량, 적어도 5개의 유지 용량, 또는 적어도 6개의 유지 용량을 투여하는 것을 포함한다. 특정 구현예에서, 방법은 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 또는 16개의 유지 용량을 투여함을 포함한다. 일부 경우에, 방법은 유지 용량 및 용량들을 약 4주 마다, 약 5주 마다, 약 6주 마다, 약 7주 마다, 약 8주 마다, 약 9주 마다, 약 10주 마다, 약 11주 마다, 약 12주 마다, 약 13주 마다, 약 14주 마다, 약 15주 마다, 약 16주 마다, 약 17주 마다, 약 18주 마다, 약 19주 마다, 또는 약 20주 마다 투여함을 포함한다. 특정 구현예에서, 방법은 제1 유지 용량을 투여하고 상기 제1 유지 용량을 투여한 후 약 4주, 약 5주, 약 6주, 약 7주, 약 8주, 약 9주, 약 10주, 약 11주, 약 12주, 약 13주, 약 14주, 약 15주, 약 16주, 약 17주, 약 18주, 약 19주, 또는 약 20주에 제2 유지 용량을 투여함을 포함한다.
특정 구현예에서, 방법은 제1 유지 용량 또는 용량들을 마지막 부하 용량을 투여한 후 약 1주, 약 2주, 약 3주, 약 4주, 약 5주, 약 6주, 약 7주, 약 8주, 약 9주, 약 10주, 약 11주, 약 12주, 약 13주, 약 14주, 약 15주, 약 16주, 약 17주, 약 18주, 약 19주, 또는 약 20주에 투여함을 포함한다.
VI.
효력 및 효능
특정 구현예에서, 본원에서는 인간 대상체의 세포 또는 생물학적 유체에서 HTT RNA 및/또는 HTT 단백질을 감소시키는 방법이 기재되고, 여기서, 상기 방법은 치료학적 유효량의 ISIS 443139를 상기 대상체에게 투여함을 포함한다. 특정 구현예에서, 방법은 인간 대상체의 뇌척수액에서 HTT RNA 및/또는 HTT 단백질을 감소시킨다. 당업자는 방법이 HTT RNA 및/또는 HTT 단백질을 감소시키는지의 여부를 결정할 수 있고, 예를 들어, 이는 투여 전에 수득된 제1 생물학적 샘플에서 제1 양의 HTT RNA 또는 HTT 단백질을 검출하고/정량하고 투여 후 수득된 제2 생물학적 샘플에서 제2 양의 HTT RNA 또는 HTT 단백질을 검출하고/정량하고, 상기 제1 양을 상기 제2 양과 비교하여 HTT RNA 또는 HTT 단백질에서의 감소를 검출하거나 정량함에 의해 수행된다. 특정 구현예에서, HTT RNA는 mHTT RNA이다. 특정 구현예에서, HTT 단백질은 mHTT 단백질이다.
특정 구현예에서, 방법은 HTT RNA 및/또는 HTT 단백질을 1 내지 100%까지 또는 이들 값의 임의의 2개에 의해 한정되는 범위까지 감소시킴을 포함한다. 특정 구현예에서, 방법은 HTT RNA 및/또는 HTT 단백질을 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100%까지 감소시킴을 포함한다. 특정 구현예에서, HTT RNA는 mHTT RNA이다. 특정 구현예에서, HTT 단백질은 mHTT 단백질이다.
특정 구현예에서, 방법은 HTT RNA 또는 HTT 단백질을 적어도 약 5%, 적어도 약 10%, 적어도 약 15%, 적어도 약 20%, 적어도 약 25 %, 적어도 약 30%, 적어도 약 35 %, 적어도 약 40%, 적어도 약 45%, 적어도 약 50%, 적어도 약 55%, 적어도 약 60%, 적어도 약 65%, 적어도 약 70%, 적어도 약 75%, 적어도 약 80%, 적어도 약 85%, 적어도 약 90%, 또는 적어도 약 95%까지 감소킴을 포함한다. 특정 구현예에서, HTT RNA는 mHTT RNA이다. 특정 구현예에서, HTT 단백질은 mHTT 단백질이다.
특정 구현예에서, 방법은 HTT RNA 또는 HTT 단백질을 약 5% 내지 약 10%, 약 10% 내지 약 15%, 약 15% 내지 약 20%, 약 20% 내지 약 25%, 약 25% 내지 약 30%, 약 30% 내지 약 35%, 약 35% 내지 약 40%, 약 40% 내지 약 45%, 약 45% 내지 약 50%, 약 50% 내지 약 55%, 약 55% 내지 약 60%, 약 60% 내지 약 65%, 약 65% 내지 약 70%, 약 70% 내지 약 75%, 약 75% 내지 약 80%, 약 80% 내지 약 85%, 약 85% 내지 약 90%, 약 90% 내지 약 95%, 또는 약 95% 내지 100%까지 감소시킴을 포함한다. 특정 구현예에서, HTT RNA는 mHTT RNA이다. 특정 구현예에서, HTT 단백질은 mHTT 단백질이다.
특정 구현예에서, 방법은 ISIS 443139를 대상체에게 투여하고 상기 대상체의 세포 또는 생물학적 유체에서 HTT RNA 또는 HTT 단백질의 양을 검출하거나 정량화하는 것을 포함한다. 특정 구현예에서, 방법은 투여 전에 수득된 제1 생물학적 샘플에서 제1 양의 HTT RNA 또는 HTT 단백질을 검출/정량화하고 투여 후 수득된 제2 생물학적 샘플에서 제2 양의 HTT RNA 또는 HTT 단백질을 검출/정량화하고, 상기 제1 양을 상기 제2 양과 비교하여 HTT RNA 또는 HTT 단백질에서의 감소를 검출 또는 정량화하는 것을 포함한다. 특정 구현예에서, 제2 생물학적 샘플은 투여 후 약 24시간 미만에 수득된다. 특정 구현예에서, 제2 생물학적 샘플은 투여 후 약 1주 미만에 수득된다. 특정 구현예에서, 제2 생물학적 샘플은 투여 후 약 1주, 약 2주, 약 3주, 약 4주, 약 5주, 약 6주, 약 7주, 약 8주, 약 9주, 약 10주, 약 11주, 약 12주, 약 13주, 약 14주, 약 15주, 약 16주, 약 17주, 또는 약 18주에 수득된다. 특정 구현예에서, 방법은 상기 제1의 양을 상기 제2의 양과 비교한 후 용량을 증가 또는 감소시키는 것을 포함한다. 특정 구현예에서, 방법은 상기 제1의 양을 상기 제2의 양과 비교한 후 보다 빈번하게 또는 덜 빈번하게 투여하는 것을 포함한다. 특정 구현예에서, HTT RNA는 mHTT RNA이다. 특정 구현예에서, HTT 단백질은 mHTT 단백질이다.
ISIS 443139의 효능 평가
특정 구현예에서, 본원에 기재된 방법은 인간 대상체에서 HD의 적어도 하나의 증상을 개선시키기 위해 충분히 효과적이다. 특정 구현예에서, 적어도 하나의 증상은 운동 기능 손상이다. 특정 구현예에서, 운동 기능 손상은 안절부절증, 조정력 부족, 의도하지 않게 개시된 동작, 의도하지 않게 완료되지 않은 동작, 불안정한 보행, 무도증, 경직, 몸부림치는 동작, 비정상적인 자세, 불안정, 비정상적인 얼굴 표정, 씹기 어려움, 연하곤란증, 말하기 어려움, 발작, 수면 장애 또는 이들의 조합을 포함한다. 특정 구현예에서, 적어도 하나의 증상은 인지 기능 손상이다. 특정 구현예에서, 인지 기능 손상은 계획 손상, 가요성 손상, 추상적 사고 손상, 손규칙 습득 손상, 적절한 행동 개시 손상, 부적절한 행동 억제 손상, 단기 기억 손상, 장기 기억 손상 또는 이들의 조합을 포함한다. 특정 구현예에서, 상기 적어도 하나의 증상은 정신과적 증상이다. 특정 구현예에서, 정신과적 증상은 편집증, 방향 감각 상실, 혼란, 환각, 치매, 불안, 우울증, 둔화 정동(bluned affect), 자기 중심주의, 공격성, 강박 행동, 과민성 및 자살 생각으로부터 선택된다. 특정 구현예에서, 적어도 하나의 증상은 감소된 뇌 질량(뇌 위축증), 근육 위축증, 신경 변성, 심부전, 손상된 내당능, 체중 감소증, 골다공증, 고환 위축증, 또는 이들의 조합이다.
특정 구현예에서, 본원에 기재된 방법은 건강한 대조군 대상체에 비해 HD를 갖는 인간 대상체에서 뇌 위축증, 감소된 뇌 활성 또는 감소된 뇌 활성을 개선하기에 충분히 효과적이다. 특정 구현예에서, 건강한 대조군 대상체는 HD를 갖지 않는 대상체이다. 특정 구현예에서, 방법은 인간 대상체에 대해 뇌파검사(EEG) 또는 자기공명영상(MRI)을 수행함으로써 결정된 바와 같이 뇌 위축증, 감소된 뇌 활동 또는 감소된 뇌 활동을 개선하기에 충분히 효과적이다.
특정 구현예에서, 본원에 기재된 방법은 임상적으로 관련된 시험, 스코어 또는 스케일에 의한 평가시, 인간 대상체에서 HD의 적어도 하나의 증상을 개선시키기 위해 충분히 효과적이다. 특정 구현에에서, 상기 적어도 하나의 증상은 전반적인 기능 손상, 운동 기능 손상, 인지 기능 손상, 일상 기능 손상, 주의력 손상, 시각 지각 처리 손상, 작업 기억 손상, 정신 운동 속도 손상, 언어 운동 아웃풋 손상, 독립성 정도 손상, 무감각증 손상, 학습 능력 손상, 정신 집중력 손상, 언어 손상, 우울증, 과민성, 분노, 운동능 손상, 자기 관리 손상, 통증, 불편함, 불안증, 자살 생각, 자살 행동 또는 이들의 조합이다. 상기 임상적으로 관련된 시험, 스코어 및 스케일의 비제한적인 예는 하기를 포함한다.
총 기능적 능력 스케일
특정 구현예에서, 본원에 기재된 방법은 총 기능 능력 스케일(TFC)에 의한 평가시 HD를 갖는 대상체의 전반적인 기능 손상을 개선하기에 충분히 효과적이다. TFC는 문헌(참조: Huntington Study Group, Mov. Disord. 1996; 11:136-42)에서 보다 상세히 기재된 HD에서 전반적인 기능의 확증된 척도이다. TFC는 일, 집안일, 재정 관리, 식사, 옷 입기, 목욕을 포함한 기본적인 일상 생활의 다양한 활동 범위를 수행하는 대상체의 능력에 대한 조사자의 평가를 나타낸다. TFC 스코어는 0에서 13까지의 범위이고, 스코어가 높을수록 보다 양호한 기능을 나타낸다. TFC 스코어에서 1점 변화는 대상체 기능의 임상적으로 의미 있는 변화이다(예를 들어, 1점 감소는 정상적인 능력으로 작업하는 능력의 상실을 나타낼 수 있다). 특정 구현예에서, 방법은 적어도 1, 2, 3, 4, 5, 6, 7, 8, 9, 또는 10점까지 TFC 스코어를 개선시킨다.
총 운동 스코어
특정 구현예에서, 본원에 기재된 방법은 총 운동 스코어(TMS)에 의한 평가시 HD를 갖는 대상체의 운동 기능 손상을 개선하기에 충분히 효과적이다. TMS는 TFC 스코어, 독립성 및 구동 상태를 기반으로 하는 기능적 능력 둘다와 연결된 HD에서 운동 기능에 대한 전체론적 척도이다(참조: Beglinger et al., Mov. Disord. 2012; 27:1146-52; Schobel et al., Neurology 2017; 89:2495-2502). TMS 스코어는 조사자가 UHDRS의 31개 항목 운동 평가 부분을 관리하여 수득된 개별 운동 등급의 합계이다. 스코어는 0에서 124까지의 범위이고, 스코어가 높을수록 보다 중증의 손상을 나타낸다. 특정 구현예에서, 방법은 적어도 1, 2, 3, 4, 5, 6, 7, 8, 9, 또는 10점까지 TMS 스코어를 감소시킨다.
기호 숫자 양식 시험(Symbol Digit Modalities Test)
특정 구현예에서, 본원에 기재된 방법은 기호 숫자 양식 시험(SDMT)에 의한 평가시 HD를 갖는 대상체에서 주의력 손상, 시각 지각 처리 손상, 작업 기억 손상, 정신운동 속도 손상, 또는 이들의 조합을 개선하기에 충분히 효과적이다. SDMT에서 대상체는 해독 키에 따라 추상 기호와 특정 숫자를 쌍으로 형성한다. 시험은 90초 동안 올바르게 쌍을 형성한 항목의 수(최대 110개의 올바른 쌍)를 측정한다. SDMT는 강한 신뢰성과 타당성을 갖는 것으로 나타났다. SDMT는 문헌(참조: Smith, A. Symbol Digit Modalities Test (SDMT). Manual (rev.) Los Angeles: Western Psychological Services, 1982.)에 상세히 기재되어 있다. 특정 구현예에서, 방법은 적어도 1, 2, 3, 4, 5, 6, 7, 8, 9, 또는 10개의 항목에 의해 올바르게 쌍을 형성한 항목의 수를 개선한다.
스트룹(Stroop) 단어 읽기 시험
특정 구현예에서, 본원에 기재된 방법은 스트룹 단어 읽기 시험(SWR) 시험에 의한 평가시 HD를 갖는 대상체에서 주의력 손상, 처리 손상, 정신운동 속도 손상, 언어 운동 아웃풋 온상, 또는 이들의 조합을 개선하기에 충분히 효과적이다. SWR 시험 동안에 대상체에게 검정 잉크로 인쇄된 색상 이름(즉, "청색", "적색" 또는 "녹색")이 표시된 페이지를 제시하고 주어진 시간 내(45초 내)에서 가능한 한 많은 단어를 큰 소리로 읽도록 요청받는다. 올바르게 판독된 단어의 수를 계수하고 스코어가 높을수록 인지 능력이 우수함을 나타낸다. SWR 시험의 추가 기재에 대해 문헌(Stroop, J. R., J. Exp. Psychol. 1935, 18, 643-662)을 참조한다. 특정 구현예에서, 방법은 대상체가 주어진 시간 동안 소리내어 읽을 수 있는 단어의 수를 적어도 1, 2, 3, 4, 5, 6, 7, 8, 9 또는 10개의 단어 만큼 개선시킨다.
복합 통합 헌팅턴 질환 평가 스케일(cUHDRS)
특정 구현예에서, 본원에 기재된 방법은 복합 통합 헌팅턴 질환 평가 스케일(cUHDRS)에 대한 대상체의 평가를 개선하기에 충분히 효과적이다. cUHDRS는 운동 기능, 인지 기능 및 전반적인 기능을 평가한다. 결과 측정은 TFC, TMS, SDMT의 Z 스코어와 UHDRS로부터의 SWR 스코어의 동일한 가중치 합으로 구성된다. 이는 근본적인 진행성 뇌 변화를 추적하고 일상적인 기능적 능력의 변화와 관련된 임상 쇠퇴의 다중도메인 측정이다. cUHDRS는 문헌(참조: Schobel et al., Neurology 2017; 89:2495-2502)에 보다 상세하게 기재되어 있다. 특정 구현예에서, 방법은 적어도 1, 2, 3, 4, 5, 6, 7, 8, 9, 또는 10점까지 대상체의 cUHDRS 평가를 개선시킨다.
복합 헌팅턴 질환 평가 스케일(UHDRS) 기능 평가
특정 구현예에서, 본원에 기재된 방법은 UHDRS 기능 평가에 의한 평가시 HD를 갖는 대상체의 전반적인 기능 손상을 개선하기에 충분히 효과적이다. UHDRS 기능 평가는 25가지 일반적인 일상 작업의 체크리스트이다. 상기 체크리스트는 문헌(Huntington Study Group, Mov. Disord. 1996; 11:136-42)에 의해 기재되어 있다. 조사자는 모든 "예" 응답에 1 스코어를 부여하여 대상체가 작업을 수행할 수 있는지 나타낸다. 이어서 체크리스트를 합산하고 스코어는 0(작업을 수행할 수 없음)에서 25(체크리스트의 모든 작업을 수행할 수 있음)의 범위일 수 있다. 특정 구현예에서, 방법은 대상체의 UHDRS 기능적 평가 스코어를 적어도 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 또는 15만큼 개선시킨다.
독립 스케일
특정 구현예에서, 본원에 기재된 방법은 독립 스케일(IS)에 의한 평가시 HD를 갖는 대상체의 전반적인 기능 손상을 개선하기에 충분히 효과적이다. IS는 기능 손상 및 독립 정도의 질환 진행 척도이다. 이것은 UHDRS의 서브스케일이다. 상기 스케일은 10 내지 100(5로) 범위의 19개의 개별 수준으로 이루어져 있고, 100의 스코어는 특별한 치료가 필요하지 않음을 나타내고, 10의 스코어는 대상체가 튜브로 영양을 공급받고 전체 침대 치료를 필요함을 나타낸다. IS는 문헌(참조: Huntington Study Group, Mov. Disord. 1996; 11:136-42)에 보다 상세히 기재되어 있다. 특정 구현예에서, 방법은 대상체의 IS 스코어를 적어도 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 또는 50점만큼 개선시킨다.
헌팅턴 질환 일상 활동 스케일
특정 구현예에서, 본원에 기재된 방법은 헌팅턴 질환 평가 일상 활동 스케일(HD-DAS)에 대한 대상체의 스코어를 개선하기에 충분히 효과적이다. HD-DAS는 대상체의 일상 기능을 평가한다. 대상체 및/또는 대상체 동반자와의 반-구조화된 인터뷰 후, 대상체의 식사 또는 전화 사용과 같은 일상 작업을 수행하는 능력 수준이 기록된다. 각 항목은 4점 리커트(Likert) 유형 스케일로 스코어되고, 여기서, 0은 영향이 없음을 지적하고, 3은 심각한 영향을 지적한다. HD-DAS는 문헌(참조: Bylsma et al., Mov. Disord. 1993; 8:183-90)에 보다 상세히 기재되어 있다. 특정 구현예에서, 방법은 대상체의 HD-DAS 소코어를 1, 2, 또는 3점까지 개선시킨다.
전반적인 인상, 중증도 및 변화 스케일
특정 구현예에서, 본원에 기재된 방법은 전반적인 인상, 중증도 및 변화 스케일에 대한 대상체의 스코어를 개선하기에 충분히 효과적이다. 상기 평가는 임상의(CGI-S), 동반자(CrGI-S) 또는 대상체(PGI-S)가 수행할 수 있다. 대상체는 11점 수치 평가 스케일(NRS)을 사용하여 평가되고, 여기서, 보다 높은 스코어는 보다 큰 중증도를 나타낸다. CGI-S는 문헌(참조: Guy W: ECDEU Assessment Manual for Psychopharmacology Rockville, MD: U. S. Department of Health, Education, and Welfare; 1976)에서 보다 자세히 기재되어 있다. 특정 구현예에서, 방법은 1, 2, 3, 4, 5, 6, 7, 8, 9, 또는 10점까지 대상체의 NRS 스코어를 감소시킨다.
몬트리올(Montreal) 인지 평가
특정 구현예에서, 본원에 기재된 방법은 몬트리올 인지 평가 (MoCA)에 의한 평가시 HD를 갖는 대상체의 인지 기능 손상을 개선하기에 충분히 효과적이다. MoCA는 인지 손상을 검출하는 데 사용되는 대상체 완성된 평가이다. 여기에는 주의력 및 시공간 작업을 포함한 일련의 기본 평가가 포함된다. 총 스코어는 0 내지 30의 범위이고, 여기서 보다 낮은 스코어는 보다 큰 손상을 지적한다. MoCA는 문헌(참조: Nasreddine et al., J. Am. Geriatr. Soc. 2005 53:695-9)에 보다 상세히 기재되어 있다. 특정 구현예에서, 방법은 적어도 1, 2, 3, 4, 5, 6, 7, 8, 9, 또는 10점까지 대상체의 MoCA 스코어를 증가시킨다.
작업 생산성 및 활동 손상 시험
특정 구현예에서, 본원에 기재된 방법은 작업 생산성 및 활동 손상 시험(WPAI)에 의한 평가시 HD를 갖는 대상체의 전반적인 기능 손상을 개선하기에 충분히 효과적이다. WPAI는 질환이 고용상태에 미치는 영향(예/아니오), 질환으로 인한 결근 시간, 기타 사유로 인한 결근 시간, 근로 시간, 생산성 및 일상 활동에 미치는 영향을 평가하는 6개 항목을 포함한다(모두 11점 NRS를 사용하고, 여기서 더 높은 스코어는 보다 큰 영향을 나타낸다). WPAI는 문헌(참조: Reilly et al., Pharmacoeconomics 1993 4:353-65)에 보다 상세히 기재되어 있다. 특정 구현예에서, 방법은 적어도 1, 2, 3, 4, 5, 6, 7, 8, 9 또는 10점까지 대상체의 WPAI 스코어를 감소시킨다.
무감각증 평가 스케일
특정 구현예에서, 본원에 기재된 방법은 무감각증 평가 스케일(AES)에 의한 평가시 HD를 갖는 대상체의 무감각증 손상을 개선하기에 충분히 효과적이다. AES는 명백한 행동, 동기 부여의 인지적 측면, 정서적 반응성을 포함하여 무관심에 대한 18개 항목의 평가이다. 각 항목은 1("전혀 그렇지 않다")에서 4("많이")까지 4점 리커트 스케일로 스코어링된다. 총 스코어는 18개 항목(스코어 범위는 18 내지 72점 범위, 3개 항목은 역 스코어이다)을 합산하여 생성되며 스코어가 높을수록 보다 큰 무감각증을 나타낸다. AES는 문헌(참조: Marin et al., Psychiatry Res. 1991 38:143-62)에 보다 상세히 기재되어 있다. 특정 구현예에서, 방법은 적어도 1, 2, 3, 4, 5, 6, 7, 8, 9 또는 10점까지 대상체의 AES 스코어를 증가시킨다.
Neuro-Qol 인지 기능 짧은 형식, 버전 2
특정 구현예에서, 본원에 기재된 방법은 Neuro-Qol 인지 기능 짧은 형식에 의한 평가시 HD를 갖는 대상체에서 정신 집중력 손상 및/또는 학습 능력손상을 개선하기에 충분히 효과적이다. Neuro-Qol 인지 기능 짧은 형식은 8개 항목("집중 문제" 및 "새로운 작업 또는 지침 학습"의 어려움 포함)을 포함하고, 각각은 5점 리커트 스케일을 사용하여 평가되며, 여기서 스코어가 낮을수록 어려움(4개 항목)이 크고 빈도(4개 항목)가 높음을 나타낸다. 미가공 합계 스코어는 T-스코어 분포(평균 50, 표준 편차 10)로 변환된다. 문헌(National Institute of Neurological Disorders and Stroke (NINDS). User Manual for the Quality of Life in Neurological Disorders (Neuro-QoL) Measures, Version 2.0, March 2015)을 참조한다.
헌팅턴 질환 말하기 어려움 항목
특정 구현예에서, 본원에 기재된 방법은 헌팅턴 질환 말하기 어려움 항목 (HD-SDI)에 의한 평가시 HD를 갖는 대상체의 말하기 손상을 개선하기에 충분히 효과적이다. HD-SDI는 7일 동안 말하기 어려움을 평가하는 단일 질문을 포함한다. 5점 리커트 스케일을 사용하여 평가되고, 여기서 스코어가 높을수록 어려움의 빈도가 높다는 것을 나타낸다. 특정 구현예에서, 방법은 적어도 1, 2, 3, 4, 또는 5점까지 대상체의 스코어를 감소시킨다.
주요 우울증 장애 스케일의 증상
특정 구현예에서, 본원에 기재된 방법은 주요 우울증 장애 스케일(SMDDS)에 의한 평가시 HD를 갖는 대상체의 우울증을 개선하기에 충분히 효과적이다. SMDDS는 우울증의 자가 보고 평가이다(참조: McCarrier et al., Patient 2016, 9:117-134). 이것은 슬픔, 과민성, 걱정, 수면 장애와 같은 개념을 측정하는 16개 항목을 포함한다. 각각의 항목은 "전혀 그렇지 않다"에서 "매우 그렇다"(9개 항목), "전혀 그렇지 않다"에서 "항상 그렇다"(7개 항목)까지 5점 리커트 스케일로 평가된다. 항목 중 15개 항목의 항목 스코어(2개의 섭식 항목 중 가장 덜 심각한 항목은 포함되지 않음)를 합하여 0에서 60 스코어까지를 생성하고, 여기서, 스코어가 높을수록 우울증 증상이 보다 중증임을 나타낸다. SMDDS는 문헌(Bushnell et al., Value in Health 2019 22:906-915)에 보다 상세히 기재되어 있다. 특정 구현예에서, 방법은 적어도 1, 2, 3, 4, 5, 6, 7, 8, 9 또는 10점까지 대상체의 스코어를 감소시킨다.
헌팅턴 질환 동반-보고된 과민성 및 분노 폭발 스케일
특정 구현예에서, 본원에 기재된 방법은 헌팅턴 질환 동반자가 보고한 과민성 및 분노 폭발 스케일(HD-CIAOS)에 의한 평가시 HD를 갖는 대상체의 과민성 및 분노를 개선하기에 충분히 효과적이다. HD-CIAOS는 7일 동안 대상체의 과민성과 분노 폭발에 대한 연구 동반자가 보고한 평가이다. 이것은 과민 행동의 빈도(6점 리커트 스케일: "전혀 그렇지 않다"에서 "항상"까지), 분노 폭발의 빈도(발생 횟수), 최악의 폭발의 중증도(4점 리커트 스케일 "경미한"에서 "매우 중증")의 3개 항목으로 이루어진다. 특정 구현예에서, 방법은 1, 2, 3, 또는 4점까지 대상체의 스코어를 감소시킨다.
EuroQol 5-차원, 5-수준 설문지
특정 구현예에서, 본원에 기재된 방법은 EuroQol 5-차원, 5-수준 설문지에 의한 평가시 HD를 갖는 대상체에서 이동성 손상, 자가 관리 손상, 전반적인 기능 손상, 통증/불편함, 불안증, 우울증, 또는 이들의 조합을 개선하기에 충분히 효과적이다. EQ-5D-5L은 건강 경제 분석에 사용하기 위한 건강 상태 유틸리티 스코어를 계산하는 데 사용되는 검증된 자가 보고 건강 상태 설문지이다(참조: Brooks Health Policy 1996 37:53-72 and Herdman et al. Qual Life Res. 2011, 20:1727-36). EQ-5D-5L에는 두 가지 구성요소가 있다: 이동성, 자기 관리, 일상 활동, 통증/불편, 불안/우울증을 평가하는 5개 항목의 건강 상태 프로필 및 건강 상태를 측정하는 시각적 아날로그 스케일(VAS). 공개된 가중치 시스템을 사용하면 5개 항목 스코어(즉, VAS는 포함하지 않음)에서 대상체의 건강 상태(지수 스코어)의 단일 복합 스코어를 생성시킬 수 있다. 특정 구현예에서, 방법은 대상체의 EQ-5D-5L 스코어를 개선시킨다.
건강 유틸리티 지수
특정 구현예에서, 본원에 기재된 방법은 건강 유틸리티 지수에 의한 평가시 HD를 갖는 대상체의 건강 상태를 개선하기에 충분히 효과적이다. HUI는 건강 상태의 다중 속성 시스템이다(참조: Feeny et al., Pharmacoeconomics 1995, 7:490-502). HUI2 및 HUI3 설문지(일반적으로 HUI2/3이라고 함)는 리커트 유형 응답 옵션이 있는 15개 항목을 포함한다. 이들 항목으로부터 2개의 스코어가 생성될 수 있다: HUI2 (7개 항목) 및 HUI3 (8개 항목). 스코어 둘 모두는 건강 유틸리티 지수이고, 여기서 0은 사망, 1은 완전히 건강함이다. 특정 구현예에서, 방법은 대상체의 HUI 스코어를 개선시킨다.
콜럼비아 자살 중증도 평가 스케일
특정 구현예에서, 본원에 기재된 방법은 콜럼비아 자살 중증도 평가 스케일(C-SSRS)에 의한 평가시 HD를 갖는 대상체의 자살 생각 또는 자살 행동을 개선하기에 충분히 효과적이다. C-SSRS는 자살 생각과 행동을 평가하기 위한 구조화된 도구이다. 네가지 구성 개념(construct)이 측정된다: 생각의 심각성, 생각의 강도, 행동 및 실제 자살 시도의 치사율. 이진(예/아니오) 데이터는 10개 카테고리에 대해 수집되고, 카테고리에 기반한 복합 평가변수는 대상체 안전성을 모니터링하기 위해 시간 경과에 따라 수행된다(참조: Posner et al. Am. J. Psychiatry 2011 168:1266-77). 이것은 자살 평가를 위한 콜럼비아-분류 알고리즘에 맵핑되고 임상 시험에서 자살 가능성 평가를 위한 미국 FDA 초안 지침(FDA 2012)에 나열된 기준을 충족한다. 특정 구현예에서, 방법은 대상체의 C-SSRS 스코어를 개선시킨다.
VII.
특정 조합 치료요법
특정 구현예에서, 방법은 ISIS 443139를 적어도 하나의 다른 약제학적 제제와 공동-투여하는 것을 포함한다. 특정 구현예에서, 적어도 하나의 다른 약제학적 제제는 HD 또는 그의 증상을 개선시킨다. 특정 구현예에서, ISIS 443139는 조합 효과를 생성하기 위해 적어도 하나의 다른 약제학적 제제와 공동-투여된다. 특정 구현예에서, ISIS 443139는 상승작용 효과를 생성하기 위해 적어도 하나의 다른 약제학적 제제와 공동-투여된다.
특정 구현예에서, ISIS 443139 및 적어도 하나의 다른 약제학적 제제는 동시에 투여된다. 특정 구현예에서, ISIS 443139 및 적어도 하나의 다른 약제학적 제제는 상이한 시점에 투여된다. 특정 구현예에서, ISIS 443139 및 적어도 하나의 다른 약제학적 제제는 단일 제형으로 함께 제조된다. 특정 구현예에서, ISIS 443139 및 적어도 하나의 다른 약제학적 제제는 별도로 제조되고 투여된다.
특정 구현예에서, ISIS 443139와 공동-투여될 수 있는 약제학적 제제는 항정신병제, 예를 들어 할로페리돌, 클로르프로마진, 클로자핀, 퀘타핀 및 올란자핀; 항우울제, 예를 들어 플루옥세틴, 세르트랄린 하이드로클로라이드, 벤라팍신 및 노르트립틸린; 안정제, 예를 들어, 벤조디아제핀, 클로나제팜, 파록세틴, 벤라팍신 및 베타-차단제; 기분 안정제, 예를 들어 리튬, 발프로에이트, 라모트리진 및 카바마제핀; 마비제, 예를 들어, 보툴리눔 독소; 및/또는 테트라베나진(제나진), 크레아틴, 조효소 Q10, 트레할로스, 도코사헥산산, ACR16, 에틸-EPA, 아토목세틴, 시탈로프람, 디메본, 메만틴, 나트륨 페닐부티레이트, 라멜테온, 우르소디올, 지프렉사, 제나신, 티아프리드, 릴루졸, 아만타딘, [123I]MNI-420, 아토목세틴, 테트라베나진, 디곡신, 데트로메토르판, 와파린, 알프로잠, 케토코나졸, 오메프라졸 및 미노사이클린을 포함하지만 이에 제한되지 않는 다른 실험 제제를 포함한다.
실시예
하기 실시예는 본원 개시내용의 특정 구현예를 예시하고 제한하지 않는다. 더욱이, 특정 구현예가 제공되는 경우, 본원 발명자들은 이들 특정 구현예의 일반적인 적용을 고려하였다. 예를 들어, 특정 모티프를 갖는 올리고뉴클레오타이드의 기재는 동일하거나 유사한 모티프를 갖는 추가 올리고뉴클레오타이드에 대한 합리적인 지지를 제공한다. 그리고 예를 들어, 특정 고친화성 변형이 특정 위치에 나타나는 경우, 달리 표시되지 않는 한 동일한 위치에서 다른 고친화성 변형이 적합한 것으로 간주된다.
실시예 1: ISIS 443139를 사용한 단계 1-2a 인간 임상 시험
HD를 갖는 성인 인간 대상체를 포함하는 무작위, 이중 맹검, 다중 상승 용량, 1-2a상 시험이 수행되었다. 표 1은 기준선에서 인간 대상체의 특징을 보여준다. 인간 대상체들은 통합 헌팅턴 질환 평가 스케일(Unified Huntington's Disease Rating Scale)에서 11-13의 총 기능적 능력 스코어를 가졌고, 이는 기능적 손상이 거의 또는 전혀 없음을 나타낸다.
표 1:
기준선에서 인간 대상체의 특징*
* 플러스-마이너스 값은 평균 ±SD이다. 환자들은 ISIS 443139의 위약 또는 상승 용량을 투여받도록 할당된다. 퍼센트는 반올림으로 인해 합계가 100이 아닐 수 있다.
§ 통합 헌팅턴 질환 평가 스케일(Unified Huntington's Disease Rating Scale)의 총 기능 능력 스코어(TFC) 범위는 0에서 13까지이고, 스코어가 높을수록 기능 손상이 적음을 나타낸다. 11 내지 13의 스코어는 평가 항목(직업, 재정, 가사일, 일상 생활 활동, 돌봄 수준)에서 기능적 손상이 거의 또는 전혀 없음을 나타낸다.
‡ 몬트리올 인지 평가의 스코어는 0에서 30까지의 범위이고, 스코어가 높을수록 인지 기능이 더 우수함을 나타낸다.
¶ 총 운동 스코어는 0 내지 124의 범위이고, 스코어가 낮을 수록 손상이 적음을 나타낸다.
† 독립 스케일 스코어는 0 내지 100의 범위이고, 스코어가 높으면 보다 높은 수준의 독립을 나타낸다.
** 질환-부담 스코어는 다음과 같이 계산된다: (CAG 반복 길이 35.5) × 연령. 보다 큰 수는 보다 높은 질환 부담을 나타낸다.
인간 대상체는 3:1 비율로 무작위 배정되어 ISIS 443139 또는 위약을 볼루스 척수강내 투여로 4주마다 4회(1일, 29일, 57일 및 85일) 투여받았다. 1차 평가변수는 안전성이다. 2차 평가변수는 CSF에서 ISIS 443139의 약동학이었다. 사전 지정된 탐색 평가변수는 CSF 중의 mHTT 단백질 농도를 포함하였다.
인간 대상체는 위약 또는 ISIS 443139를 10 mg, 30 mg, 60 mg, 90 mg 또는 120 mg의 상승하는 용량 수준으로 투여 받았다. 각각의 인간 대상체는 네가지 용량을 모두 투여받고 시험을 완료하였다. ISIS 443139를 투여받은 인간 대상체의 모든 부작용은 중증도(예를 들어, 시술 통증 및 경막 천자 후 두통)에 있어서 경증(83%) 또는 중등도(17%)였다. ISIS 443139를 투여받은 인간 대상체에서 심각한 부작용이 관찰되지 않았다. 실험실 변수에 임상적으로 관련된 불리한 변화가 없었다.
CSF(20 mL)는 CSF mHTT 단백질의 최저 농도를 얻기 위해 1, 29, 57 및 85일차에 투여 직전에 표준 요추 천자 수집 키트를 사용하여 환자로부터 수득하였다. CSF는 연구 113일차 또는 연구 141일차에 치료 후 기간 동안 유사하게 수집되었다. 인간 CSF mHTT 단백질은 문헌(참조: Weiss et al., Anal Biochem. 2009, 395:8-15)에 기재된 MW1 항-HTT polyQ 항체 (카탈로그 03-0076-02; Singulex)를 사용하는 문헌(참조: Wild et al., J. Clin. Invest. 2015, 125:1979-1986)에 기재된 인간 mHTT 단일 분자 검출 검정을 사용하여 3회 측정하였다. ISIS 443139를 투여 받은 환자에서, 투여 후 28일 마지막 가용한 샘플링 지점에서 용량 의존적 감소가 있었고, 표 2를 참조하면 개체 환자 (120-mg 코호트에서)에서 최대 감소는 63%였다. 90 mg 용량 및 120 mg 용량은 CSF mHTT 단백질의 대략 40% 평균 감소를 성취하였다. 퍼센트 변화는 투여 전 1일차부터 마지막으로 가용한 28일 투여 후 시점(85일 및 113일 중 후자)까지 계산되었다.
표 2:
용량 그룹에 의한 CSF mHTT 단백질의 변화 퍼센트 요약
*호지-레흐만(Hodges-Lehmann)은 ISIS 443139 용량 그룹과 위약 그룹 간의 차이(95% 신뢰 구간(CI))를 추정한다.
상기 시험과 병행하여, 복합 헌팅턴 질환 평가 스케일(cUHDRS)이 초기 HD의 임상 진행의 척도로서 사용하기 위해 개발되었다. mHTT 단백질의 CSF 농도 저하 정도와 cUHDRS 스코어 및 이의 네가지 성분의 변화 사이의 관계를 조사하였다. mHTT 단백질의 CSF 농도 감소와 cUHDRS 스코어 및 이의 성분 2개의 개선 사이의 상관 관계가 관찰되었다.
실시예 2: HD에 대한 ISIS 443139를 사용한 단계 2 시험 인간 임상 시험(4주 및 8주 결과)
실시예 1에 기재된 단계 1-2a 시험에 따른 공개 표지 연장 연구에서, HD를 가진 성인 인간 대상체는 1일차에 120 mg의 초기 부하 용량을 투여 받은 후 28일에 120 mg의 두 번째 투여 부하 용량을 투여받았다. 그 후, 인간 대상체는 4주마다(코호트 Q4W) 또는 8주마다(코호트 Q8W) 120 mg의 ISIS 443139의 유지 용량을 투여받았다. ISIS 443139의 모든 용량은 척수강내 투여를 통해 전달하였다. CSF 샘플을 수득하고 CSF mHTT 단백질의 최저 농도를 실시예 1에 기재된 바와 같이 분석하였다. CSF mHTT 단백질 최저 농도는 CSF mHTT 단백질의 평균 감소를 기준선의 퍼센트로 계산하는데 사용되었으며, 이는 코호트 Q4W에 대해 도 1a 및 코호트 Q8W에 대해 도 1b에 제공된다. 도 1a 및 도 1b에 나타낸 바와 같이, ~30-50% CSF mHTT 단백질 감소는 85일차까지 용법 둘 모두에서 달성되었다. 또한, CSF mHTT 단백질은 코호트 Q4W에서 85일 후에 계속 감소하였다. ISIS 443139는 코호트 Q4W에서 CSF mHTT 단백질의 메디안 최저 농도를 66% 감소시켰고, Q8W 코호트에서 CSF mHTT 단백질의 메디안 최저 농도를 47% 감소시켰다. 전체적으로, ISIS 443139는 코호트 둘 모두에서 내약성이 우수하였다.
실시예 3. ISIS 443139 효능에 대한 바이오마커로서의 EEG 활성
실시예 1에 기재된 단계 1-2a 시험에 참여한 인간 대상체의 휴지기 상태 EEG는 ISIS 443139의 4개월 용량의 척수강내 주사 후 스크리닝, 기준선 및 치료 후 113, 141 및 197일에 수득하였다. 10-20 시스템에 따라 배치된 어드밴스드 뇌 모니터링(Carlsbad, Ca)에 의한 20 전극 B-Alert® X24 무선 EEG 시스템을 EEG 데이터 획득에 사용하였다. 휴지기 상태 EEG 데이터는 연구 스크리닝 기간 동안 회기당 4블록(총 기록 시간 = 20분)으로 눈을 뜨거나 감고 있는(eyes open or closed) 교호 블록으로 HD를 가진 개체에 대해 획득하였다. 건강한 대조군(HC)의 경우 2개 블록이 기록되었다(총 기록 시간 = 10분). 눈을 감고 있는 데이터만이 보고되었다. 신호는 연결된 유양돌기를 참조하고 0.1-100Hz의 대역통과 필터를 사용하여 256Hz에서 디지털화하였다. 오프라인에서 신호를 1-30Hz로 필터링하고 육안 검사 및 독립 성분 분석(FastICA)을 사용하여 기록에서 노이즈 신호를 혼합하지 않음에 의해 제거하였다. Morlet 웨이블릿(0.33 옥타브)은 시간 분해 EEG 신호의 주파수 변환에 사용되었다. 그룹간 통계는 순위 합계 시험을 1단계 통계로 하여 순위 합계 시험과 클러스터 기반 순열 시험(전극 x 주파수 공간)을 사용하였다. 모든 오차 막대는 95% 신뢰 구간의 부트스트랩 추정치를 나타낸다.
결과는 일치하는 건강한 대조군과 비교할 때 HD가 EEG 뇌 활동을 감소시킴을 보여주었다. 결과는 또한 위약으로 치료받은 환자와 비교하여 ISIS 443139로 치료받은 환자에서 EEG 신호 전력이 유의하게 증가했음을 보여주었다. 기준선과 비교하여, ISIS 443139 치료는 4-8 Hz 주파수 범위 내에서 EEG 신호 전력을 증가시켰다. ISIS 443139 치료에 따른 뇌 활동의 증가는 모든 용량 수준에서 검출할 수 있었고 치료 후 EEG 모니터링 지속 기간에 걸쳐 존재하였다. 또한 EEG 활동의 기준선으로부터의 변화와 CSF mHTT 농도의 변화 사이에 긍정적인 연관성이 있는 것으로 관찰되었다.
실시예 4: Hd에 대한 ISIS 443139를 사용한 단계 3 인간 임상 시험
분명한 HD가 있는 성인 인간 대상체(25-65세)에서 척수강내 투여된 ISIS 443139의 효능 및 안전성을 평가하기 위해 무작위 이중 맹검 위약 제어 단계 3 임상 시험을 수행하였다. 인간 대상체는 CAG-연령 생성물 스코어(CAP 스코어) > 400을 갖는다. CAP 스코어는 인간 대상체의 연령에 CAG 반복체 길이 - 33.66)를 곱하여 계산한다. 상기 연구에는 2개의 아암이 있다: 제1 코호트(Q8W)는 1일차 및 28일차에 120 mg의 ISIS 443139의 부하 용량을 투여받은 후 8주마다 120 mg의 ISIS 443139의 유지 용량을 투여받고; 제2 코호트(Q16W)는 1일 및 28일에 120 mg의 ISIS 443139의 부하 용량을 투여받은 후 16주마다 120 mg의 ISIS 443139의 유지 용량을 투여받는다. 1차 효능 평가변수는 101주차에 총 기능 능력(TFC) 스코어에서 기준선으로부터 변화될 것이다. 2차 효능 목적은 101주차에 cUHDRS 스코어에서 기준선으로부터의 변화이다. 총 기능적 능력(TFC) 스코어, 총 운동 스코어(TMS), 기호 디지탈 양식 시험(SDMT) 스코어 및 스트룹 단어 읽기 시험(SWR) 스코어에서 기준선으로부터의 변화도 측정된다.
SEQUENCE LISTING
<110> Ionis Pharmaceuticals, Inc.
<120> METHODS FOR REDUCING HTT EXPRESSION
<130> BIOL0380WO
<150> 62/980,010
<151> 2020-02-21
<160> 4
<170> PatentIn version 3.5
<210> 1
<211> 175000
<212> DNA
<213> Homo sapiens
<400> 1
aacaaatcac cccagcactg tggcttggca gcacacatgt ctagtcatag agttatatgt 60
agttacgtgt agagccatat gtatcgtcac acgttctgtg ggtcaggaat ttggacccag 120
cttaaccagc tccacttctc gccagggttc agtcaaatac cagctgcctc ccacctgaga 180
gctcagccgg ggaagggtcc ctttccaatc tcacgtggtg ttggcaggat ccagttcctc 240
atggcctgct ggactgagaa cctcagttct cactgcctgt tggccagagg ccgcctttat 300
gtcctcgcca tgtgggcctc tccaacatgg cagctgactt catcagagca tccatgccaa 360
gaaggcaaca gagagggcca gggagactga agtcataccc ttttgcgacc tagtcatggg 420
gtgacattcc atcacctttg cccattggtt agaagcaggc caccaggtac agcccaagct 480
cacggggagg ggtcatacaa gggtgtcaat accaggaggt gaggggtgct ggggccatct 540
tatgagtctg cccactgagg taactaacaa ccttgaggcc tgacacagtg gacaaaggcc 600
cttattaaca gcagagaact gggaacttta tttatttatt tatttttgag acagagtctc 660
actcttgtca cccaggctgg agtgcaatgg catgatcttg gctcactgca acctccacct 720
cccaggttca agcaattctg cctcagcctc cggaatagct gggactacag gcatgcacca 780
ctacacccgg ctaatttttg tatttttagt agagacaggg tttcgccatg ttggccaggc 840
tggtctcgaa ctcctgacct ctggtgatct gcctgccttg gcctcccaaa gtgctgggat 900
tacaggcgtg agccaccgca cctcgctgga acttaatttt tttagagaca gtgtcgctct 960
atcacccaag ctggagtgca gtggtgcaat cctagctcac ttgcagcctc aaattcctgg 1020
gttcaggtga tcctcccaca tcagcctccc aagaactggg aactaacagc tgtttctctg 1080
ctgtccttct caagaaaagg gaggctactg ctaccccact ggggacaatg ctgggtttcc 1140
ctttaggaca ggctctgaga caaggcggag gtgctgtttg tggccacaga gcaggggact 1200
ctgggttgca ggtgtggcct ggctaaagta ggctttactg ggctcctctc tgcctgcatc 1260
accccccggc tgggcggttg tctctgaggc caaccttact ccctgctggg caggctggac 1320
agctgccctc tccgtttgcc cctctaccac ccaaaaggca ggaggctctg gagaccagga 1380
ccctgcccgc cacggcctgt gtcccaggcg tgagggggtg ccccacagac ctctgctgag 1440
ctgctgctga atgacgcccc ttgggggtcc tgccggaagg tcagagcagg ggtgcactcc 1500
cataaagaaa cgcccccagg tcgggactca ttcctgtggg cggcatcttg tggccatagc 1560
tgcttctcgc tgcactaatc acagtgcctc tgtgggcagc aggcgctgac cacccaggcc 1620
tgccccagac cctctcctcc cttccggggc gctgcgctgg gaccgatggg gggcgccagg 1680
cctgtggaca ccgccctgca ggggcctctc cagctcactg ggggtggggt gggggtcaca 1740
cttggggtcc tcaggtcgtg ccgaccacgc gcattctctg cgctctgcgc aggagctcgc 1800
ccaccctctc cccgtgcaga gagccccgca gctggctccc cgcagggctg tccgggtgag 1860
tatggctctg gccacgggcc agtgtggcgg gagggcaaac cccaaggcca cctcggctca 1920
gagtccacgg ccggctgtcg ccccgctcca ggcgtcggcg ggggatcctt tccgcatggg 1980
cctgcgcccg cgctcggcgc cccctccacg gccccgcccc gtccatggcc ccgtccttca 2040
tgggcgagcc cctccatggc cctgcccctc cgcgccccac ccctccctcg ccccacctct 2100
caccttcctg ccccgccccc agcctcccca cccctcaccg gccagtcccc tcccctatcc 2160
cgctccgccc ctcagccgcc ccgcccctca gccggcctgc ctaatgtccc cgtccccagc 2220
atcgccccgc cccgcccccg tctcgccccg cccctcaggc ggcctccctg ctgtgccccg 2280
ccccggcctc gccacgcccc tacctcacca cgccccccgc atcgccacgc cccccgcatc 2340
gccacgcctc ccttaccatg cagtcccgcc ccgtcccttc ctcgtcccgc ctcgccgcga 2400
cacttcacac acagcttcgc ctcaccccat tacagtctca ccacgccccg tcccctctcc 2460
gttgagcccc gcgccttcgc ccgggtgggg cgctgcgctg tcagcggcct tgctgtgtga 2520
ggcagaacct gcgggggcag gggcgggctg gttccctggc cagccattgg cagagtccgc 2580
aggctagggc tgtcaatcat gctggccggc gtggccccgc ctccgccggc gcggccccgc 2640
ctccgccggc gcagcgtctg ggacgcaagg cgccgtgggg gctgccggga cgggtccaag 2700
atggacggcc gctcaggttc tgcttttacc tgcggcccag agccccattc attgccccgg 2760
tgctgagcgg cgccgcgagt cggcccgagg cctccgggga ctgccgtgcc gggcgggaga 2820
ccgccatggc gaccctggaa aagctgatga aggccttcga gtccctcaag tccttccagc 2880
agcagcagca gcagcagcag cagcagcagc agcagcagca gcagcagcag cagcaacagc 2940
cgccaccgcc gccgccgccg ccgccgcctc ctcagcttcc tcagccgccg ccgcaggcac 3000
agccgctgct gcctcagccg cagccgcccc cgccgccgcc cccgccgcca cccggcccgg 3060
ctgtggctga ggagccgctg caccgaccgt gagtttgggc ccgctgcagc tccctgtccc 3120
ggcgggtccc aggctacggc ggggatggcg gtaaccctgc agcctgcggg ccggcgacac 3180
gaacccccgg ccccgcagag acagagtgac ccagcaaccc agagcccatg agggacaccc 3240
gccccctcct ggggcgaggc cttcccccac ttcagccccg ctccctcact tgggtcttcc 3300
cttgtcctct cgcgagggga ggcagagcct tgttggggcc tgtcctgaat tcaccgaggg 3360
gagtcacggc ctcagccctc tcgcccttcg caggatgcga agagttgggg cgagaacttg 3420
tttcttttta tttgcgagaa accagggcgg gggttctttt aactgcgttg tgaagagaac 3480
ttggaggagc cgagatttgc tcagtgccac ttccctcttc tagtctgaga gggaagaggg 3540
ctgggggcgc gggacacttc gagaggaggc ggggtttgga gctggagaga tgtgggggca 3600
gtggatgaca taatgctttt aggacgcctc ggcgggagtg gcggggcagg gggggggcgg 3660
ggagtgaggg cgcgtccaat gggagatttc ttttcctagt ggcacttaaa acagcctgag 3720
atttgaggct cttcctacat tgtcaggaca tttcatttag ttcatgatca cggtggtagt 3780
aacacgattt taagcaccac ctaagagatc tgctcatcta agcctaagtt ggtctgcagg 3840
cgtttgaatg agttgtggtt gccaagtaaa gtggtgaact tacgtggtga ttaatgaaat 3900
tatcttaaat attaggaaga gttgattgaa gttttttgcc tatgtgtgtt gggaataaaa 3960
ccaacacgtt gctgatgggg aggttaattg ccgagggatg aatgaggtgt acattttacc 4020
agtattccag tcaggcttgc cagaatacgg ggggtccgca gactccgtgg gcatctcaga 4080
tgtgccagtg aaagggtttc tgtttgcttc attgctgaca gcttgttact ttttggaagc 4140
taggggtttc tgttgcttgt tcttggggag aatttttgaa acaggaaaag agagaccatt 4200
aaaacatcta gcggaacccc aggactttcc ctggaagtct gtgtgtcgag tgtacagtag 4260
gagttaggaa gtactctggt gcagttcagg cctttctctt acctctcagt attctatttc 4320
cgatctggat gtgtcccaga tggcatttgg taagaatatc tctgttaaga ctgattaatt 4380
tttagtaata tttcttgttc tttgtttctg ttatgatcct tgtctcgtct tcaaagttta 4440
attagaaaat gattcggaga gcagtgttag cttatttgtt ggaataaaat ttaggaataa 4500
attattctaa aggatggaaa aactttttgg atatttggag aaattttaaa acaatttggc 4560
ttatctcttc agtaagtaat ttctcatcca gaaatttact gtagtgcttt tctaggaggt 4620
aggtgtcata aaagttcaca cattgcatgt atcttgtgta aacactaaac agggctcctg 4680
atgggaagga agacctttct gctgggctgc ttcagacact tgatcattct aaaaatatgc 4740
cttctctttc ttatgctgat ttgacagaac ctgcatttgc ttatcttcaa aatatgggta 4800
tcaagaaatt tcctttgctg ccttgacaaa ggagatagat tttgtttcat tactttaagg 4860
taatatatga ttaccttatt taaaaaattt aatcaggact ggcaaggtgg cttacacctt 4920
taatccgagc actttgggag gcctaggtgg acgaatcacc tgaggtcagg agtttgagac 4980
cagcctggct aacatggtga aaccctgtct ctactaaaaa tacaaaaatt agctggtcat 5040
ggtggcacgt gcctgtaatc caagctacct gggaggctga ggcaggaaaa tcgcttgaac 5100
ccgggaggca gagtctgcag tgagttgaga tcacgccact gcactccagc ctgggtgaca 5160
gagcgagact ctatctcaaa aaaaattttt tttaatgtat tatttttgca taagtaatac 5220
attgacatga tacaaattct gtaattacaa aagggcaata attaaaatat cttccttcca 5280
cccctttcct ctgagtacct aactttgtcc ccaagaacaa gcactatttc agttcctcat 5340
gtatcctgcc agatataacc tgttcatatt gtaagataga tttaaaatgc tctaaaaaca 5400
aaagtagttt agaataatat atatctatat attttttgag atgtagtctc acattgtcac 5460
ccaggctgga gtgcagtgat acaatctcgg ctcactgcag tctctgcctc ccaggttcaa 5520
atgcttctcc tgcctcagcc ttctgagtag ctgggattac aggcgcccac caccatgtcc 5580
agctaatttt tgtattttta gtagagatgg ggtttcacca tgttggccag gctggtcttg 5640
aactcctgac cttgtgatct gtccacctcg gcctcccaaa gtgctgggat tacaggtgtg 5700
agccaccatg cctggctaga ataataactt ttaaaggttc ttagcatgct ctgaaatcaa 5760
ctgcattagg tttatttata gttttatagt tattttaaat aaaatgcata tttgtcatat 5820
ttctctgtat tttgctgttg agaaaggagg tattcactaa ttttgagtaa caaacactgc 5880
tcacaaagtt tggattttgg cagttctgtt cacgtgcttc agccaaaaaa tcctcttctc 5940
aaagtaagat tgatgaaagc aatttagaaa gtatctgttc tgtttttatg gctcttgctc 6000
tttggtgtgg aactgtggtg tcacgccatg catgggcctc agtttatgag tgtttgtgct 6060
ctgctcagca tacaggatgc aggagttcct tatggggctg gctgcaggct cagcaaatct 6120
agcatgcttg ggagggtcct cacagtaatt aggaggcaat taatacttgc ttctggcagt 6180
ttcttattct ccttcagatt cctatctggt gtttccctga ctttattcat tcatcagtaa 6240
atatttacta aacatgtact atgtgcctgg cactgttata ggtgcagggc tcagcagtga 6300
gcagacaaag ctctgccctc gtgaagcttt cattctaatg aaggacatag acagtaagca 6360
agatagataa gtaaaatata cagtacgtta atacgtggag gaacttcaaa gcagggaagg 6420
ggatagggaa atgtcagggt taatcgagtg ttaacttatt tttattttta aaaaaattgt 6480
taagggcttt ccagcaaaac ccagaaagcc tgctagacaa attccaaaag agctgtagca 6540
ctaagtgttg acatttttat tttattttgt tttgttttgt tttttttgag acagttcttg 6600
ctctatcagc caggctggag tgcactagtg tgatcttggc tcactgcaac ctctgcctct 6660
tgggttcaag tgattctcat gcctcagcct cctgtttagc tgggattata gacatgcact 6720
gccatgcctg ggtaattttt tttttttccc ccgagacgga gtcttgctct gtcgcccagg 6780
ctggagtgca gtggcgcgat ctcagctcac tgcaagctcc gcttcccgag ttcacgccat 6840
tctcctgcct cagtctccca agtagctggg actacaggcg cctgccacca cgtccagcta 6900
atttttttgt atttttaata gagacggggt ttcaccgtgt tagccaggat gatcttgatc 6960
tcctgacctc gtcatccgcc gaccttgtga tccgcccacc tcggcctccc aaagtgctgg 7020
gattacaggc atgagccact gtgcccggcc acgcctgggt aatttttgta tttttagtag 7080
agatggggtt ttgccatgat gagcaggctg gtctcgaact cccggcctca tgtgatctgc 7140
ctgccttggc ctcccaaagt gctaggatta caggcatgag ccaccatacc tggccagtgt 7200
tgatatttta aatacggtgt tcagggaagg tccactgaga agacagcttt tttttttttt 7260
ttttttgggg ttggggggca aggtcttgct ctttaaccca ggctggaatg cagtatcact 7320
atcgtagctc acttcagcct tgaactcctg ggctcaagtg atcctcccac ctcaacctca 7380
caatgtgttg ggactatagg tgtgagccat cacacctggc cagatgatgg cttttgagta 7440
aagacctcaa gcgagttaag agtctagtgt aagggtgtat gaagtagtgg tattccagat 7500
ggggggaaca ggtccaaaat cttcctgttt caggaatagc aaggatgtca ttttagttgg 7560
gtgaattgag tgagggggac atttgtagta agaagtaagg tccaagaggt caagggagtg 7620
ccatatcaga ccaatactac ttgccttgta gatggaataa agatattggc atttatgtga 7680
gtgagatggg atgtcactgg aggattagag cagaggagta gcatgatctg aatttcaatc 7740
ttaagtgaac tctggctgac aacagagtga aggggaacac cggcaaaagc agaaaccagt 7800
taggaagcca ctgcagtgct cagataagca tggtgggttc tgtcagggta ccggctgtcg 7860
gctgtgggca gtgtgaggaa tgactgactg gattttgaat gcggaaccaa ctgcacttgt 7920
tgaactctgc taagtataac aatttagcag tagcttgcgt tatcaggttt gtattcagct 7980
gcaagtaaca gaaaatcctg ctgcaatagc ttaaactggt aacaagcaag agcttatcag 8040
aagacaaaaa taagtctggg gaaattcaac aataagttaa ggaacccagg ctctttcttt 8100
tttttttttt tgaaacggag tttcgctctt gtcacccggg ctggagtgca atgatgtgat 8160
ctcagctcac taaaacctct acctcctggg ttcaagtgat tcttctgcct cagcctccca 8220
agtaactggg attacaggcg tataccacca tgcccagcta atttttgtgt ttttagtaga 8280
gatggggttt caccatgttg gccaggctgg tctcgaactt ctgacctcag gtgatccact 8340
cgcctcagcc tgccaaagtg ctgggattac aggtttgggc cactgcaccc ggtcagaacc 8400
caggctcttt cttatactta ccttgcaaac ccttgttctc attttttccc tttgtatttt 8460
tattgttgaa ttgtaatagt tctttatata ttctggatac tggattctta tcagatagat 8520
gatttgtaaa aactctccct tcctttggat tgtcttttta ctttcttgat agtgtctttt 8580
gaagtgtaaa agtttttaat tttgatgaag tcgagtttat ctattttgtc tttggttgct 8640
gtgcttcaag tgtcatatct aagaaatcat tgtctaatcc aaagtcaaaa aggtttactc 8700
ctatgttttc ttctaagaat tttagagttt tacatttaag tctgatccat tttgagttaa 8760
tttttatata tggttcaggt agaagtccaa ctttattctt ttccatgtgg ttattcagtt 8820
gtcccagcac tgtttgttga agagactatt ctttccccat ggaattatct tagtaccctt 8880
gttgaaaatt aatcgtcctt aattgtataa atttatttct agactgtcag ttctacctgt 8940
tggtctttat gtcgatcctg tgccagtacc atacagtctt gattactgaa gtttgtgtca 9000
cagtttaaat tcatgaaatg tgagttctcc aactttgttc cttttcaaga ttgatttggc 9060
catgctgggt cccttgcatt tccgtacgaa ttgtaggatc agcttgtcag tttcaacaaa 9120
gaagccaagt aggattctga gagggattgt gttgaatctg tagatcaact tggggagtat 9180
tcgcatctta acaatattgt cttccaccta tgaacatggg caaactttgt gtaaatggtc 9240
agattgtaag tatttcgggc tgtgtgggca cagtgtctct gtcacagcta cgcggctctg 9300
ccattgtagc atgaaagtag ccataagcaa tatgtatgag tgtctgtgtt ccaatagaat 9360
tttattaatg acaaggaagt ttgaatttca tataattttc acctgtcatg agatagtatt 9420
tgattatttt ggtcaaccat ttaaaaatgt aaaaacattt cttagcttgt gaactagcca 9480
aaaatatgca ggttatagtt ttcccactcc taggttaaaa tatgatagga ccacatttgg 9540
aaagcatttc tttttttttt tttttttttt tttttgagac ggagtttcac tcttgttgcc 9600
caggctggag tgcagtggcg cgatctcggc tcactgcaac ctctgcctcc caggttcaag 9660
acattctcct gcacggcctc cctagtagct gggattacag gcatgcgcca ccacacccag 9720
ctaattttgt atttttagta gagacggggt ttctccatgt tggtcaggct ggtcttgaac 9780
tcctgacctc aggtgatcca cccgcctcag cctcccaaag tgctgggatt acagggtgtg 9840
agccaccaca ccctgctgga aagcatttct tttttggctg tttttgtttt ttttttaaac 9900
tagttttgaa aattataaaa gttacacata tacattataa aaatatcttc aagcagcaca 9960
gatgaaaaac aaagcccttc ttgcaagtct gtcatctttg tctaacttcc taagaacaaa 10020
agtgtttctt gtgtcttctt cccagatttt aatatgcata tacaagcatt taaatgtgtc 10080
attttttgtt tgcttgactg agatcacatt acatatgtat ttttttactt aacaatgtgt 10140
catagatatt gttccatagc agtacctgta attcttatta attgctatgt aatattttag 10200
aatttctttt taaaagagga cttttggaga tgtaaaggca aaggtctcac atttttgtgg 10260
ctgtagaatg tgctggtgac atattctctc taccttgaga agtccccatc cccatcacct 10320
ccatttcctg taaataagtc aaccacttga taaactacct ttgaatggat ccacactcaa 10380
aacatttagt cttattcaga caacaaggag gaaaaataaa ataccttata aagcactgtt 10440
taatattgta ttaaattgga tcaatttggg ggctagaatg tatgttagag acatgatatg 10500
tccataggtc cttgctatca cagtgaggtc tcagggacag tcgtttggta tcatttggga 10560
tctcataagc agactctctc tgcttgacct gacaaatcag agtctgtgtt ttaacaggtt 10620
cagtgagtga cttacatgca cattggagtt tgggaagctc cactgtaggt gcttagacct 10680
tacctttgtt gttgctaata acaatgcaag catttgggag gaagacctgt gttgctcata 10740
tgtgtccagg tgtagctgag gtggccttgc ttatctgctg tagggccgtt gagcatttct 10800
gtagctgtga tgagtgagct gaggtgagcc tgcggagagc tcccagccat tggtagtggg 10860
actcgcttag atgaactgga aggacccttt catctgagca gccactatgg agaaaaacaa 10920
ccgaatgagg ggagagacaa tgtgcaattt tatttagggc acaaaggaga gctgtggtta 10980
gaaggtgaca tttgagtgga aagggggcaa gccatgtgta tagcgggaga agagaggtcc 11040
aggcagagtt aacagaaggc agaaatgctt tccatgtttg agaaccagta aggaggccag 11100
tggctgaagt aaggtgaagg gcagaaataa ggatgaggct gcgagagatg agaggttaga 11160
gacgagcgtc ttgtgcacca agataagctt gtgtggtcaa aacaagtagt ttaatttatg 11220
tttttaaaag atcattttgg ctgggcacaa tggttcatgc ctgtaatacc agtagtttga 11280
gacggtgtgg tgggaggatt gcctgaggcc agacgaccag catagccaac atagcagcac 11340
ctataaggtc tctacaaaaa actttaaaaa attagctggg catagtggtg tgtgcctgta 11400
gtcccagcta ctcaggaggc tgaggaggct ggaggattgc ttgagtccag gagtttgagg 11460
ctgcagtgag ctatgattat gccactacac tacaacctgg gcaagagagt gagaccctgt 11520
ctctaaatat acacacacac acacacacac acacacacac acacacacac acacacacac 11580
acacacatat atatgtatat atatgcattt agatgaaaag atcactttga caataccaca 11640
tgctggtgag gatttagaaa aactaggtca cttattgctg gtgggaatat aatatagtac 11700
ggccactctg gaaaacagtt tggcagtttg tcataaaact gaacataccg ttagtataca 11760
gcccagcagc aactacaatc ctgggcatta atcctagaga aatgaaacct taatgttcac 11820
ataaaaacct atactcaagt atgcatagca gctttaccca taatatctaa gaactggaat 11880
cagctcagat gtccttcaac aggtgaatgg ttaaactact cagtaataaa aaggaatgag 11940
ctactgatag catgcaacag tttaggtgaa gttatgctaa tgaaaaaagc caatcccaaa 12000
aggttataca tactgtatga ttctatgttt ttttgcaatg gcacagtttt agggatggag 12060
aatagattag tggttgcctg gggttagaga tggggtagta gagtaggtta gtggtggcag 12120
aggagagaaa agagagggag gtgaatgtgg ttataaaagg acaacacagg ggaatacttg 12180
taatggaaat gctttgtctt tttttttttt tttttttttt tggcgacaga gtcttgctct 12240
gttgcccagg ctggagtgca gtggcatgat cttttctcac tgcaacctct gcctcctggg 12300
ttcaagtgat acttgtgtct cagtctccca tgttcagagt gaaacaaacc agaggtaatg 12360
ttcatccaaa taatccaaca cacatgacat taaaacatca agatcaggtc ggacgtggtg 12420
gctcatgcct gtaatcccag cacttttggg aggccaaggt gggcagatca cttgaggtca 12480
ggagttcgag accagccggg ccaacatgat gaaaccccat cttgactaaa aatacaaaaa 12540
ttagccgggc atggtggtgt gcacctgtag tcccagctac ttgggaggct gaggcaagag 12600
aactgcttga acccgagggg cagaggttgc agtgagctga gagtgcgcca ttgcacttca 12660
gcctgtgtga cagagtaaga ctccatctcc aaaaaaaaaa aaccaagatc aattaaaata 12720
cagcattact gggccgggtg tggtggctca cacctgtaat cccagcactt tgggaggccg 12780
agatgggcag atcacgaggt caggagatcc agaccatccc ggctaacacg gtgaaacccc 12840
gtctctacta aaaaatacaa aaaattagcc gggtatagtg gtgggtgcct gtagtcccag 12900
ctacttggga ggctgaagca ggagaatggt gtgaacccgg gaggcagagc tggcagtgag 12960
ctgagatcgc gccactgcac tccagcctgg gcgacagagc aagactccgt ctcgggggaa 13020
aaaaaaaaat aaataaatag aatgctgtag tgtccttgag tttacatgcc cctccttacg 13080
cttgtgtgcc cgtgcagatt gcttgattac acaattagag gaggctggcg gaggattgtt 13140
ttaatttttt tttttttgag acagtctggc tctgttcccc aggctagagt gcaatggcgc 13200
aatcttggtg cactgcaacc tctgcctcct gggttcaagc agttcttctg ccgcagcctc 13260
ccgagtagct gggattatag gcgcccgcca ccacgcccaa ctattttttg tatttttagt 13320
agagcagcgt ttcaccatgc tggccaggct ggtctcgaac tcctgacctc agatgatctg 13380
ctgccccagc ctcccaaagt gctgggatta caggcgtgag ccacacctgg ccgtttgttt 13440
taattttgaa ggtgaagtga aagtgactac atttaccaaa agtgattgaa aagccaggac 13500
tgttcttacc ctgtttttcc agttcttgct cagagcaagg tggtttcttt ttcacttaat 13560
caccatactt acttttcatg tagaacaagt cagtttgagt tatcagttca tcatcttaac 13620
taaattccat gggggaagga attagtttta gtttcttaaa cttccaggtt tgcttattgg 13680
acaaaatgag atagcaaggc agtgttttta agttagattt tttatttctt tggtaataca 13740
attttctcag aaacttagta gtcttttagt ttagttgttt ttagttggtc ctatgttttg 13800
gatcacccct ctctacttta ttttgatagt gccaactgtg aagacatctg aagccatagg 13860
tttggatggg aaggaggcat ctttagcctg atcatcttcg ccaggctgtt tatctccttt 13920
tgcttggctg agaagtctta ataggaggct tattcccagc tatttgggga catagaagca 13980
gttagccatt gcttatattt tactgaggtc tgtgtggtat gttgattgta gtcagttaac 14040
gattttgaga actgaaggca gcctggtata tatagagtag gtattagact gtgtttcttc 14100
taattgaatt tcccatctct tgtaatctat gccatcatct tctgtactgc tgagaaagaa 14160
agaaagtttc taatcaaact ataccactgg ttgtaagatg cagtttggct ttagtgatgt 14220
taacacatga ttcaaacgtg aaattgattg agtattggtg aaatacagag gagatttaaa 14280
gccagaagac ctgggtttaa atgctggctg tatgacttca tatctgtgtg atcttgggca 14340
tgtcatggtt ggcacttcaa tttcttctct ctataatggg ggaagtgagg ccagtcatgg 14400
tggctcatac ctataatccc agtgctttgg gaggccaaga tgggaagatc gcttgaggcc 14460
aggagtttga gcaattgggc aacatcgtga ggccccgtct ctacaaaata ttttgaaaaa 14520
attagccagg cccagtggtg cgtgcctgtg gtccgcgcca ctcaggaggc tgagacggga 14580
ggatcctttc agcctaggag tttaaggcta aagtgagcca tgattgtgct atcgtactcc 14640
agcctgggca gcagagcaag atcctgactc taaaaaaaag taaaataaag taaaatgggg 14700
gaaatgaact gctttagtaa catcatctgt tttttctgtg agcagcgtag cttgacagcc 14760
attggtgaac tcgtgccctg tgcttccctg tccagatccc cattctgccc gcaacatgga 14820
gtataacggt ttattcatag tagtcgagaa acactcactg aatgaatgaa tgaggtgtag 14880
aactaagtgg agtgggtaat tcaacacata ttaatttcct tctttttttt atttttagaa 14940
agaaagaact ttcagctacc aagaaagacc gtgtgaatca ttgtctgaca atatgtgaaa 15000
acatagtggc acagtctgtc aggtaattgc actttgaact gtctagagaa aataagaact 15060
ttgtatattt tcagtcttaa tgggctagaa tattctttgt gtcccagcta ttttaaatgg 15120
attcagaaat ccatttaaga tgaagaagga cccttttccc atatttctgg ctatatacaa 15180
ggatatccag acactgaaat gaataatgtt ccctttttgt aatcttttat gcaaaaatta 15240
aaaccattat ggtaattgaa caacatgttt atgtttagtt aacaccctta gcaactatag 15300
ttattttaaa accatctatg gtttgatatt tttgcatttg ttgcaatagt aggaacagca 15360
caagacagtt cagtttgtct ctcttatttg ctttttcttg gcagtttgct gtcctattgt 15420
acctctgctc ctagcagtgg ctggagccca ctcctctgtg cttcgggatt agtggggatc 15480
gtggggcatt gactgtaggt cagctttcct tgcttgatct ttctcactgg gatgaactag 15540
cagcaccttc ttttgtagct gctttgcttt tgactatctt tctgaccgtt gttcctagta 15600
gctgtagatg gtaaatatat ttaggcctgt ttccaatggc tcagtaggag acatattcac 15660
ctatgatatc tgaattctgt tacccacatg ggcatgcgtg aaatagttgc cttgccttac 15720
tttcccttgg aataaataat tcatgttatt ctcctggtag aagctagaaa aagcctttat 15780
agtcagtcag aaaaaaattt ttagacaaat aatcttgatt ttagtactga caaaaacgtg 15840
tggtgattct ttttttaatt tttttttgag acggagtttc actcttgttg cccaggctgg 15900
agtgcaatgg cgtgatctcg gctcactgca acctctgcct cctgggttca agtgattctc 15960
ctgcctcagc ctcccaagta gctggagtta caggcatgtg ctactgtgcc cagctaattt 16020
tgtattttta gtagagatgt tggtcaggct gatctcgaac tcccaacctt aggtgatctg 16080
cccgcctcag cctcccaaag tgctgggatt acaggcgtga gccagggcgc ccggtgattc 16140
atttgttttt tcaaaaaatt tcctcttggc cattgctttt cacttttgtt tttttttttt 16200
ttttgagacg gagtcacgat ctgtcaccca ggctggagtg cagtggcatg atcttggctt 16260
actgcaagct ctgcctccca ggttcacgcc attctcctgc ttcagcctgg cgagtagctg 16320
ggactacagg tgctcgccac cacacccggc taattttttg tatttttagt agagatgggg 16380
tttcaccgtg gtcttgatct cctgacctca tgacccgctc aactcagcct cccaaagtgc 16440
tgggattaca ggcgtgagcc accgcgcccg gccctctctt gtctttttat tgtggtaaaa 16500
tgcacataaa attgactgtc ttaaccattt ttaggggtac agttcagtat atatattcgt 16560
aatgttgtac agccatcact gccatctact tcataagttt ttcttctgtc aaaactgaac 16620
atctgtcttc attaaactcc ctatcatcca ttctttcctg tagtcccttt ctactttctg 16680
tctgtatgag tgtaactgct ctggagacct catgtaagtg gattcctaca ggatttgtgt 16740
tttttttttg gtgatctgct tatttttaat gcctctgtgc atttgtatta tatactttca 16800
aagtgatttc acaaaaccgt ttcattttag gttaactcat ttctgttgtt tgtgaaatac 16860
tgtgtatgat tctgttctgt ttctgtctaa tttgtggaaa tgttgtggga agaaaatgaa 16920
ataacaaatg agcatatgtc ctgaaaataa aaatataaaa attctaagtt agcatgctat 16980
tgtagaatac aacgctatga taaaagtagg aaaaaaaaag gtttgaattc tatctctgct 17040
acctgtgtaa gctgggtgac tttagataag ctgtaacgtg tttgagcctt actggctcat 17100
ttttgaaatg taatccctag ttacacagtt cttgtgggat cagatggtac atgtgaaaca 17160
ctgtgaaaaa gcaactgcat agatatgttc attagccacc tgagcgggaa gcgtatccca 17220
ttgcgatgcc catcatccaa agctatatgt tatctttact tttttttttt tgagacagag 17280
tcttgctctg ttgcccaggc tagagtgcag tggtgcaatc tcagctcact gcaagctcca 17340
cctcccgggt tcacgctatt ctcctgcccc agcctcccaa gtagctggga ctacaggcac 17400
ccgccaccat gcctggctaa atttttgtat ttttagtaga gatggggttt caccgtgtta 17460
gccaggatgg tcttgatctc ctgacctcgt gatccgcccg cctcggcctc ccaaagtgct 17520
gggattacag gcgtgagcca ctgcccctgg ccatctttac tttttttgtg aaatgacttt 17580
aaatacttgg caaacatttg gtcattgttc atctgatctc caccatccag gtctcagaga 17640
acataatttc tctctgaaag cttattgacc caggaaataa gatctctttc aatctgagtg 17700
cgtcaggctt tattcttgtc attttgtctt ttgataattt tcaaatggaa ttcatggaat 17760
gttggcttat attcatatat tagtaaagta tgttgagaca tcttaagatt gatttgtggt 17820
tctatatgcc atattaaatc aaaataatag ctgttaatgg ttttcacatt agtctgtctc 17880
ttgtttttat ggagtaatgc tgagagttca ttatgcttgt tctacagaag agcatgttaa 17940
aaggagtttt tggagtcaga gaggttattc ttggtttcat aggatacact ctatactttt 18000
tagggatttc agagtatata gctgaaggtg atattttatg taaatatgtt ttatggaaac 18060
ttattgctca tcgctgtttc ctgttaactc tcctaaaata taattaaact tttggaactt 18120
ttttatagct tttgtgctag actaattttt gtctctaatg aggttatata aatggcagct 18180
tctgacgttt tcaatgtagg aagtcattta aaacttcatg tatattgtga aaatgtagtc 18240
tgctttaagc tctctaaagt ggtctaagtt actggttcct aagtatggat gagcatcaaa 18300
atcatctgga aaatttgtta aaaatacagt aatgaaggca cctcactgtc ctttttccca 18360
aacatacttc tgcattctgt ttgagtaggt agggactaca catttttcac aagtatcctc 18420
ttgggaatac ccaggaatgc ttacttgagc aacctcttac taatatgtac cttgataagg 18480
tggctaggta aacataaata tacaaaaatc catagatctc ccatatatta gcataaatca 18540
gctagaaaat ataacgttta aagatctagt tcacagtagc accaatatat cgaactctaa 18600
ggaatcgata aatatgcaaa aactttataa aaacttctgt taatgtttct gaaagatata 18660
ggtgaccact ttctagatag gaagatttta tattactaag ttgaattttc tctaaattaa 18720
cacagaaatt taaaataatc ttgatcaaaa ttctagtaga ggtatttttg aacttgttca 18780
ctgcaagaat aaatacataa ttgcaaagaa tatctcaaaa tcatcaccag gcctggtgtg 18840
gtggcccatg cctgtaatcc cagcactttg ggaggctgag gcaggcagat cacctgaggt 18900
caagagtttg agaccagctg gaccagtgcg gtgaaacact gcctctacta aaaatacaaa 18960
aattagctgg gtgtggtggt gcatgcctgt agtcccagct acttgggagg ctgaggcagg 19020
agaattgctt gaacccagga ggtacaggtt gcggtgagcc tagatcgcac cactgcattc 19080
cagcctgggc gacaagagca aaattctgtc tcaagaaaaa agagaaaaaa gaaaaagaaa 19140
tcaacactaa tatggtgaga cttaatgtat gtgacattaa aatagtgatt ggatgttaaa 19200
acaggtatag aacagaaaga agagtgtatg tgtgtatctg tatgaattta tgatgggtgt 19260
aacatatatg tattagggaa atgagggaaa tgatacattt ctctgacttt gggagaacat 19320
tatatctcta cctcatattg caaacaaaca taaagttcag attaattacc taaatgtgaa 19380
aaaatgaaat aatttcttta aaaaatgtaa tcttagtttg aggaaggtta acattataaa 19440
ggaaaaaact gttttgagtg gaatatagtt caatatgtca aaatccacct tcaacaaaat 19500
tgaaagtaaa ttgaacttgg ggaaagtatt gacagcatat agatcaaagg ttactagcct 19560
gtgtaaagag cagttataaa tatcgttaag aaaaacactg tcgacctgtc ggcaccttgt 19620
tctccgactc ccagcctcca gaactgtgac gagtaagtgc ttattgttta aaccacccag 19680
tctgtatgtg gtattttgtt atagaaactc aagctgatta ggacactagt aatcagtaga 19740
ctgaaactga aacaaaaata agaacctttt ttacctgtca aattggcaaa cattaagaat 19800
attcagattt ttgtcagagg tgatacaacc ttctaagaag gcaatttggg aaaatataaa 19860
gctttagatt attatatgtc tgacctagca gttttacctc tagggtgctt acccctagga 19920
aagtgtgtaa tgatattggt gcagtgccct tcatcccatt agaaaattaa aaataacctt 19980
aatggcctac cactaaaagg ggattgaaaa tttaagatat atttatttat gtgtttattg 20040
agatggagtc ttgcactgtc cgcctgggcc agagtgcaat ggtgcgatct cggctcactg 20100
caacctctgc ttcccgggtt catgtgattc tcctgcctca gcctcctgag tagctgggat 20160
tacaggctca caccaccgca cccggctaat tttttgtatt tttagtagag atggggtttc 20220
actgtgttgg ccagactggt ctcgaactcc tgacctcatg atccgcgccc ctcggcctcc 20280
cagtgttggg attacaggtg tgagccactg cgcctggcca gatacattta tacaagagaa 20340
tgttagttaa cattcataga tatttatatt ttgtttactt tttattaaaa aaattttttt 20400
tagagacagg atcttactct gtcacccagg caggatgcag ttgcacaatc atagcccact 20460
gcagcctgaa ctcctgggct taagtgatcc ttctgcctca gccttttgag tacctggggg 20520
actttaggca gtgctactat acctggctaa tttttaaatg ttttatagat gagatcttgc 20580
tgtattgccc aggctggtct agaattcctg ggcccaagtg atcctcccac cttggcctcc 20640
caaagcgctg agattacagg catgagccac cacttctgac caatagatat ttatatttgt 20700
gactggaaaa tatattaaca atgtgttaaa aaattcagtt aaaaaataat gaaagatttt 20760
tgcttctggc taagatagaa taacaaggac agcatttatc ttcttgcctt gaaatagttg 20820
aaaacggaag aaatatatgt aacagtggtt ttcaagttat tgggcatcag gcaaagaaga 20880
atagttatcc caggaaaatg aatgtggaga gccctacaat ttccttacat tactgcctgg 20940
tcatggcaag aggaaaaact gagaggagac tgaggctgag ccagtggttt gctgggttga 21000
ggaggcagag ctgggagtgc agagatgcaa ggtggtgaga gcccatatgg aagaatacca 21060
gggaagagag ctgcagaggg agctccggag acctgcaccc tgccctctca gtaccctgtc 21120
atgtgtgtag ctgagtactg acgagcactt gcttgtgcgg aaatgaccca gggctggagg 21180
tagagccacc tgaaaggatt agaaggaaca gttgctgaaa gtcacacagg gccaggaaga 21240
atttctaatc acaccagttg gagtggaaaa cctcagctct catagagcag gtagggtact 21300
cagaagggtt tgcccaccta gccccagact aagtttcgtt actctgaccc tacctaatat 21360
taaaaagaga ttaattaaat tgttcgcaac aaaaataata tatttcagtg tttgtaacac 21420
gtagaagtga attgtatgac aatagcataa aggctggaag agcagaaatt gacatgtatt 21480
tgcgctgggc agaataatgc tcccctcttt ccccaaaaga tatcaagtcc taatccctgg 21540
agcctgtaaa tattacttta tatggaaaat tgttttatga tgtgattaaa ttcaggatct 21600
tgagatgagg gggctatctt ggatgatctg ggtaggcact aaatgcaatc acatatatat 21660
aaaaaggagg cagagggaga ttttacacac agagagaagg ccctgtgaag atggaacaga 21720
aagatttgaa ggtgctggcc ttgaaaattg gagtgatgaa gctataagcc aaggaatgca 21780
gcagccacca aagctggaag aggcacggag cagttctcat ttagagccta ctccagaggg 21840
aatgtggtgc tgccaattcc tttttttttt ttttttttaa gatatcattt acccctttaa 21900
gttggttttt tttttttttt ttttttttta gtatttattg atcattcttg ggtgtttctt 21960
ggagaggggg atttggcagg gtcataggac aatagtggag ggaaggtcag cagataaaca 22020
tgtaaacaaa ggtctctggt tttcctaggc agagggccct gccacgttct gcagtgtttg 22080
tgtccctggg tacttgagat tagggagtgg tgatgactct taacgagtat gctgccttca 22140
agcatctgtt taacaaagca catcttgcac cgcccttaat ccatttaacc cttagtggac 22200
acagcacatg tttcagagag cacggggttg ggggtaaggt tatagattaa cagcatccca 22260
aggcagaaga atttttctta gtacagaaca aaatggagtg tcctatgtct acttctttct 22320
acgcagacac agtaacaatc tgatctctct ttcttttccc acatttcctc cttttctatt 22380
cgacaaaact gccaccgtca tcatggactg ttctcaatga gctattgggt acacctccca 22440
gatggggtgg cggccgggca gaggggctcc tcacttccca gatggggcgg ccgggcagag 22500
gcgcccccca acctcccaga cggggcggcg gctgggcggg ggctgccccc cacctcccgg 22560
acggggcggg tggccgggcg ggggctgccc accacctccc ggacggggcg gctggccggg 22620
cgggggctgc cccccacctc ccggacgggg cgggtggccg ggcgggggct gccccccacc 22680
tcccggacgg ggcggctggc cgggcggggg ctgcccccca cctcccggac ggagcggctg 22740
ccgggcggag gggctcctca cttcccggac ggggcggctg ctgggcggag gggctcctca 22800
cttctcagac ggggcggctg gtcagagacg ctcctcacct cccagacggg gtggcagtgg 22860
ggcagagaca ttcttaagtt cccagacgga gtcacggccg ggcagaggtg ctcttcacat 22920
ctcagacggg gcggcggggc agaggtgctc cccacttccc agacgatggg cggccgggca 22980
gagatgctcc tcacttccta gatgggatga cagccgggaa gaggcgctcc tcacttccca 23040
gactgggcag ccaggcagag gggctcctca catcccagac gatgggcggc caggcagaaa 23100
cgctcctcac ttcctagacg gggtggcggc tgggcagagg ccgcaatctt ggcactttgg 23160
gaggccaagg caggcggctg ggaggtgaag gttgtagtga cccgagatca cgccactgca 23220
ctccagcctg ggcaacactg agcactgagt gagcgagact ccgtctgcaa tcccggcacc 23280
tcgggaggcc gaggctggca gatcacttgc agtcaggagc tggagaccag cccggccaac 23340
acggcgaaac cccgtctcca ccaaaaaaca cgaaaaccag tcagacatgg cggtgcgtgc 23400
ctgcaatccc aggcacttgg caggctgagg caggagaatc aggtagggag gttgcagtga 23460
gtagagatgg tggcagtaca gtccagcctt ggctcggcat cagagggaga ctgtgcgagg 23520
gcgagggcga gggcgaggga attccttaat ttcagtttag tgatactaat tttggactct 23580
ggcctctaaa actgtgaaag aaaaaatttt ttgtttgttt gtttctttta agccacatag 23640
tttgtggtaa tttgttacag cagctgcagg aaactaattt atgctgcatg tgaaatggtg 23700
taataaggta gattgtgatg aagatacata gtataaacaa ttaagcaaca actaaaagca 23760
caacaaggaa ttatagctaa tgaaccaaaa aaggagatta gaataataaa aatggtgaat 23820
cccaaagaag ccagaaatag gggaagaggc aaataaagga aagaaagagc ttgatggtag 23880
atttcaacct aactatgtca aaaaggacat tacatgtaaa aggcagcgat ttttcagatt 23940
gaatggaaaa gtaagactcg gtatatgctg ctgcctgcaa gaaacacatt ctaaatataa 24000
aggcaaaaat aacctacagg taacagaacg gaaagaagtt cactgtgctt acaagaatta 24060
gatgcaagct agactggttc tgttaatatc agacaaagtg gatttcaaag caaaggctct 24120
tgcccaggat gagatggtca tttcataatg atgaagggga ttcgttcatc agcctggcat 24180
agcaagctga aatgtttatg caccggacta cagagctaaa atacatgaag caaagcctga 24240
cagaactaca agtagaaaca gacaaatcca cagtgataga gatttcagta gccgctctca 24300
atgatttgta gaacacgtag ccataatatc tggatctaga acacttgacc aacactgtcc 24360
cctgtgcaac ctcattggca tttacaggac actccaccca gcaccagcag aagagacact 24420
ctctcaagtg ctcacagaat gtttgccaag atagagcaga tgctgggcca taaaacaagt 24480
ctctaaatta aaagcattca aattattcag agtatgtttt ctgacctcag tatcattaag 24540
ttggaatata ttataggaag ataacctgga aaagcctcag atatgtggaa aaacccattt 24600
ccacatggcc catgggtcag aagtgaagtc aaaagggaaa tttgaaagtc ttttggattg 24660
actgatataa aaacaataga tttctaaact tgtggggtgc tgttacagca tagtaaatgg 24720
aaatttctag cattaaatgc ctgttttagg aaagaaagat ttcaaatcaa tgacctcagc 24780
ttctaccttt ggaaacttga aaatgacaag caaatggaat ccagagttac cagaagggcc 24840
aggtacggtg gcttatgcct gcagttctgc cactttggga ggccgaggca ggtggattgt 24900
ttgagactgg cagttgaaga ccagcctggg cagcctaggg agaccccata tctacaaaaa 24960
acaaaaaaat tagccaggtg tggtggcatg tgcctgtagt cccagctaac caggagtcta 25020
aggtgggagg attgcttgag tctgggaggt tgaggctgca gtgaactgtg attgtgccac 25080
tgtgttccat cctgggcaac agaatgagac cctgtctcaa aaacaaaaac agttactaga 25140
agaatggaca tcataaagat aggagcagaa gtcagtaaaa tagaaaacaa aaatacatag 25200
gaaatcaata aaaccaaaag ctggttcatc aagaacatca ataaattggt aaagctgata 25260
ggaaaaacag tgaagtcaca aattagcaat atcaggaatg agggagatga cagtagtata 25320
gattatatag atattaaaag gactgtatga ggcaggtgtg gtggttcacg cctgtaatcc 25380
cagcaccttg ggaggccgag gtggacagat cacctgaggt caggagtttg ggaccagcct 25440
ggccaacatg gtgaaactct gtctctacta aaaatacaaa aattagttgg tcgtggtgct 25500
gtgtgcctgt aatcccagct acttgggagg ctgaggcagg agaattgctt gaacctggga 25560
ggcggaggtt gcagtgagct gagattgtgc cgttgcactc cagcctgggt gacagagcaa 25620
gactccatct caaaacaaat aaataaataa aaaggactat atggtaatat tatgaacaac 25680
tttatgccaa taaatttgac aacttataga tgaaatggat gagttccttg aaagacacag 25740
aaactattaa agctctctca agaagatata gataagctga ttagccctat atctatttta 25800
ttgaatttaa atgtaaaaat caatatttag ttactggaaa acttttaagt gtggttggaa 25860
atggtatacg aactttttca actgaatttt atgaagtcta atcacaggta aaggttttct 25920
gatgaaaatt tagtgtctga attgagatat actgtaaaaa atgttatata tcttaattat 25980
ttcttcacat taattacatg ttgaaataat actttgggtg tattgggtta aattaaatat 26040
tatgaaaatc ttgcctgttt tctttttact tttgatgcgt cagctaggaa atataaaagt 26100
gtagctcaca ttctgtttct gttgacagta ctgctttgga gcacagtgtt tgaatgatct 26160
atcatttcaa agacctttcc tcagttcgtt attcatggct gtctgtattc cacatagata 26220
aggtctgaaa tactgctaag tggcatgttt tgttttatgc ttttataagt ttgttgatca 26280
ttactgatgt ggacttttgg tgcctcttag gctcattgct atcttccaac cattgtttgc 26340
aatttttacc tagagataaa gagaaagaga catttggttt cagagtagtt agattgggat 26400
catgaaagag caacctcatt ttgatgcttc aaaaatagca catcccccgt attactggga 26460
tttgctattc ttgggattac ttcaagaaca tccttgtgtt actggtttgg atgcttctga 26520
atgctgtgaa gtcagtttca tgtacatggc tcatcagttt agctctctct tggctttgtt 26580
tagacagttg gagcatgatg gcctaaacag cttctttcaa ttaaacattt taaaatagtt 26640
tacaaatagt aaacaaactc cagtttttgt gactctttgt ctcgcacaac aaaaacacaa 26700
tctgaccatg atcatctggc atcttagggt gaaatatggt tatactttgg cccataccga 26760
aagcaagatt aaaaaggggc aggagagata gactgctgaa ctgattttca aggttccaag 26820
aatattgtag gttaagagta aaagtaaact tttggtagaa agcagtgggt tgtctaggat 26880
tgaagtatct gaagttttta aacgaaaatt taaaaagaaa aatgagaatt gccttacaag 26940
tacaatctct tcttttttaa aaaataaact ttattttgaa atagttttag atttatagaa 27000
aaaaattaga tagggtagga agttttcata taccctacat ccagttaccc cagttattat 27060
catcctaatt tagtgtgaga cattttcatg tttaatgaat caatattgat atgctattaa 27120
cttaagtcca gactttattc agattttctt aatttctatg taatgtcctt tttctgttcc 27180
agaattccat gcaggacacc ggatacctca ttacatttca ttgtcatgtc accttaggct 27240
cctcttgaca gtttctcttc tttttttgct tagaaattct ccagaatttc agaaacttct 27300
gggcatcgct atggaacttt ttctgctgtg cagtgatgac gcagagtcag atgtcaggat 27360
ggtggctgac gaatgcctca acaaagttat caaagtaaga accgtgtgga tgatgttctc 27420
ctcagagcta tcattgttgt aggctgagag aagaagcgat cattgagtgt tcttctgttt 27480
tgagtccctg aggatgtctg cacttttttc ctttctgatg tatggtttgg aggtgctctg 27540
ttgtatggtt tggaggtgct ctgttgtatg gtttggaggt gctctattgt atggtttgga 27600
ggtgctctgt tgtatggttt ggaggtgctc ttgtatggtt tggaggtgct cttgtatggt 27660
ttggaggtgc tctgttgtat ggtttggagg tggtcttgta tggtttgcag gtgctctatt 27720
gcatggtttg caggtgctct attgtatggt ttggaagtgc tcttgtatgg tttggaggtg 27780
ctcttgtatg gtttggagat gctctattgt atggtttgca ggtgctctat tgtatggttt 27840
ggaagtgctc ttgtatggtt tggaggtgct cttgtatggt ttggaggtgc tctgttgtat 27900
ggtttggagg tgctctgttg tatggtttgg aggtgctctt gtatggtttg gaggtgctct 27960
attgtatggt ttggagatgc tctggtatct gcctgcattg cttgccacac ctgcccggtc 28020
agaaggcgct atgttgacaa ttgtgcctgc acggtgccta ggtcaatgaa gggaaccgat 28080
ggtagccact ggatgctcct gggaaaatgt cactacaggc accagagaag ccagagctat 28140
gcccaaattt ctatgagtct cagttttctt aaccataaaa tgggatcaat gtttttgtgg 28200
catgtgtatg agtgtgtgtc tgtgtatgtg tgaggattaa attgtgtatg tgtgaggact 28260
aattgccact actggatcct caaagtggta agaagtgttc ttattaataa tgacatcctt 28320
acactcttac ccagcaagat tgatgggtgt ggcactgctt ctctttttcc atcacatggt 28380
ttccatggta tccttttgcc cagggaatct ttgctttgtg gctagcactt tgttgtttgg 28440
ctaatcacgc tttctgtggt caggacgctg gcttctctgg agccatggga ttctagctcc 28500
ctgtcttgtc cctagagtgg tcactgtctt ctctctccgc ttgcaattcc tgctttgctc 28560
gcatctcact tatgcagtga cgtatatcag tttcaccttg ttctccgtgc ctgctgatca 28620
ttggcaccac ttgcatggtg ccatttaggg cctgcttcca gttaagcttg cttctccaca 28680
ggcctaaata tccttgcttg cttcttttat tctcactggc aggaccaggg cggtctgtct 28740
ttgcatgaga cagggtctcg ctcagtcacc caggctggag tgcagtggct gatcacggct 28800
cattgcagcc ttgagctacc gggctcaagc tatcctcctg gcttggcccc ttgagtagct 28860
gggactacag gcgtgcacca ccatgcccag ctaattttta aaattatttg tagagatggg 28920
atctcgccag gttgcccagg ctggtcttga acgcctgggc tcaagtgatc ctccctcctt 28980
ggtttcccaa agtgctggga tcacaggtgt gagccactgt gcctggccct tgatgtttca 29040
gttcttgata tttgatcctc agagtcagaa aatctaaaaa gagggctatc ccaggttgcc 29100
ttggttcatg gcaaatggga cgttaagagg gcagagagaa tatgaacaga aactgttcta 29160
atattggtca tttaatgtgt aagtattgtt cttttttaaa cctccttcat tttttttcca 29220
ggaattgctg gacacagtgg cttggtgtgt gtctgaggac tgtaggccat ggccctaggt 29280
tgtggtttta ggtctcaggt gctcttcctg gctgtctcct tgcttctttc ccatgtcctc 29340
ttctttgttt ccagccattt ctcccttatg cttaagtttg gtgcagcagg gtttggctgc 29400
tctcagattc ctgcttcctc agatgctgta gttgtcaggc ccagcgggct ggcagcggga 29460
tcaggatctg gctaggtttg ctctcactgt ggcagagtag ggggaggcgt gggagagcac 29520
gtgtgacccc aggccagctg tagggagcat aggcatggtc acgtagcctt caggtcctag 29580
actttgtctt ctcatgagta tggctgtgtg tgtatggtga aaactaggtt ctacttagcc 29640
caagaaaatg ggcacatttt gcatgtggtt tctgtagaga aatgcactgg gtatctgaca 29700
tagcctggca gcatgcctcc ctcaggtagg ttagtctcag gcggtgaagc acgtgtgtcc 29760
agcaagaact tcatatgtgg cataaagtct ccgttctgtg aggtgctggc aaatcaccac 29820
caccgtcaag aggctgaagt gatttttgtc tagggaggca ggaaaggctt cctggagtca 29880
gcagccagta ggtgaaagag tagattggag accttcttaa tcatcaccgc ctcttgtctc 29940
aaggggtgcc aggaagctgt ggaggctgaa cccatcttat gctgccagag agtgggacac 30000
catgagggtc aggtcaaggg gttgtacctt gtttggtaga gaattagggg ctcttgaaga 30060
ctttggatgt ggtcagggga gtgtatcatt taggaagagt gacccggtga ggacgtgggg 30120
tagaggagga caggtgggag ggagtccagg tgggagtgag tagacccagc aggagtgcag 30180
ggcctcgagc caggatggtg gcagggctgt gaggagaggc agccacctgt gtgtctgcgg 30240
aagcaggggc aagagggaag aggccagcag cgtgctgcca tcacccagcg actggcgtag 30300
attgtgagag accattccct gctcttagga ggggctgagt tttagttttc tcttgttata 30360
caataagctt ggtatttgtt tacaaaacat ttgtaaagct aaatcaaggt ttgataaggc 30420
ttctagtttt atttaagaag taatgttgaa ataaatgttt gtccaattcg ctttgctcat 30480
ttaaggactt tcagtacaaa ctgcaacaac aggattagga tttaaacgtt tctgagatgt 30540
ttttactcct cagaatttcc cagaatgtga tctggttttg attttcaagc ttgctgaccc 30600
aataggttaa cccacaagtt ttacgaagac catctcagtc cacttacatc aactgcccat 30660
gccacggtta aagagatcat cgactgatgt ttggcacagc ttcctccctc ttgggtgggc 30720
aagcatttgg aagagaaggc tcctatgggt gagagtgggg caccaaagtc ttccctgtcc 30780
catcccctag cttgagaagc ccttctctaa tgtggacttt gtgccgttag catcgttact 30840
agcttgaagt tgaccatctg gacgtacttt ctggtttagc ctcacaagtg agcaaggagg 30900
gttgagagat gtgctgtgag gaatgtgggg ccccagctgg cagcaggctc tgggtcaggg 30960
gggcagggac cacgggcata cctgacagtg aggaggggcc acacctgcag aaaaggatgc 31020
aggactccgc cttgggaagt gttctaggcc agagcgaggg tctgtggttt ataagtacac 31080
ccacagtgct cgggaccctg cagatgtcca gggtgccgtc tgagcccgta tcatccaaca 31140
gaatgttctg ctagtgaaga ttaaagattt actccagggg ctttaggatt tattatatat 31200
atataaatcc tatatatata attttttttt tttttttttt tgagatggag tttcgctctt 31260
gttgcccagg ctggagtgca atggcgtgat cttggctcac tgcaacctcc gcctcccggg 31320
ttcaaactat tctcctgcct cagcctctcg agtagctggg attacaggcg cccaccacca 31380
cacccggcta atttttgtat tttttagtag agacggagtt tctccatgtt ggtcaggctg 31440
gtcttgaact cctgacctca ggtgatctgc ccgccttggc ctcccaaagt gctgggatta 31500
caggcatgag ccaccccacc tggccaggat ttattgtatt tgaaccatct accattttaa 31560
ttttgatgtt atgtagtatt tgatgataat gaaagttaaa ttgtttttct ttccattttt 31620
ctgtttaagt gaatgacctg tatctagttt attcagtaac ttcctgcata tatttgtttc 31680
tttcattctt aatgaatata ttcttaattt agttgctatt atgttttgct ttgccccaaa 31740
attgaaatct tagtttcctt ttagctcgtt ttagaactag tgatgggatg tgtcttccat 31800
aaatctcttg tgatttgttg taggctttga tggattctaa tcttccaagg ttacagctcg 31860
agctctataa ggaaattaaa aaggtgggcc ttgcttttct tttttaaaaa tgttttaaat 31920
tttaaatttt tataggtaca cgtattttgt aggtacatgt aaatgtatat atttatgggg 31980
tacatgagat attttgatac aggtatacaa tacataataa tcacaccatg gaaagttgga 32040
tatccatgcc ctcaagcatt tatcctttgt gttacaaaca atccagttac atgctttact 32100
tattttattt tatttttgag acagagtctt gctttcaccc atgctagagt acagtggcat 32160
gaccttggct cactgcaacc tccgcctccc gggttcaacc gaactttggg ctggtctcaa 32220
actcctgacc tcaggtgatc cgcccgcctc ggcctcccaa agtgttggga ttacaggcgt 32280
gagccactgt gccgggcctg attgtacatt ttaaaataac taaaacagtc agggcacagt 32340
ggctcatgcc tgtaatccca gcattttggg aggctgaggc aggtgatcac ctgagatcag 32400
gagttcgaga ccagcctggc caacatggag aaaccctgtc tctactaaaa atacaaaaat 32460
tagccaagtg tggtggcggg cgcctgtaat cctggctact cgggaggctg aggtagggga 32520
atcgcttgaa cctgggggtg gaggttgcag tgagccgaga tcacgccact gcattccagc 32580
ctgagcgaca gagtgagact ttgtctcaaa aaataaaaat gaaataaaat tgggccgggt 32640
gtggtggctc acaccttagt cccagcactt tgggaacctg aggcaggtgg atgcttgaga 32700
ccaggagttt gagaccagca tgggcaacat ggcaaaacgc tgtctgtaca gaaattagct 32760
gggtgtggtg gtgcacaact atagtctcag ctacttggga gattgaggtg ggaggattaa 32820
ttgagcctgg aaggttgaat ctataggtag ctgagattgt gccactgccc ttcagcctgg 32880
gcgaccaagt gagaccctgt ctcaaaagaa aaacaaaaaa acaaaaaaca aaccactatt 32940
atcgactata tattattgtc tatgatccct ctgctgtgct gtcgaatacc aggtcttggg 33000
cccttatttc catcactgag caaacttcac tctgttaagc agcaggtgtg ggatttcatc 33060
gttattcagt aattcacaat gttagaagga aatgctgttt ggtagacgat tgctttactt 33120
ttcttcaaaa ggttactctt tattagatga gatgagaatt aaaaatggta acttacttta 33180
tatctttata attgaagccc actagacctt aaagtagtta ccagatgttt tatgcattta 33240
aatggccttt tctctaaaat tagaaagtaa caaggaaaga aaatgcttcg tttctatgca 33300
accctcttgg tgactagtat gtgactctta atgcaaccct cattgcaccc cctcagaatg 33360
gtgcccctcg gagtttgcgt gctgccctgt ggaggtttgc tgagctggct cacctggttc 33420
ggcctcagaa atgcaggtaa gttgtacact ctggatgttg gtttttgtcg ggggccagct 33480
gctactgatc ctttatgtct cagctcagat gtcatttcaa aagtctgctc tgccctctcc 33540
aaattgcagt cgaccttgcc ctgtttatgt ttccctcata gcactaatcc atgtcagaaa 33600
ttgtcacgta cagtctatct gtgtgcttgt ttattttcta tcccaccctt ccgcaagaga 33660
cttatgggat gtgtgcccca ggacagcagg ggtcttactg tcttatgctc tgttgcagcc 33720
cagcagcgat aacagtgtct gcacatagta cttgcttaaa agatacttgc caaattgttg 33780
aaggttgagg taccaatttc attattgctg actataggag ttatagcaaa atatccattt 33840
gtctgttaca tgagttaaaa atatggttgt tgcactgtga atagtttggt ttagtcaaaa 33900
cagttgtatc ttaacggatt gagaaacaaa agcaggacca cttttcatca gctccctcct 33960
tctccttaac cagcaataca tgctgatgct gatatcccat agaccctcag ctccatcctg 34020
agtcactggg aatgtggtct aaaccctcac tattaatatg aactgagttt caataagaat 34080
cttatatggg tcgggcatag tggctcatac ctttgatccc agcacttcag gaggccaagg 34140
caggtggatt gcttgaccca gactaggcaa catggtgaaa cgccgcctct acaaaaaata 34200
caaaacttag ccaggcatgg tggtgcgtgc ctgtggtcac agccactcga gaggctgagg 34260
tgggaggatc acttgagcct gggaggtgga ggtcgtgttg agccaagatc gcaccactgc 34320
actccagcct gggcaacaga gtgagacctg tctcaaaaaa accaaaatcc agaaaagaac 34380
ttatatggct gcagaggtat aatcactaag gaaatttcct tttgtataat cttttttctt 34440
ttactatcat ttaaaaaaat gtgttatatt tctgaagcaa cacatccagg ttctgcacat 34500
agcagccaaa gtgaccttaa agaatataac tgggtcttgt cattccctta tttaaactct 34560
tgtacccatt tcccagtgcc gtttagatag agattccaga ctcgtcaatg gctctgtcac 34620
ctcagacacc ctgcattgac tcattagtct gattagagtc aggtttttct tcctcctgat 34680
ggtttttttt tcccccttag ttctcagcgg aacagtcact tccttaggga ggtttcccca 34740
gccaccctct gaggccgtgc ttgttgccag actctgccac tagagggcag ggctgcacca 34800
ctcctggcac ctcgcacccg gcctgccctg tcactctgtg tgttgggtga attcctgtga 34860
tctgtgactc actgctctgt gtcctacaca ttcggctttt cttctctccc cacaacccca 34920
ttttataatt ctcctttttc aggaaagctt tattcccatt taaaaatttt tgtttttaaa 34980
atggtatttt cttacactta ttttctaatt aaaaatgagt gttttaagaa gtattatgat 35040
ttactgcaaa taatttttaa acccagcctt ttagatcctc tgtgatcata agagaaatga 35100
aggatgtctc ccaacacttg agcttcatcc acatttcatc ctcctgttct ttcagctgag 35160
ttttccccat cccattaggg actgttggaa tataaaactg gcttttccct aacagggaat 35220
gaattgcttc tgtttctcct gaaggagagc tggaagaatg acttgcgttc ttttgcatac 35280
acaggcctta cctggtgaac cttctgccgt gcctgactcg aacaagcaag agacccgaag 35340
aatcagtcca ggagaccttg gctgcagctg ttcccaaaat tatggcttct tttggcaatt 35400
ttgcaaatga caatgaaatt aaggtatgat tgttgcctca ggtcacaaac atgcgagtga 35460
tgctgtgagt gagtctgtgg agggtgaggg cttctgaaca gggagtcctg tgggagtgct 35520
tcttggggta tgttgtatgt cgtaatttag actaccatca tttgtgttat ttttgaggca 35580
cctaaggact tctttccact tctcatttct tactgtgggg tgaagagttg aattgggaga 35640
tggtttctag atgcaaattg aaaaggcatt tttccagagc agatttgttt tcggcgtact 35700
agagtgactc tttaacctag ctgcgggaag atgactgtgc caagactgca ggtaggagaa 35760
agctcactga cgaggccttg tgggtctgaa cgtcctgcag ctatcagagc ctgttggctt 35820
cctgttgtgc attccaacaa atcatcttca aacccacttt agtgttttgt ttataatgtc 35880
cagaaatagt gaccctgtca catgctctac agattacagg attcttagcc tcttcctttt 35940
tggtaggtca gtcctgggtt tgagcccaag tgaccctcct gggaggtgat gatacacact 36000
gggtagagtg gaatcagatg gacttggatt agaattctgt cctctttact agttattttc 36060
ctctaggcaa actgcccaac agctctaagc tatttccttc gtattctgaa aaataagcct 36120
taatgggacc catatagggc aactctgaga gtaaaataaa ggaatatgtg ttagagtgta 36180
gcatagtcac ccacgggaag ggcttagatg ttagctgcta ctgctcttat tagctgaatg 36240
atttggaata aactgttagc ctctctcatg ttttttctct tgagcttcga agttttcttg 36300
ttaatactaa ggagatattc aaactagtca tggggttttg gaatgacgaa gggagatgat 36360
gaatctaaag aatttagtgt aatatttctt catgctcagt aaatggtagt ttctgctgct 36420
gttattttta ttaccatctc tttggaatgg gagtaggtgc tcctttgtgg tcagaggctg 36480
tgagagctcc acagcgccag tttgcccatc tgtacactgg ggtctgttga aggcagtccc 36540
ctctgtgata tctctggctg tcagagctca gatgatagat ggtatttttg tactcttagt 36600
tctcatcatt ttcatgattt cgatcaccat ttgagtatga tgatgctaac actttgttga 36660
acgtagaatc cgttaattac ttccttcctg aacctttggc attaaaaaaa atctattctg 36720
ctacctctct gctcatttat ggttattcaa atttattatc aagagcctgg tacagtggct 36780
tgtgcctata attgtagcta cttgggaggc tgaggtagga ggattgcttg aggccaggag 36840
tttgagacca gcctgggcaa gatagtgaga ccctatctct aaaaaaactg aaaaaaaatt 36900
agctggacat gatggcatgt gcctgtggtc ctagctactc aggaggctga gacaggaggc 36960
tcggttgagc ccaggagttg gagttcgagg ctacactgag ctgtgattgt gccaccacac 37020
tccagcatgg gtggtaaaac aagatgccat ttcttaaaaa aaaaaaatat atatatatat 37080
attatcaatg aaattcagta gtaccaacag gattataaac aaagatagta gttcccttcc 37140
tactttttct cttaatcctt gtgtctcaca ggcaaacata actcttagta tttcttccaa 37200
tatttacttt catgtttctt tctttctttc tttttttttc tttgagatgg agttttgctc 37260
ttgttgccaa ggctggagtg caatgacgca atcttggctc accacaacct ctgtctcccg 37320
ggttcaagcg attctcctgc ctcagcctcc tagtagctgg gattacaggc atgcatcacc 37380
acgctcggct aattttgtac ttttagtaga gatggggttt ctccgggttg gtcaggctgg 37440
tctcgaactc ctgacctcag gtgatcctcc cacctcagcc tcccaaagtg ctgggattac 37500
aggcgtgagc cactgcgccc agcaacttcc acatttctaa ataacatgct tctactgcta 37560
tttttttttt caattttaga cattttttta ctttcactat agttctatca gaattcagtg 37620
tgtacgttat tatgcctaag taaatagtca tggttgctta cgtattatat ttctttgatt 37680
gtgtttctta tttgatgaga aagctgtgtt ttttgctctg ggttgaaact ggagagagga 37740
cctggggagg aggaggagga cagatgaagt tggtgactgt accttcatgg ccatagctgg 37800
gttctcagca cccggggatc tgctgatcac ctactcatag gccaggcccc tatcgaagtt 37860
ctaggtgacc cagtgctggg gacggggggg ccacctgcaa ggtctaatca tggaggtggg 37920
ggctacagtg ttggcttgtg ctggggccag catccttagg aaggcatctt ggaggtggag 37980
gagacagccg cccacttctt gattggggcc ttcagcagca ccagcttctt gggcaggctg 38040
gtgctggctt tcatcaccat gtcgtgttca atcttcttcc agatcctgac ttctaggttc 38100
agctttcctc agaccctggt tcctttcaga ggccattgct gctgccttgc tctttgctgg 38160
cttgtgcctt gattatatgt ctttgtacaa ctttttgttt tcctggagtt aatcttcaca 38220
tctgttttct tggagttaat cgttacctct atatcgcttg cttattattc tttggccttt 38280
ttgtcttctc acaccttcca acttctttgt aatatgtgtt tagtacaatt tttcatgaca 38340
ggtagtttac tgaatcagtt tttccccagt gtggtcatcc aacttgagtt atccagctct 38400
ctgccccagt ctgggcaggt tgatcttcag gtctgtagta cacttgtatc ctaggacttc 38460
tctttgccat tagcctggaa tttcctttgc agttctcccg ttggatgccc agttcctaga 38520
tgccatatgt ttttctatcg tctagtagct tcctgagaga agatgaatgg gagggaaatt 38580
gtatgaggtt ttgcattcat aaaaatgcca ttttttttcc tgtacacttg gctgggtatg 38640
gtgttctggg gtagaaatca ttttccctca gaaatgcaaa gtctttgccc tgttgtctta 38700
aaatctccaa cgtgacccga ttccttaacc tatgaatgta cttttctttg gaagctttcc 38760
atttttgggg aggtgaagtg ctaggtactt agtaggcctt ttaatttgga aacttacatc 38820
ccttcagttc tgggaaaatt ttcttaacat ttctctgaga agttcttgcc ttttattttc 38880
tgtgttctct cctgaaattg gttagttgga tgttggtcct cctagattga ctcacatctt 38940
acctttttct tttctttttc tggtactttt tagatatcca tctcaaactc ttctattcat 39000
tgttatgttt ttaacttctt tcttttcttt gtctcttgat ggggtcttgc cctgttgccc 39060
aggttgtggt gcagtggtgc gatcatagct cactgcagcc tcaaattcct gggctcaagc 39120
agctgttctg cctcaccctc ccaagtagtt gggactacag gtatgcacca ccacgtccag 39180
ctattttctt tacttttttt tttttttttt tgagatggag tcctactctg tcgcccaggc 39240
tagagtgcgg tggtgggatt ttggctcact taagcctctg cctcccaggt tcaagcagtt 39300
ctcctgcctc agcctctcaa gtagctggga ttacaggtgt gcaccaccat gcccggctaa 39360
tttttgtatt tttagtagag ccagagtttc accatgttgg ccaggctggt ctcgaacgcc 39420
tgacctcagg tgatccgcct gccttggcct ccgaaagtgc cgggattaca ggcgtgagcc 39480
catcattaga tctttaaata ccagtatcta taagtctttt cctcttgagt cagctagtat 39540
ccctggaagg aaattactca ttttcctgct tggaggctat aagcttggct atgtttatcc 39600
tgcaaccggg gactggaagg gaggggactg acagtgttgc tggtcagggt gccctcttac 39660
tttttgtttt ctgtgtgcat ctcacgtctg tcctcagcct atgtaaacac ctcttgagat 39720
tatccctctc aatctttgcc ggaggtgggg gaggggctgc ttcctgggct gccttggatt 39780
ggagggaaga cctcaggtga gtgggtggga atttgcccaa ggagccatga gaccagccac 39840
tatttcaccc tctccatccc tccactttca gatgtatgtg gcgcctccaa agcccgagct 39900
cttcttggcg tctgtggctt caataagctt gctttttgct ggtatccctc ctaccctccc 39960
ctgtccccag caaagcttgc atttgaactt cttcctacgg gctaacaaat cagtcagtta 40020
tgtagctctt gttacttttt agcttccgaa gttttgttga cacccgtagt ctgctaatgt 40080
ccctgttctg ttctttctgt tcgtgtaaat atatgcttta tacaacttct ttacatgatt 40140
tttgtggggt ttctgggtag cagagcttca caagttcaat ccagcgtgtt ggattagaaa 40200
tctcccaccc tctggtttat tcttattctc aaaattacct gccaaacact gatactccct 40260
tgtttttcct tttcctgaca ggaaatgtac ataccataca ggacagaaat cattagtgta 40320
tcccttggtg aataaccaca aagtgaactt aacccttgta accgccaccc aggtcaagac 40380
agaatattac caagcactca gaagcctctc ccctattccc ccgtcactgc tcctgccttc 40440
ctccccaagg tcatgactgc tggcttctaa ttccagagtc tgtttttaaa ttctgtgtac 40500
atagaccatg gattaagtgt tctttttgtc tggtttattt tggtcgacat taagttcatg 40560
agagtcttct atattatcgt gtgtattagt attcctgtag ttttaggagc ttcatagcat 40620
tccattgtag ggatatacca cagtttattc attgtattat cactgggttg tttctagttc 40680
ttggctattg cgagcagtgc tactgtgacc actcttaggt gtgtcttttg gagtacatgt 40740
gcaggtttcc atcttgcaca gctagaggtg gagttgttgg gtgatagggt gtgtgcatct 40800
cagctgcagt agaaactgcc aaatagcttt ccttgagtgc ttgtaccagc tcaccctttt 40860
gccactgtgt atggggattc caggagctct ggtcctcgct agcacttgga attgctgatg 40920
cttttactct tagccttcct gatgggtgtt ttctggaatc acattatgat tttaatttcc 40980
attccttaaa gtacccttgg ctctgaagtt taatgattca tgcatctctt cccttttgaa 41040
gtactcttac aggtatgttg tgcatgtgtt gaaaagtggc actatctatt ctaaaataca 41100
gtatgcctcc tctgtgtttg aacagttgta gcgtggcctt ggggcctcct gttagctggc 41160
ttggagaagg gattcttggg attgtagaga ttagacctga ggaggcccct tggagctctc 41220
tgactaaatt ttattcttta ttattccaaa ctatttaagc tcaccgtgtg ctgactcatc 41280
ataataatga gtagctctca ttgtgcttgt ctatttggac tcatacaatg attttttttt 41340
tttctttgag acagagtctt gctctgttgc ctaggctgga gtgcagtggc acaatctcgg 41400
ctcactgcag cctccacctc ccaggttcaa gtgattcttg tgcctcagct tctcaagtag 41460
ctgagactgc aggtgcgtac caccatgcct ggctaatgtt tgtattttta gtagagacgg 41520
ggtttcacca tgttggccag gttggtctca aactcctgac ctcaagtgat ctgccttctt 41580
cagcctccca aagtgctggg attacaggtg tgagccactg agcttggcca aagtagtttt 41640
ttaagatgtt agtatctttt cttgcagcta aaaaagtttg tcagagatga ttctactttg 41700
ttctccaggt gttttctcag ggagaaattg gaggcagtaa gccactgggg gagtcctgtg 41760
gctggggggt ggggtagtcc tgtggctcct tgtcagggag tcctgtggct ggcaaggaga 41820
gaagtcctgt ggctgggttg ggagggagtc ctgtggctgg ggtctcatcc tgtgcctaac 41880
agtgtccaga ggtgccgaga ccagctcagt cggggagacc ctaacccagc agcgctagag 41940
gaattaaaga cacacacaca gaaatataga ggtgtgaagt gggaaatcag gggtctcaca 42000
gcctttagag ctgagagccc tgaacagaga tttacccaca tatttattaa tagcaaacca 42060
gtcattagca ttgtttctat agatgttaaa ttaactaaaa gtatccctta tgggaaacga 42120
ggggatgggc cgaattaaaa gaagaggttg ggctagttaa ccgcagcagg agcatgtcct 42180
taaggcacag atcgctcatg ctattgtttg tggcttaaga atgcctttaa gcggttttcc 42240
accctgggtg ggccaggtgt tccttgccct cattcctgtc aacccacaac cttccagtgt 42300
gggcattagg gccattatga acatgttaca gtgcttcaga gattttgttt atggccagtt 42360
ttggggccag tttatggcca gattttgggg ggcctgctcc caatacagag gtctcgtgta 42420
aattccctgg gaggcgataa gcctctgaga aacagactat gctaaccacg ccatgaaaga 42480
gaaacttatt tataaatcag atgccagtta ctagtttact gcttatttgc ccaggcgtag 42540
ctctgacaga gtccccgact catagtgctt gctcagtgca tgctgaacaa tgattggaat 42600
caagtcatgg ctcagagcat agttttgaat aatgggaaat ggatgttctt aagtaacata 42660
gtcaccaaga taatgcgact agctgggtca ccccttttca attttaggat atttttatca 42720
agatttaaat ggccatcatt agagttatag cactttctcc tttggattgt cctagaggcc 42780
catgagaaag tattccctaa tttcttagga gaacagtttg tgggtagtat gcggtcatgt 42840
ccagttaaat tgcagatatt tccgatcgaa gatgttccag tcctgagaac ttcgtgacat 42900
tagcaggact tctacaagcc atctcttagg gtggggcatt tactgcagtt ggctagtact 42960
cttttctcct taactttgtc atttgttgat ttttttttaa ctgtccccaa atactgtggg 43020
cagagtgtat ctagaattga ggcctccacc attgcggaga ggacatggat gctgagcagt 43080
cccctgagtg aaggttataa agaagcaaat agactacaca tgtctgtaaa ctgctcttga 43140
gtgtcccaaa tttggggtac ttcagttcag ctgtaggaaa agcctcaaac tgtttatact 43200
ttgcaagaat tggaaacttc taattcacgt taagttttat gtaatacatg ataagcttca 43260
taggagcttc atcttttatc tacttggact tttgcttccg taggttttgt taaaggcctt 43320
catagcgaac ctgaagtcaa gctcccccac cattcggcgg acagcggctg gatcagcagt 43380
gagcatctgc cagcactcaa gaaggacaca atatttctat agttggctac taaatgtgct 43440
cttaggtaag gtggaggcat atgagtggaa gagtctccag catgtactca agatagacct 43500
ttgaaataaa taaaaccaga tgatccctca gcttctagac caggctattt ggcactggtt 43560
gattgaatgt gaactgcact ggggctgctg tgagcccgca tgggtctctg tgaccctgca 43620
gatgcagccg tgcccaggga ctgggcagtg ggtgtgggct ggtgtgagcc ctgtctgcca 43680
cccagggcct ggccctctgt ctgtgtcggc catgactatg gtgagtcttg taggcttgag 43740
actgtgcctc gggttcctgc gggttctctg taggtcagtt gacagtttct cctgttgttt 43800
gggtaactgt ggaaacgaac actggcaagt gctgaagcga gcatgtggac gtgcgatatg 43860
aaataacgac ctggctttca aaggcagtga ggctctctgg aaaggacctt gctgagctag 43920
ggatgtgggt gtgtagccat tcccagtggg cctcatggcg tactcgttca tgatcatgtt 43980
tgtgccatct tgatctctca ggatctcttc ttttttaaca gattaagccg ggaatctcca 44040
aacagtgagt cagatgttaa gatgtcttgc ttccaccccc acaggcttac tcgttcctgt 44100
cgaggatgaa cactccactc tgctgattct tggcgtgctg ctcaccctga ggtatttggt 44160
gcccttgctg cagcagcagg tcaaggacac aagcctgaaa ggcagcttcg gagtgacaag 44220
gaaagaaatg gaagtctctc cttctgcaga gcagcttgtc caggtaggag cacagggttt 44280
actctaggcc ctgcatgtga atgactgaca ttcaaagaac cgattaattt ggaagagaag 44340
cggcagaacc gagagttaga ggtgtggact ctggagctgc gctgctcgtt tccaacccta 44400
ggtgctgacc tctagctgtc ttccctctgt atgtccctgt caccgtgagt caaatgcggg 44460
tgatgcctcc tcaggtgccg tgttacctaa gcctctcaga gaccactgct accctgtttc 44520
taaaaccaga ggtcacgata tgtgttcatc cacccagtaa atactgattg agcacccact 44580
gtgtgctagg ctctgggata ggggctgggt atacaatggt gagtatttca gctgcagctt 44640
ctgccccgtg gaggctgtgg cctagcacac tggtctaggc acggtggtat atgctcactc 44700
aaggagatag ggacgtggtc gtttggggtg tcggaacaaa atgtcggaac ttctctttcc 44760
aatgcagaga aaccttgcag taattctaat gtactgtgat tggcagttga cttcagttct 44820
ttgtagcacg cttactcagg ttatttcact aactatgtaa ccatgcagcc tcattttaag 44880
caattggatt ttttgaactt tacttaaaat gttatgtcag ggtttttatt gtgcttaatg 44940
tgtgccattt agctaagttt tgtaggatac gaaattgtaa gtggcttaaa atgattctta 45000
atagaatcat gaattgaaga taatgctaat aatttaagca ctgagttagg tagtgtttgt 45060
aaaatgctta gaatgcttcc tggcacatgt taaggccatg taagtgctgc gtgttgataa 45120
acagctgagc aaaagtggac tcttaagaaa gtattggggc tgagagttct gttccaacca 45180
gctgcccttt ggttattttt cagaataaaa gcagagtctc atgggatatg acatttatat 45240
ttccttcaca aaaaacactg ctgagtgttt tgttgagtaa aaagggtgta gccatggtaa 45300
taatacattt aaaatatagt ttatttcatc tttaccttgc cttgtttttt ttttaagcta 45360
gctttttatt gagaattcca cacatacaaa agtatcaact catgaccagt tatatttcat 45420
ttataatcct acttctccct ttttttatta tttgaaagca aaccccaatt atcctcttat 45480
ttcatctata agtatttcag tatctctata gatgaggact cttctttatt tttaaaactt 45540
tatttttaaa atgatggtca gatgcagtgt tcatgcctgt aatcccagaa ctttgggagg 45600
ccaagctggg cggatcactt gaacctggga gtttgagacc agcccgggaa acatggcgaa 45660
accccatgtc ttaaagaaaa aaatcagcca agtgtggtga tgcatgcctg tagtcccagc 45720
tacttgggag gctgagatgg gagggtcaca tgagcctgga agatcaaggc tgcagtgatc 45780
catgattgta ccactgcact ccatcctggg tgatggagca agattctgtc tcaaaaaaac 45840
aaaactgcaa aacaacgtca caaaacagtg ccattgttag acctgaaaat attaaacatt 45900
tcctacatca aatacccacc aactcattat caatttttct ctctactctt ttggaatcag 45960
catctaaata aaattggtcg ataaggattg taaatctctt tgatgaactg gttcccctcc 46020
atcccagttt ttttccctta gagttcattt attgagaaac cagattgttt gtcttctaag 46080
ttttcctgtg gtctgatata ctgcttccat ctccactgtg taaattaaca cctttttctc 46140
ttctctgtat ttcctgtaaa tcaataattg gaggaaaagc cttgtcagat ttagtgtata 46200
ttttatatct gagtccagta tttcttatat aatattttaa gataagtgta ctcttttaaa 46260
aagtattgaa actatatgct caattttttt taactgatgc ttttaagaag gctgcttgat 46320
cataaaagtt tagagatcat tggtctgatg ggaaaagcaa ataattacta aaccgtttag 46380
caaggttgag gtgcacatgg tggggcctgg agaagttcag tcatgagccg tcacttatgg 46440
gcacgtggaa tctgacccgg cacagagttg ggagaagaca ggagctttat agacagaaaa 46500
tgtggtcttt gctaagtccc aggagtgaaa gggtgagaca gtgctcacag cacacgagtg 46560
tgggtgcgta gacagagcaa gggtgggtcc tgaaaaggcc tgcaggcttt ctcatagatt 46620
agcaagagtg ctggttacgg aggtttctaa catttgtgaa cagatcgaaa ctgtgttaaa 46680
ttgggattgc agtaatcctg gaaggacagg gatagagggt gaaggggaaa aaagggtatg 46740
gatgtgagac ttaattgctg attttcttaa gacctttctc caaagtaaat aaatgatgtg 46800
gcacattttt gaactggcaa attctaaact ctagatatga ttatctctat aacatatctt 46860
actccatctt cttttgacta aaaactgttc ttaattaaat taccatgaga cgttcaattc 46920
agcaaatgta gtttggctaa ccatatttaa ttagaattta atataatcct aggcctggcc 46980
aaactattaa gcaagtgtgg gcaaaatatt gataatttta gatatgcagg aacttagttt 47040
gctttccatg tgtgcttttc gaaaaaggaa taaattgaaa aatagaggaa gccctgaaat 47100
ccaagaagca aactctctca cctaggcatg cagtaaaagc aattctagga tgattgctgt 47160
ttggcgcgta gttcgtatta gaaaccattc ttcttgaata aatagtatgt ttaagaagct 47220
gggcagaggg aaggcatatg catatattat caacaaggag ggagaaaaag gcaattagta 47280
accatccata ggagggtcag caagatttat aaaggaaatt tgtgatccaa gtatgaagca 47340
aaataaggtg cagaataaat tttaagcaag taatagatta gagtaagaga acccatttga 47400
ccattaacct tgggacattc tctttcaaat gacatggagt agtactgaaa tctttctttc 47460
tttctgagtc taggttattg tgactggact cagaaagaaa tatttcatta ttgcagtgaa 47520
taacatttgt gaacattatt gttcataaat tatgcagtga ataacattta tgaacacgtg 47580
atgtgtaaga tacatactgt ttatttttag ttaagttttt tggctcaact tctaggcaga 47640
gaacattaaa tgtaaatagt gttacctagg agcatgtaaa tggaaatctc catagtatga 47700
aagcagtgct gttgctaaca gaatttagga gggggcagat gaggtgaagg aaatgtgggt 47760
gctgatttcc ttattacatt gagaggagcc aggagattct ttgttcaaaa tggatggctt 47820
aagaagtcaa agtataagct gattacgtag agcaggtacc caaaaatgtt ttgtgtaagg 47880
ggccagatag taaatatttt cagtcttgca ggccatccca agtctgtggc agctactcaa 47940
cactaccttt gtagcatgaa agcagccaca ggcagcccat aaatgtggct ctgttccggt 48000
gaaactttag gtacaaaagc aggtgcaggc cagacctgac ctgtgcactg tggtttgctg 48060
acctgggatt caggggtata gaagttacca tcagaagagc taaaagtgag actttttact 48120
ttatactctt ctacactgtc tgattttgaa aaaaagaaac atgtatttta taatattaaa 48180
gatagggttg gcaaatagca aataaaaata cagaatacca gtgaaatttg aacttcagat 48240
acattatgag taattttatg gtgtaagtat attccaaatc atgtgggaca tacttacact 48300
acaaaattat ttgttgtttg tttacagttt aaatttgagt gccttgtatt ttatctggca 48360
actgtaatta aagggaaaaa gaataaattc attatgttca tataatgtga tatagcaggg 48420
gtccccaacc cccaggctgc agagtggtac tggtccatgg gtccccaacc cccaggctgc 48480
agagcggtat tggtccatgg cctgttagga accaggctgc ccagcaggaa gtgagcagca 48540
ggtgagctgg cattcccacc tgagcaccgc ctcctgtcag atcagtggca gcattagatt 48600
cccataggag tgcaaaccct attgtgaact gcacatgtga ggggtctagg ttgtgcgctc 48660
cttatgagaa tctaatgcct gatgatctga ggtggaacag tctcgtcttg aaaccatccc 48720
ctggccctgt ggaaaaattg tctcccatga aaccagtctc tggtgccaga aaggttgggt 48780
agcactgtga tatagtatta aaagtgctaa taaatatggc atactgcctt taaaatgtct 48840
ggtagctctt tctcagtggc actcataata gtgttttttg atttttaaat gtgtgtcaag 48900
ctgactctcc cctccgtgta tgctgggctt tattttccct ttcctagtca ccagttttgg 48960
gaaatagaga tcttcattct catgctgctc ctctagtgca agtgctccat ttatttttaa 49020
ggaattaata taacaaaaaa tcatgggaat ttagaaaaca acatggaagc taatgatcac 49080
attggtggaa gtgataggga aatatttagg gggagaagtt aaggtataaa ctttgtcaat 49140
gaagtcctat taaaaacaac aaaaaagtga agcttaggat gcattttata aactctgacc 49200
agaacacctg tgtttctctg tttctaggtt tatgaactga cgttacatca tacacagcac 49260
caagaccaca atgttgtgac cggagccctg gagctgttgc agcagctctt cagaacgcct 49320
ccacccgagc ttctgcaaac cctgaccgca gtcgggggca ttgggcagct caccgctgct 49380
aaggaggagt ctggtggccg aagccgtagt gggagtattg tggaacttat aggcaagtta 49440
ttagcaaggt ctactcttac aattaacttt gcagtaatac tagttacact ctattgatta 49500
tgggcctgcc ctgtgctaag cagtctgcat tccatcttcc ttgccaaaac ttataataca 49560
aatttcatct ttattttata aataggggag ttgggctggg tgtggtggct cacgcctgta 49620
atttcagcac tttggaagga tcgcttcagc ccaggagttt gagacaacct ggccaagtga 49680
gaccctgtct ctacaaaaaa aaaaaaaaaa aaaaaattag ctgggcatgg tggcacatgc 49740
ctgtagtccc agctgctttg gaggctgagg tggtaggatt gcttaagccc aagaggttga 49800
ggctgcagtg aatcttgatg gcagctgcac tgagcctggt gacagagcaa gatgctgtct 49860
caaaataaat ttaaaaataa aataagagaa ttaaagttta gcaggttggg tggcaaaatg 49920
aggccacaca tttaaagccc ctcctcctga ttcttttctc tgccttggct gcctcctgtg 49980
gcattttagg tgctgagaaa tgaaaacagt agggaaaata gttccaggat cctcatgtta 50040
atttgccaga aatggcatct tcaagtcgtc agagggatct gagagttcct tcctggcctg 50100
acttgagaaa atccgtctgt ccccagctct gcgtctgcct ccactgccca gtcacctcct 50160
ctccatgctc ttggggctgg gccctacccc accatgcagt gctgccctgg agcagtgagc 50220
ttggtgggtc ctgtctggca tgagagctgc ctttgggagc tggatcccag cctctaccac 50280
tgggtctggt gcctagcagg ctatggataa acttctgctg actccggcct ctcctaagcc 50340
actgcaacgt ggtcggtgta gtgcacagtg tgtgtgcagc gtggccttac tcacagcctc 50400
cacattagag agaatctgac tgaagtctta ctgctgcctc gtgtgaacat aaatgtttgc 50460
cagaaccatg agcaggaaat gttaatctgc cttgtttcct gtcctttaca cggaagaatt 50520
tttttctgta tggaatgcgt gccttacaaa taatgagtgg aaatacccat cgctaatgaa 50580
aagttatact tgactgttag tcagctaaat aatctgagat ttctaatact tttaatttgg 50640
cttttacaat gcaatttatc ttagcttttt tgatttctta ggtcatatct ttagaactat 50700
atatttgaat gttaatgtaa ttttcatatt gaaattaaaa tgttgaactg cgatgttaag 50760
tgtttcctgt ggaaaaacgt tcacattttc tctagtttta aagttgaatc aagctgtttg 50820
aagattttca catttcttct agattttatc agcttgttac tttatctgtc actttctgtg 50880
atttgcagct ggagggggtt cctcatgcag ccctgtcctt tcaagaaaac aaaaaggtga 50940
ttatttcaga aatcagagtc ttgtgttgaa tcttactgat tttcttgtat ttctgtaatg 51000
taatgtatct tgtatttctt gtaatactgt attggactct gtgtatatct cttctcagat 51060
gagtgattat atgtgtgaat gttgctggaa tctgataacc aggcctgaat agttttgtag 51120
ggtggctttt aaaaattact ttcatatcag aattgctttg tcataaattt tgaacgcatc 51180
ataaatttct aatgttcggg gtcagcagac tttttttgta aagggacaga gtgtaaacat 51240
cttagcttta tgggccatat ggtctctttt gcaacattca gctctgccct gtgacaggaa 51300
tgcagttgta aagacatgag ctactggcca gctatgttcc agtagaactt tacttacaga 51360
aacagacagg ctgtagtttg ccaatacctg ccttagggaa tgtgttgtta tattttgtga 51420
gttaccttct cagtaaattt tatttagtat tagtcaggaa tattattaag tagcttcttt 51480
tccagcctgg tcaacatagt gagacccggt ctctaccaaa acaaaacaaa acaaaaaaac 51540
agccacgcat gtggcatgtg cctgtagcct cagctgctgc tcagggggct gaggcaagag 51600
gattgtttga gcccaggagt ttgaggtcac agtgagctgt agtcatgcca ctgcactcca 51660
gcctaggcaa cagaatgaga ccttgtgtct taaaaaaaaa aagtttcctt tgttgggtta 51720
ttttaatttg gacctggtta tcatttttca gccatattta actttgtaca tatcagaatg 51780
ttctgataaa acttaacttt tattaaagtg tttgtgatat aatctgctag ttttggtaca 51840
cattatcttt tgcaatgcca gttattttct tttccagtgt gggtttgcat aggaaaagaa 51900
ttgctgtcac tttctatttt gaaatcttaa aagactgatc cttttttgtg tcatgatttg 51960
agtatttaat tgagagccta atgcctaata ttatttgcag tattaaatgg gatcttaaca 52020
ggaatagcat tctagccttc attgaattaa gtaaacattt cttaagagaa cttggaatct 52080
ataatatttg cgtcatcata gtatgagata cttaatcaag tttgagattt tagtgaaaca 52140
ttgtttagaa gccaaaagga ttctaggaaa aattaatgtc tatattcttg aattaggaga 52200
gattttggga cgtgtgacta agttacgctg acacttgttt gtttcttagt cgctttttcc 52260
agtggcggtg agaacgaaga tgactgattc acattgctca gatgagttta tcctcttctg 52320
gctgggacat gggatatatc ctgtctcttt taagcctttt tggtattttt cccccattga 52380
gagctgtgtc ttcaaactct tctgttatag ctggaaaatc ctttttaagt gaaatctgcc 52440
caaattataa gacagatgaa ggtagagttg tgttggatat aggattaggg tgaaagtagt 52500
gggggtgtcc tggagcctct cttctggtgg cagcctagct cttgtgcctt tgaggaaatt 52560
accctgggga cggctctgtg gaacatattt gcaaaccact gatttggaag atagagatgg 52620
cttttgttaa gatctgaatt cacctttttg gcattttatt tgatttctca aggtaaagaa 52680
cttattttgt aataaagttt cctattattt agtagatagg ccaagttgct gtgttaattc 52740
catgtagatt ttgggtttcc tttgctcatt ttttcactct taatctcaca tcattgtaag 52800
tttatggaag ttatcatact tctgactttt tctttgaaga gcagaaatta gaaattccca 52860
ataattattt tgatagtgtc atttaatgac actcacatgt gatgtagcca caaagattta 52920
atgagttcag ttttaaatca tattaagact gttggtttca tttgttctca ttaatgtaat 52980
tctgaagatg aacaataaaa tgtattttta gaactttcaa atgaaatatt atttcatcct 53040
tccagatcat ataatgctta agttctgatt gttaatcata aagtctagaa aattaaaaga 53100
taataaaatg aaagtgactt ttaggtatta gagttttatt ataaattctg gtgtgtcatt 53160
ggagctatga catgaatatt tcaaaggcca atagcattgg atctttacag ttataactta 53220
ccatttttaa gtttaagtag taatatagat tatttaataa tcaaaatcaa taaatattaa 53280
ttattaaaat gttttgtggt atagtttgag aatcattgct tttaactttt tccatatagg 53340
tttattgact ttaatagcat tctaaacata acatctctac attctttgtg tttaatactg 53400
tggaggtata aaaatactta tatatgatga taaactatat tagagtaaat taaatattct 53460
tatgagtttc attttagagt gcatttactt aattttgaag tccttatttt tagcaaacta 53520
aaaggaatgt tggtacatta tttactaggc aaagtgctct taggagaaga agaagccttg 53580
gaggatgact ctgaatcgag atcggatgtc agcagctctg ccttaacagg tagttctcac 53640
tagttagccg ctggtgtgga ccttcactgt ctgccttcca ccccttgccc ttcctgctcg 53700
tccccctgca cctggtggac agcacgactg ggggcagcag tggagccagg ttgcttaaat 53760
ggggcatatt cgggcttctt ttataatact tactctgaag cttgtgtgtc tgtggtgttt 53820
gcatcatata tttgttgttt tccatggttt aggctgtttt aaaattaggt ttatggcttg 53880
agcatagggc tttgtgagta ggggatggca ggtcgaaaca tctcatgagt tggatgggtt 53940
atgctggggg ttgggaaatg ggatgaaaaa ttatgggatg aaaaattgcc tatggatagt 54000
ttaacttgaa agaatctgcc tttgtttaca gatagttatc ttttttcttt tttgagatag 54060
agtctcacac tgtcacccag tgcagatacc cagtgtcact ggagtgcagt ggtgtgctct 54120
tggtgcactg cagcctccgc cttctgggtt ccagcgattc tcctgcctca gcctcccaag 54180
tagctgggac tacaggtgcc cgccaccacg cttggctaat ttttgtattt ttttgtggag 54240
acgggttttt gccatgttgg tcaggctggt cttgaactcc tgacctcaag tgatctgcct 54300
gcctcagcct cccacagtgc cgggattaca ggagtgagcc actgtgcccg gccagttaca 54360
gatacttatc taatgaaatt ctctgtgtac tttataaaag atgaggatta actgaaggta 54420
ctaataactg gattatatga gggtggtttt ggttgtataa tcctatctaa aagaatattt 54480
tagctataac tgaaagtaag acttaaatat ttagagagga aaatctgaat aattctagta 54540
gtaattattt atttacaaaa taaaaataga tttttttttg attacacaaa ttaaacaaca 54600
ataaaacatc acagcaatcc ggatactata aagctcacat gcttaccgac ccaactgccc 54660
caggagtgac cactgccaac agcttcatgt cgaccttttt gccataattt ttatatagcc 54720
ttttttgttt ttaaatggta atttagaaag tcaactagga aaatgtgtta caggtttatc 54780
ttccaggaga ataggactgg agtcgagatc ttgaatgtgg cttggaagaa ggcaagccca 54840
ccccagagag atgagttgac agttgtttct gaccactgct tgcttagagg gcctgcgtgt 54900
ctgtgaccgc ctagctttgc gcccctgact aggctgcccc ttaattacaa atgtctttat 54960
atattgctcc agctaaggct tggagtagtc ggttaagaac ttgaacttcg gtttttgcag 55020
tgaaacagca tttgagaata tcaccttctg ataagcctta ttttataagg tgggtactgt 55080
agtgggaggc agtgtgagag atgcttgaag gatgcactgc tgtcctgcat ttcagcatct 55140
tcaggatgct gtgcagctga aacatttgat aacggtggaa ctgttcgtta ttttgcaagc 55200
ctgtgattcc ctattgaatg ttttctctcg ccatttgaca aatgagtgtt tctctgtctt 55260
cagcctcagt gaaggatgag atcagtggag agctggctgc ttcttcaggg gtttccactc 55320
cagggtcagc aggtcatgac atcatcacag aacagccacg gtcacagcac acactgcagg 55380
cggactcagt ggatctggcc agctgtgact tgacaagctc tgccactgat ggggatgagg 55440
aggatatctt gagccacagc tccagccagg tcagcgccgt cccatctgac cctgccatgg 55500
acctgaatga tgggacccag gcctcgtcgc ccatcagcga cagctcccag accaccaccg 55560
aagggcctga ttcagctgtt accccttcag acagttctga aattgtaagt gggcagaggg 55620
gcctgacatc ttttttttta ttttttattt gagacagagt ctcactccat agtgcagtgg 55680
aggccgggca caggggctca tgcctgtaat cccagcactt tgggagactg aggcaggcgg 55740
atcacttgag gtcaggagtt cgagaccagc ctggccaaca tggtgaaacc ctgtctctac 55800
taaaaataca aaaattagtt gggcgtggtg gcacatgtct gtagtcccag ctgttaggga 55860
ggctgaggca ggagaattgc ttgagcctgg gaggcagagg ttgcaatgag ccgagatcgt 55920
gacactgcac tccagcccgg gcaacagagc aagactccat ttcaaaaaaa ataaaaaaat 55980
aaagtgcagt ggctcgttct cagcccactg caacttctgc ctcccaggct cgagcgattc 56040
tcccgcctca gcctcctgag taggtgggat tacaggtggg caccaccaca ctcagctaat 56100
gtttgtattt tcagtagaga cagggtttca ccatgttggc caggctggtc tcaaactcct 56160
gaccttagat gatccaccca ccttggcctc ctaaagtatt gggattatag ttgtgagcca 56220
ccatgcccgg ccctgccacc tgccatcttt tgagttcttc cctggagacc tagacctgaa 56280
ccctcctgct tgttctcttg ttatctaata cccctattga cagcgcagct tagatcatta 56340
atggagagct tgacctcatc tgataccttc actgaaggaa acaacttagt gtcttttgtg 56400
ttgaacactg aggtaaaaaa ttggaatagt tgattatatg aactctgcta aaattgagtg 56460
cattttacat tttttaaggc cttgttgggc cctggttaaa taattatttt taaaaatcct 56520
taaggagcct attataaaca gatctgtggt cttaatgaaa tgtgattaat actgtgcatt 56580
attttaagaa cttttgactt ttcaaaaaac ttttacaaca tttcccattt gatagcggca 56640
taggtttaag cacttctcat ctctaagtta gtggacaaaa aaccctcatg gatagtctaa 56700
taatgtttgc tacaagtcca tgttgagttt tatactccat tttattttca gttttaaaaa 56760
ctgtggttaa atatgtgtaa cataaaattt atgttcttaa ccattttttg cgtatacagt 56820
tcgctggtat taaatacatt taaataatgt catggaatca ttgctaccac ccatctctgt 56880
aaccttttga tcatgtaaca ctgaagctct gttcccattg aactctattc ctcctttccc 56940
gccaagtccc tggcaaccac gattcttctt tctgtcttct gaatttgact actttgggtt 57000
ctcatatact ttaggagtca cacagtattt gttttactta gcataatgtc cccaaagctc 57060
atgcatgttg tagcctatgt tagaacttcc taatgtttca ggccaaatac tattccattg 57120
tatggatagg ccacattttg cttttccatt cctctgtcca tggacacttg tattgcttca 57180
tgttttagcc attgtgaatc atgctgttat gaacgtgggt gtacagatag ctcctggaga 57240
ctctgctttc catttttttg gctaaatacc cagaaatgga gttgctttta cattccaatt 57300
ttaatttaaa acattcatat cattgagtgt tttacttaat agtatagtag ttaacaaact 57360
taataaaata gtattttggt aataatttgc tggtagtcca ttgttcagtt tttttaggta 57420
aattacacag gacatttcaa gtggacatga aacatcttgt gatgtggaat catgccccaa 57480
gctgatggct aaacatatga aataccatac cctaaattta gtagatttag tctttgcaat 57540
ttaggagata acctgttata ttgttaggtt tttgtcgaaa agctttgtcc tcatatttcc 57600
aacttgctgt aaaatttgtt tgtgaagaca aatatttttg tatgggtttt ttctttttca 57660
tattaaaaag aaatgtccac attggaattt ttttggagtt tttagagcta atagagcttt 57720
tcataatgta gtgggaatga gtgatcagta agctcttagc agtttccatg cgtgcatttc 57780
tgtgccttga aataaatgac agatgagtac atttgtgttc tgtgtgtaaa atgtgctctt 57840
tcctcattgc acttccatgt tggagggctt gtctcttggt gatcacactt caaaattctc 57900
acagcccccc ttgaaccgtt taggtgttag acggtaccga caaccagtat ttgggcctgc 57960
agattggaca gccccaggat gaagatgagg aagccacagg tattcttcct gatgaagcct 58020
cggaggcctt caggaactct tccatgggta tgtggactac aggtgatgcg ctacaaagtg 58080
gtttgtattc agacctggac atcttaatta tatctttgct tccaagaaga agtcctttga 58140
tactgttttc tgagttctga atagctgatg aaaatgacca attgaggaat aatcatactt 58200
tttcttgatc taaatcttat acttttgagt tatcttagca taaatgtata attgtatttt 58260
aagtggaaat ttgtcactta atcttgattt ctctgttttt aaagcccttc aacaggcaca 58320
tttattgaaa aacatgagtc actgcaggca gccttctgac agcagtgttg ataaatttgt 58380
gttgagagat gaagctactg aaccgggtga tcaagaaaac aaggtgaggg acataggctt 58440
gagacgactt ggtgtttctg agcttgtgtg aggatttaaa atcgccctgg ctactgtcta 58500
ctttattgct ttcccatccc tgggccttta aatttcccct ttaaatacca gctcttccca 58560
ggcctgttgt tttctgcctt tccaggtact acccacagcc ttgagaattg cctgagttct 58620
gcctcctttg agagtgtgcc ccagacaaat ctattctgta ctgaatgttt ccttgtctga 58680
tttcttggat cattcatttg atggttgcgt atggcctgca acgtttcttg ttttggttct 58740
actgaactgt tctaaaagtc tctcttcata ttatcttttt acatgtaaat gtaactgtct 58800
tcacttttaa ttcctcaagg acaaggaata gcgtttcaca gttcgtccca tcaatcagaa 58860
ttatagcctt tggcatctcc ctatctacca ggcccacttc ctcttagatt tgggcttccc 58920
caggctgttg cctttcccca agtagcttct gcttgtcctg tagaagacct ttcatgcttt 58980
gcttctgcag cagccgttcc tgaatgccta gtgtcaactg ccttcttacc acgcccaccc 59040
tccctgcatg ctgcatttat cccctgccac agccctgtga ccctgtgtcc tgctgcctct 59100
gacttgtctg tttctgcttg gccatggtct ctgtgaggtc aggtgtgcat atgggcacaa 59160
accagggcat ctctttatcc ccagcacctg gcttaagtgc tgctctggaa ctatctgttg 59220
aatgaactaa tgcatgaatg tattgttgag tatgagacaa acaagtgtca ttgtctcctt 59280
tctagccttg ccgcatcaaa ggtgacattg gacagtccac tgatgatgac tctgcacctc 59340
ttgtccattg tgtccgcctt ttatctgctt cgtttttgct aacaggggga aaaaatggtg 59400
agtacaaaag gggatgtgca cagttgaagg aaataactag gtttcagagg tcagcttggt 59460
ggcctgtttt tgccttgcgt gcagcagagg aagtagaatc tgaggatgag tttggttttc 59520
actagccgag gggagggagg aaatgatggg agcaggtagg ttattgggtc tggttttgtt 59580
catttgaaaa caatctgttg tttgaggctg aaggtggctt gggtgatttc ttggcagtgc 59640
tggttccgga cagggatgtg agggtcagcg tgaaggccct ggccctcagc tgtgtgggag 59700
cagctgtggc cctccacccg gaatctttct tcagcaaact ctataaagtt cctcttgaca 59760
ccacggaata ccctggtatg ttaaaagttc acatcttatt ttctcagatt taatcattat 59820
tgtaaaaact atttcagtat tgactatttt agttttagag cagtaagtgt tttgagttca 59880
tttgggatat ttgacctgcg ttgtagctct tcagaaaaca catgaatagt gaagttcttt 59940
gtttcatggg ttccctttag atgaaaccca tagaggagaa aagtagaaac ctcagcacgt 60000
aagagccaac atatatacac atcggattta aacctaaagc acaaattgtg cctggtcgca 60060
gtggcgctga gtcgcactca gccaggccag gcattcacac tcagggtgag tgggaaccag 60120
gactggctga ggcagcagtg gacccaagtc tccatcgcgc ccatgcttac tatggagcct 60180
tctcgttctc tctttttctt tgggtgagag ggtacacttg tgtttttgaa tttatatgag 60240
gtaagtgtgt aatagggttt tttctaatct tttttaagtg gaatctggaa ttttaatcag 60300
atttattatc tgacaaccta gaattataat ccagaaagtc tgtggtattg aggacatatt 60360
ggcaatatga tgaatctcta attcttaaat cctgaaactt tttttttttt aatcacttag 60420
ggttattata gtgaagtcat ttctgaattt ggatcttctc ttcacacctc tttttctctt 60480
tcctgagaat taagcttttg tttcgagtta gaaagttgat agtagggaat tgttccatgg 60540
ctgagcaatt tatctccaca gaggaacagt atgtctcaga catcttgaac tacatcgatc 60600
atggagaccc acaggttcga ggagccactg ccattctctg tgggaccctc atctgctcca 60660
tcctcagcag gtcccgcttc cacgtgggag attggatggg caccattaga accctcacag 60720
gtaacggcca gtttttcagc tgtgtttttt ctagttatgc ttactaaggt ttaagtttag 60780
atgatgatgt ttgttgcttg ttcttctggt taggaaatac attttctttg gcggattgca 60840
ttcctttgct gcggaaaaca ctgaaggatg agtcttctgt tacttgcaag ttagcttgta 60900
cagctgtgag ggtgagcata atcttctgtg gaaccatttc ttcacttagt ggacatttta 60960
tcattgctac aattaaaatt ggagcttaat aggaaatatt tccatgcact ctaaagctgt 61020
aaccagtaat acccaccatg tatccatctc tcagctttag aaagaaaacg ttgccagtaa 61080
agttaatgct tcataaactt cagtttaagt tctaattctc agaatatttg tttgaaatag 61140
acctcttcct aaaggatata tttagaaata acctatcatt aagtgtaaag tctgttgaat 61200
atgctgggca cggtgactca cacctgtaat ctgaccactt tgggaggcca aggtggaagg 61260
attgcttgag cccaggagtt caagactatg ggcaacatag ttgaccctgt ccctacagaa 61320
aattaaaaaa aaaaaaaaaa aaagtagctg ggtatggtgg tgcatacctg tagtctcagc 61380
tactcgggaa gctgaggtgg aggggggatt gcttgagccc cagagatcaa ggctgcagta 61440
aggcgtggtt acaccactgc cctctagcct gggcaacaga gtgagactgt ctcaaaaata 61500
atagtaataa taatcagttg aattaaaaaa aaaaaaaaaa aaaccactgt gctaggccca 61560
tagtatggta agagttaaag tgagccttag ggattattta ctcaacctct gtttctgtat 61620
aaagtggaat aggctcaatt ctttaagtga tagcatgttg aacctttcca taccaactgg 61680
ctcataagtc acaactggcc agtcaacaag agtaaaaatt aactggtaaa aatcaaagca 61740
aaaaacctac aattgtcaaa tttgtgggat aactccccct tttaaaatgt catgcctgac 61800
agtaatttct ctctagtttc caggttttca gtcagttgtg tcttttttga gcagaaggaa 61860
gcatgctaag agctcaatct tgtggctagc tgggggtctt tgtgtcagcc atgcatgtga 61920
tggtgcccct gggtgcttgg ggctgcaggg gaggggtaca gcagtagggg cctgttctgt 61980
tctctcgtgc tgtggagtac atagtgacat agtggggtgg tccttggtgt aggtcccttg 62040
ttcctacccc tgggtctgag atttatttag aagtggtgtt ggggctgtgc ggcaggcccc 62100
tctgtaactg atcaatgttt gtgaagttgc tgtttgagag ttgaaaccat gacataagca 62160
gaaatggaag gaagaaagaa ccagttatgt gaaagggaca catttacttt taagcttgta 62220
tttactgaga taaagtattc ttaatcaatg ttcttgagag gtgtgggaaa aatgcaacat 62280
cctggttgca gttaaaccca gaacattgtg tgttgaagag tgacggttct caaaccgtca 62340
agacgcgggt actgagtggg actaacctgc tgtcctcttg ccttggacct tgtgttccag 62400
aactgtgtca tgagtctctg cagcagcagc tacagtgagt taggactgca gctgatcatc 62460
gatgtgctga ctctgaggaa cagttcctat tggctggtga ggacagagct tctggaaacc 62520
cttgcagaga ttgacttcag gtaagtgagt cacatccatt agatttcatg aactaagctc 62580
aattgaaagt tctgggatca cttgatgcaa ggaatgatgt tatcaagtac cctgtccatc 62640
agaaatccga gtggtttagg tagatgacag tgattttctc ctcccagtgg ctttttgctg 62700
aactttgccc tatgcttgga attttatttt attttattat ttatttagag acaagatctt 62760
gctctgtcgc ccaggcttga atgcagtagc acaatcatag ctcactgaag ctttgaactc 62820
taggactcaa gtggtcctcc tgcctcagcc tcccgattag ctaggagaat aggtgtgtgc 62880
cgtcacactg gctaatattt tttgtagaaa tggggtcttg ctatgttgcc caggctggtc 62940
tcaaactcct gggcttgatt gatcctccat cttggcctcc caaagtgctg ggattacagg 63000
catgagccac tgtgcctggc ctagaatttt aaaatataag tagaagagta gatttttttt 63060
tttggtagtc ctcgtcattt aagtattctg gatagtggga ataaaagagc ttagaatttt 63120
tcatctttgt cttaaacttt taaaaaaatg tagcttatat taattctgct tgtttaaaaa 63180
gaatatactc ttcattatac tgaacctagg taagacagct ggtttatatt ttgttgcaat 63240
taaaaaacgt gagctgtggt tgcagtgagc caagattgtg gccattgcac ttcagcctgg 63300
caacagagtg agacttggcc tcaaaaaaaa aaaaataaca tgagctgtgt tggcactttc 63360
attttctaag agtagttttg gctggagaag ttttctttca gtactttctt ttagaaggga 63420
aattttcctt tataatttag ggtttgtttt ttttttttcc aagccacctt ttatagagcc 63480
cttgtgggtt atttcattta atccttagaa tgtttataaa tctgggcttg ttctcggctc 63540
cacccacaga tagggacgct gagcgtgcat gagtgggcag caagatagca ggttatggag 63600
ggcccagctc accccttctg tggcttgagc caattttata gggcacttac agagtctttt 63660
gaaatagtat ttattttgaa gaaaaagaaa aacagtttac tgagtactgt cttattgagt 63720
ctggaattgt gagaggaatg ccacctctat ttatttaaag ccattggcct tttttgttgt 63780
tttgagtaag tgctgcccaa ggtccttcca gggcacctgg atgagcctgc tctggagcaa 63840
gctggcggta agtgtttact gagtaactaa atgatttcat tgttaaatgt gctcttttgt 63900
taggctggtg agctttttgg aggcaaaagc agaaaactta cacagagggg ctcatcatta 63960
tacaggggta agcggtttat ttttgtgaga tgctgtttta ccttcaagaa ggtgaaagtg 64020
aggctttcct tgtggaattt ctctaaatgc attcgtcatg ttttagatgt ttatttcaca 64080
gtttatatca tgaaagttat aatcttgtca tatggattta agtctagtaa tgttgagttc 64140
tttctcacta gctttccaaa atatcttacc taaaatttag tcaaatacaa gattatgttt 64200
atttttatta tccttctctc taaagctttt aaaactgcaa gaacgagtgc tcaataatgt 64260
tgtcatccat ttgcttggag atgaagaccc cagggtgcga catgttgccg cagcatcact 64320
aattaggtat ttaccaatat tttatctctt ttcctttttt ggttgaagta ctaaaagata 64380
cgagaatgga aagagaggga agaattcaaa ggatgtagag cagtattcct gaatctgagc 64440
tcatttcagc cattctattc ttaaactata atgaaaaaaa aatccaaaaa agtctaaaat 64500
tataattaaa aaaacaacaa aatactaact gtccattgta aaaagtaatg cactttcatt 64560
gtaaaaattt tggactatag agaatagtac taagaagaaa aaaaaaatca ccttcaattc 64620
tgctgccacc tggaggtaat cactgttaat attttgctat atactctatg agtttcttgt 64680
tcaaaatcag gtcaaaatta catgcaattt tgtaatctga caatttccac ttaatatttt 64740
attagcattt tcctgttatg aaacagtaat tttagttatg ggtcgttgtt ttgctatgcg 64800
gttgggataa aattttatat actttttttg gcaattactt attatacata aatgtttgtg 64860
tatagttttc tttttctgag aattcctgga agttgagtta ccaggcccgg ctttgaattt 64920
ttttttttat tttttttttg agacagagtc ctgctctatt gtccaggtgc tatctcggct 64980
cactgcaacc tctgtctccc tggttcaagc gattctcctg cctcagcctc ccgagtagct 65040
gggattacag gggcacacca ccacgcccaa ttaatttttg tatttttagt agagacaggg 65100
tttcacgata ttggccaggc tggtctcgaa cttctgaccc cgtgatccac ctgcattggc 65160
ctcccaaagt gctgggatta caggcgtgag ccatggcgcc tggccaggct ttaaatttaa 65220
aacaaatctt ctaatagctt tatggaggtt ataatttaca tttcttgaaa tgtactcact 65280
ttgagtgtat agtaaactcc aattttatca catttctgtc accccaaatg tatccttgtg 65340
cccatttgct gtaacctccg gttcctgccc caactcctag gcagccactc atctattttc 65400
tgtcccttaa gatttgtgtt ttcgccaggc gctcatgcct gtaatcccag cactttggga 65460
ggccgaggtt ggtggatcac ttgaggtcag gagttcgaga ccagcctggc caacatggtg 65520
aaaccttgtc tctactaaaa atacaaaaat tagtcggatg tggtggcaca cgcctgtaat 65580
cccagctact cgggaggctg aggcaggaga atcacttgaa cctgggaggc ggaggttgca 65640
gtgagcagag atcgcgccac tgccttccaa cctgggcaac agagagagac tgtctcaaaa 65700
caaacaaaga tttgtatttt ctggacattt tatagtactg gggtcatagt atagatggac 65760
ttttgcattt ggcttctttt acttaattgt gagattggtt cttgttgtag catgtatcag 65820
tagtttgttc atttttattg gcgaaagtat tctattatat gaataatacc atattttatc 65880
tatccatcag atggatatta tagagttcat gttttggcta atttatgaat tatggtactg 65940
tgaacatttg cctgcaagat tttgtgtaga catgtcttca tttctcttga gtagatcacc 66000
tagaagtgga tttttaaata attttggtac ttactgtgaa actgctcttc aaaaacatac 66060
cattgttcct tccttccttc cttccttcct tccttccttc tttccttcct cccttcctcc 66120
ctcccttccc tacttccctc tccctttccc tttcccttcc ccttttccct tccccttccc 66180
gcctgcctgc ctgcctgcct tccttccttc cttccttcgt ttctttctac atatacacat 66240
ttttttaaat ttcaatggtt tttggggtac aagtggtttt tggttacatg gctgaatttt 66300
ggttacatgg tgaagtctga gattttagta cacctgtcac ccgagtagtg taccttgtac 66360
ccaatatgta gttttttgtc cctcaccttc cagccttccg ccttgtgagt ctccaatgtc 66420
cattatacca cactgtatgc ccttgcgtac ccacagctca gctcccactt ctgagaacat 66480
atagcagaaa catgccaaag tatactccca ctaccagaat gtgattgtgc ctgattcttc 66540
tcaccagtac aaatatttca aaaaaagtta aatatgtatc agttttttgg gcagaagttg 66600
atacttctct ttatttattt attttttttg agatagggtc tcattctatg atgcccaggc 66660
tggagtgtgg tggtgcgatc tcggctcact gcagtctctg cctcccaggt tcaagtgatt 66720
cccacgtcag cctcccagga agctggaatt acaggcgagg gccaccactg ccagctaatt 66780
tttgtatttt ttggtagaga tggggtttca ccatgttggc cagactggtc tcaagctcct 66840
gacctcaagt gatccacctg ccttggcctt ccaaagtgct gggattacag gcgtgagcta 66900
ccacacccgg ctgatatttc tttttaaaat aacttacctt cttttgaaag taatacatgt 66960
ttaatgaaca gaatttaagg aaaatataaa aaaacgaaat aatctttgta atcaaactac 67020
tgaaaagaaa accaaagtta cattttggtg catattcttt ttcattttca tcattgtaat 67080
ttgcatttct ttgattactt gtgagacact cctttcattt acttaatagg tttatatgac 67140
ttgcctattc agagattttg cagctttacc attttctgca aatgatagca acttcttttt 67200
gtttgtttgt ttgtggagac agagtctcgc tctgtcactc aggcaggaat gcagtggtgg 67260
aatcttggct cattgcaact attgcctcct gggttcaagc gattttcctg cctcagcctc 67320
ccaagtagct gggattacag gagtgtgcca ccatgcccgg ctaatttttg tatctttagt 67380
agagatgggg ttttgccatg ttggccgggc tgatcttgaa ctcctggcct caagcggtcc 67440
ccctgtctcg gcctcccaaa gtgctgggat tacaggcgtg agccaccgta cccagccagt 67500
agttacttct tatattctag aaaaaattct actcatgatc aagtctccat gaggaaagag 67560
actttaattg aagatcatgg ggcttgcaga ccaatatgat aaaatagttc attgtttcta 67620
aaagtattac tgagtgttga tggcagatat gaaccctttt gtttttgtag gaaaatgtta 67680
cccgtattct ccatttgaat tcagtttaga tttgttagga atcgcagctt aagctttgcc 67740
atctgggagt gtttgggaca gttttgcaga caaaattgca aaagtgccta aggaatgcag 67800
ctggcattca gacctgctct gtgctcagta ctctgtggac agacactgtt cagcacttgt 67860
tgatcagaag gtttagaaag agaactttca aagttggttt ttaattaaag catttaatag 67920
tgtaaataga aagggattaa attttatgac agacaaaaga aagtacagca cccagctggg 67980
cgtgggggct cacgcctgta atccagcact atggggggct gaggtgggtg gatcacgagg 68040
tcaggagttc aagagttcaa gaacagcctg gccaaggtga tgaaaccctg tctctactaa 68100
aactacaaaa attagccggg cgcggtggca ggcgcctgta atcccagcta ctcaggaggc 68160
tgaggcagga gaatcacttg aacctggacg gcagaggttg cagtgagcca agattgcacc 68220
attgtactcc ggcctgggcc acagagtgac attctgtctc aaaaaaaaaa aaaaaagaaa 68280
aaaagaaagt acagcaccca gttatgtccg agtgggtgca tgagagtgac cctgagattg 68340
gagacaacgc tgtcacgtgc ttgaagaacg ccacctgaga aagggggcga gaagtggtgt 68400
ccgctggtaa ccagaggtgt tggcttagcc atctgcaggg aggagggtgg tctatcacag 68460
gtgagtttca tctactttct taagcaaatt aaccttactt ttgtgttagg cttgtcccaa 68520
agctgtttta taaatgtgac caaggacaag ctgatccagt agtggccgtg gcaagagatc 68580
aaagcagtgt ttacctgaaa cttctcatgc atgagacgca gcctccatct catttctccg 68640
tcagcacaat aaccaggtat gctgacccag tggcatcttc acattgtcgg gaaaatgccc 68700
tttcctgatg cctttcttta ggctttaatt gaaaacattt tattttctag aaaaaagctt 68760
cagctcagga tgtttgagtg taggtcagtc ctttgatagg atattatcat tttgaggatt 68820
gaccacacca cctctgtatt taagctctgc cacaatcact cagctgtgac actgtaaatc 68880
tcttaatagt ttattacatt ccatgtgctg acagttgtat ttttgtttgt gacacttacg 68940
tattatctgt taaaacattt tcactttagt tgtgttacct ttaaagagga ttgtattcta 69000
tcatgcctgt tgattttttg gtgagcgggc tattaaagtc agtgttattt agggttatcc 69060
actagttcag tgatttgcga gattatcatt cacatttatt gtggagcttt tgaatatcgt 69120
gtcaaatggc cacatatatc ccattcttat ctgcttctta ggtgagtggg acacagtgct 69180
ttaatgaagc tataatcttc agaattctag cttgcagaga agattgcaga agtgataaga 69240
cttgtgcttt ttaattttgt cttttaaatg ttattttaaa aattggcttt atatgatact 69300
ctttttttct gctgagtaac agtgttttac aaaacttgga ctaaatgact tctaagctta 69360
aatgatcact tgatgctttt tttctgaatt aggaactcag cttatcaaat atcaaagtca 69420
taattcctga ataaataacg tcttttttca tgtaaagact gctttaaaaa acacatggaa 69480
ggctgggtgc ggtggctcac gcctgtaatc ctaacacttt gggaggccca ggtgggcagg 69540
tcgcttgagc tcaggggttc aagaccaccc agggcaacat ggcaaaaccc acctctactc 69600
aaatacaaaa aattagccag gcgtggtggc gggcccctgt aatcccagct actcgggagg 69660
ctgagggatg agaatcactt gagccccgga ggcagaggtt gcagtgagcc aagattgtgc 69720
cattgcactc ccagcttggg ctacagagtg agactctgtc tcaaaaaaag acacacacac 69780
aaacaaaaaa aacatggaga catttttttg gccaccttaa tatttcccct cagataattt 69840
cctttgttta aactcagaac tggcattttc tctcttggag aagattcagg acaaatactc 69900
ctttaagata agtagaagca gtgaaagagg atttgattat caggaatttg ataagcttag 69960
aataaattgt tgcttcttaa tgtcatttca gaagatgaat atttattaat agatgccaac 70020
tgagatatca ttaaaattga ttactaacta ctacttggaa aagtctccca gttccaaact 70080
tcagcaggcc tcttgacaat tcagctgtgg tcaattgggt cttgcgtgat agatacaatg 70140
accaattgtg cagcagagtg tgctgcttag ctgcctattc tgttagcatt catgtgttaa 70200
cttaaaatca taatctcctt agttttgttg agtgtctccg tggacaagac actgtgaggg 70260
atacaaaatc agattggctt tattcaaacc actggggtat tataattcat ttataattta 70320
ttttattttt tgcctttttt ccatgtgttc taaaggaatt agagtttgta tataactata 70380
atgggggata gaaattgaca tgtgccatga agggaatgca aaaaagtgcc gtgggagatg 70440
agaagtggag aaaggaattt cttttttctt ggaagcagga ataacttcat gaagcatgta 70500
tttcaactta aacagatagt aggcaacgct gtaaggggag tatggctgca gcaaaagtgt 70560
tcggggcaga ctgggaggaa gggagggaat aaattcagcc attgttatgg aataatgatc 70620
aaaatttatt ttcagcccgt ttcacttaaa agttgagact gcttaacttt ttttaatctt 70680
taatcttaaa cttttaaatg ccatttgatc tttaaaaata tatgttttaa tagtgtattt 70740
taagtctcta tatttttgtt attagaatat atagaggcta taacctacta ccaagcataa 70800
cagacgtcac tatggaaaat aacctttcaa gagttattgc agcagtttct catgaactaa 70860
tcacatcaac caccagagca ctcacagtaa gtctctttct tgatcggtct tactgacatt 70920
gtaatagttt ttggtagctt gtatggccag ttagttgtat ggtcatctta cggtgaggtg 70980
cttgtcttac agctcttact tatccatgag gcttgctaag aaattgtgct tctgtgaaaa 71040
gaatctcagc ttactccagg aatgtaaatg actatgtttt ttctgattat taaagtaata 71100
cacgcccaaa ataaaaaaat tcagccaatt taggaagaca caacaattaa aataagccag 71160
gcatggtggc tcatgcctgt aatcccagca ctttgggagg ccaaggttgg gggctcactt 71220
gaggtcagga gtcggatacc agcctggcca acgtggtgaa accccatctc tactaaaaat 71280
acaaaaatta gctgggcgtg gtggcgggcg cctgtaatcc cagctactca ggaggctgag 71340
gcaggagaat cgcttgaacc tgggaggtag aggttgcagt gagctgaggt caagccactg 71400
cactccagcc tgtgcaatag agcgagactc tgtctcaaaa aaaaaaaaaa aaaaagaaaa 71460
gaaaaaagta aactactgtc acctgcattg gtaatgtatc agaagtttaa aatgtctaga 71520
ttataattaa ctcagtgacc tggtaatata tactaaggga aaaatattta taatttacat 71580
ttttacattt ttattttttt aattttatta tttttttttt gagacagagt tttgctcttg 71640
ttgcccaggc tggagtgcaa tggcatgatc tcagctcacc acaacctcca cctcccgggt 71700
tcaagcaatt ctcctgcctc agcctcctga gtagctggga ttacaggcat gcaccaccat 71760
gcccggctaa ttttgtattt ttagtagaga cagggtttct ccatgttggt caggctggtc 71820
tcaaactccc aacctcaggt gatccgccct cctcgacccc ccaaagtgct gggattacag 71880
gtgtgagcca ccatgcctgg ccttacattt ttataataag aatttatgtt gctgacatta 71940
gaaaagaacc ataatatcca agaatccaag aataattaaa ttatgtacat atgctagtat 72000
atagtgtgat gctttggaga atttttaaca atatggagat gtataatctg gattgtaata 72060
ttgagtgaaa aaaggcagaa tacaaacctg gtgggggtat agtcggattt cagttaagaa 72120
aaataatatt tacatatata catttctcac actggcagat aatcaccaag ataaattttg 72180
ggattgtgga tgattttttt cttctttata tttttcagat attctcaaat tttctaaaat 72240
gagcaagtat aacttttgtt atcagaaaaa aataatatac aaaagtaatg ttaatttgct 72300
ggtgaccagg ttaaaccttt ttatttttat tttttgagat ggaatctcac tctgttgccc 72360
aggctagagc acagtggcat gatcttggct cactgcagcc tccgcttcct gggttcaaat 72420
gattctctgg ccccagcctc ctgagtggct ggaattacag gcgtgtggca ccacacctgg 72480
ctaatttttg tatttttagt agaggtaggg tttcaccagg ttggtcaggc tggtctcgaa 72540
ctcctgacct cgtgatccac ccacctcggc ctcccaaagt gctgggatta caggcgtgag 72600
ctactgcgcc cagccagacc tttttatttt atttgacaaa agaaatactt ccatgttata 72660
gaagactaaa tattgtttgg gctgtctgca gtatggtctt cccttgattt gttcaaaata 72720
tcgtaaactt tgcttattta tttttattgt ggccgactgt gtcgggcact gttgtaggct 72780
tgggatggaa aaacaggatt cctgccctta gggtttctgc aggctggtca gggagacgat 72840
gtggtaagct ggagctcagc tcctaaggat gtgcaggggc agttgagagg cggaagggtg 72900
ggagatcatt ccagggtgtg ggcagcacag gaacctctct tcattgggat ataattgcca 72960
ttctgataac acgtgtttga ggtgtctaaa gtaggaagtt gtaccatggt gggacagata 73020
tcctgtggtt atcatacaca gatctcagtt ttcttctcat tgtttgtact ttttataaag 73080
ggtaacagga gatataattc aataaacctt tgtggtgttt gggtgtgatt ttattgtttc 73140
tttcttctca gtttggatgc tgtgaagctt tgtgtcttct ttccactgcc ttcccagttt 73200
gcatttggag tttaggttgg cactgtgggt atgtattttc ctcagtatat attaatagtt 73260
gtctacaaca gtatgacata aacatagtta ttaggatgcc ctttttcttt ctttttaagt 73320
cttttatcaa tttggctttt tggaaaaata tctgatggaa tacttgtttc tgctatatta 73380
gctgtgtgag actagtgaca ggagctgtgg gaaatgaatg ccaaatgttc ttaggcattg 73440
atgggaattt cagggtgtgg tcttcaagtt catttaaggg aattttcata tgctggcaaa 73500
aggcttttct cattagcttg actctttcca aaattatttg ctgtgaatta gaagtttagg 73560
aacctttttt cacttaattg tgacctagca tacgaaatgg tgatgattta ggaactactg 73620
ttcttgtatt aacagctttt atttaaaaat gattttcctc cagtagatgg ccctactagc 73680
atctgggaaa taatttcaag tcttctccag cattcaggaa taggctttca ttttgtgtat 73740
caattactga gaatgatttt ggtgactcac atcacatttg agaagtaaac ctgcagattt 73800
cttgtgtgtg tcagcaaatg accaactgat atttgcttga agtggattac attatctgct 73860
ctagaatgat tgctttccca ccttcctcac atacagactg agcagctacg gtttctaatc 73920
ataggtctgg cactagactt cacttctggg caactttggc attggagtaa aatgtattaa 73980
tttaaagaaa gttaaaaatc cgttcaagta aacatacagt tctaatactt tttacaattt 74040
aaaatataga tttaaatgat aaaataaaaa agaaaatatg ggtagacacc ataatcctcg 74100
tttctgcatc tgttcacaag gggttgatat ttatgagttc tattctccat atccattcta 74160
tgttctctta atgctcagtc agcacctcag gtggttggag ttcaatgctt ggtagtttga 74220
cttacactgt cttttctagg ggattgagcc ctgggtagtc ctgcttattt gaggttgcaa 74280
tttgtctttc aataactttt actacaagat atggcgtgtt aaaggatacc attggggaac 74340
caacataata atatcaggaa aactaaccac gtcagacctg ccccattgtg tatcaagtac 74400
actatttttc catagtaata aagagttcac cccagccaat tctcttttat tttgtgcctg 74460
tttactcaat ggcattaaca tgcccaaatg tctgggtagc tgtctcatct ccagttcagc 74520
agaaccattg tcatatgccc tagtaaaagc attccttcat tggacactta ggccccaata 74580
ctttcattca gatctactac ctgatttcat ttctcaaatg atttttatgg agctctgatt 74640
tataggaaag atgttagttg attaaaaata aaacaatttc tgagctggta taaaatgtat 74700
tgtgacatgc cttcctcttg gaattgcaag agaaaggaag actgttgttt gcttaaaaat 74760
tgtctataat ttgactttgc aaatgtctgc ttccagagtg cctccactga gtgcctcaga 74820
tgagtctagg aagagctgta ccgttgggat ggccacaatg attctgaccc tgctctcgtc 74880
agcttggttc ccattggatc tctcagccca tcaagatgct ttgattttgg ccggaaactt 74940
gcttgcaggt actggtactg agttgaaaca gggactccag gacttggatt ttgatttcct 75000
tagggggaat gggggtggtg agcatatgag gggaaaatac tataaggtca ttgccagtga 75060
tggcttgtcc ctttagtcaa atttcagatg ttacctatat gcataaacac atgcagttgg 75120
cagctgttct gtgctgagta ttttaaagta gcctcttccc aatatagccc ctcagttaac 75180
tacaagtaaa ctcattttga atttcatttt aatgggcacc atatgccagt actccctcgg 75240
gcactgggat gttaagaaag tataatgtat ggacttcatt ctcaagttag ttttagatta 75300
gagggggata cacgtaaaca aaagtgcagt ggtcacacag agtggcccta atcactctcc 75360
ttgggcagat ttatgggctg gtaggaaaga gcacaacacg gagagggtgt agcaccttgg 75420
cgatgataat ggaggatgtg gccagcaagg aagacggagt ccattgaaat tgattttggg 75480
agaagttgcc aatctccatg aaagaattgg ggcctgtgct atttgcttca gggggctata 75540
ggagagtttc gtgaaaggga ctaaaagatg agtattttaa taagatcatt catccaactt 75600
gaacatgggc tggaggagaa ggtagggaga ctcaggagat taatgttgat gctaaggcaa 75660
gataatggct ttgggactgt agggaagaca ctgattgtaa gagaatgaag gaggcagaat 75720
tgccaggcct ggttcaccaa ctgaacttcg gttgtgaaga caaagaaacc tgggatgact 75780
tcacatcctg ggcaggtgtg tggtggtgac agtcatggaa attgggaaca cagatttgtg 75840
cgggaaacat cagtttcagt ttgagtttgg cttatcagtt gaatatcagg cacagatgtc 75900
tggccaactc tcaacatagg gtcttaaatg acttcagttc cccaagcaat ttgtccttcc 75960
catgctattg gggtggagag gtaatgtctg tgcccatatc acagccagtg ctcccaaatc 76020
tctgagaagt tcatgggcct ctgaagaaga agccaaccca gcagccacca agcaagagga 76080
ggtctggcca gccctggggg accgggccct ggtgcccatg gtggagcagc tcttctctca 76140
cctgctgaag gtgattaaca tttgtgccca cgtcctggat gacgtggctc ctggacccgc 76200
aataaaggta atgtcccact tgggtgctgg attcatacag ccttaatgac tatgggtttc 76260
cagactacct ttgtttagta atctgtccct tctttattct ctttttgctt taaatgaaca 76320
aaattgctca gattgtgaca ctaaatttaa catcaaaatg tgaccatgtg gatgggtgca 76380
gtggctcgtg cctgttattc cagcactttg ggagactgag gcaagtggat cacttgaggc 76440
caagagttcg agaccagcct gggcaacatc acgaaacccc ctctctacta aaaatacaaa 76500
aaattagatg ggttgggccg ggcgtggtgg ctcaagcctg taatcccagc actttgggag 76560
gccgaggtgg gcggatcacg aggtcaagag atcaagacca tcctggctaa cacagtgaaa 76620
ccccgtctct actaaaaata caaaaaaatt atctgagcat ggtggcgggc gcctgtagtc 76680
ccagctgctc gggaggctga ggcaggagaa tggcgtgaat ccgggaggcg gagcttgcag 76740
tgagccgaga tcgtgccact gcactccagc ctgggtgaca gagcgagact ccgtctcaaa 76800
aaaaaaatta gatgggcatg gtggtgcgtg cctgtaatcc cagctacttg ggaggctgag 76860
gcaagagagt tgcttgaacc tgggaggcgg agtttgcagt aagccttgat tgtgccgctg 76920
cactccagcc tgggtgacag agtcagactc tttccaaaag aagaaaaaaa tgtgaccatg 76980
tgttttatag ctcttttagt atcatcagtc actgttatcc ctaagaggga aatacctagc 77040
tttagtttta ggtttccagc attagccaag aaagctcaga attgatgttc ctggccaagt 77100
acctcattgc tgtctcctta aatcttggtt aatggctact gtcctggcta gcatagttat 77160
ggagcatttc catggttgta gaatgttctg ccaatctcag ggacagtttt gcttttctgt 77220
gaagcaataa aatcaacttc aaaacaaatg ttaactattt gtacaatgga tttaagatag 77280
accagttcac atactttttt tttttttttt ttttgagatg gagtttcatt cttgttgcct 77340
gggctggagt gcaatggtgt gatctcagct cactgcaact tctgcctcct gggttcaaac 77400
gattcttctg cctcagcctc tcgaggcaga ttacagctgg gattacaggc atgcaccacc 77460
acacccagct aatttttttg tagttttagt agagacgggg tttcaccatg ttggtcaggt 77520
tggtctcaaa ctcctgacct gaagtgatct atccgcttcg gcctcccaaa gtgttgggat 77580
tacgggcatg agccaccacg cccagcctaa gatagaccag ttcacttact gtttatatct 77640
gattactctc tctttgcctt gtcttctacc tttaaaaatc tccctactaa cttcccattc 77700
tcctttagct gccatcagtc ttctcccttc tctgcaaaca tctctggaga gtcccagcct 77760
cagcccacag agcttcccac tgctctgagg tggaccttgt ttgcaaggct tctttggctc 77820
tcttggcctg gaccctgtct actacttcag ccatccttcc ttaacccctg ctggtggttt 77880
ctgttgccac actccatagc agcgtttccc gcccagatca tgtctttaca tctctgggca 77940
ctgctctggt cctgcctgcc tttccctctt tgtatcctgc aggctgctac ccccatcttg 78000
agtgtcctct tcagttggct ttcagagggc ctcctgggtg ttcccttacc cacttgccac 78060
tccccagtca ctgggttcag tccttcctgc ccaccagcac atgctttcta ggctctgtcc 78120
taggccgtct tctctctttg tagtctctgg gccagtgctg ttctagagag tggcagaatt 78180
ttctataacc atggcagtgc tccatagcta tgccaggcaa gacagtagcc actaaacaca 78240
tatagctgtt gagcccttga aatgcagcta gtgtgactga agaactgaac cccgattcgg 78300
tttaattttc attaaattta aatttaaata accttatgtg ggtagtggct ccagtattgg 78360
gcagggcagc ctgagagtcg gggctgttct cctgtcttca gtgtctagat gagggacctc 78420
agaggacctg tctctggagc tgcagttcaa tgtagccagc tgccccgtga cacttacata 78480
tagctgattt gtggatatgt cagacacggt gtgatgagct cagctttctg tcctcctccc 78540
cacatctgcc cctgccccat ttaccccact ttgtgtctta tcaagctaga aacaggtcac 78600
cacaagtctt catttccact caccaagtct tttgtttccc ctactaaata ttttgcgaga 78660
agaaagtgtg tacctttgta ttcacataca tgtacatgca catatacatg cacatatgca 78720
ggggtcccca acctctgtta aaaaccggac tgcaggccgt gcgtggtggc tcacgcctgt 78780
aattccagaa ctttgggagg ccgagaccag tgcatcacaa ggtcaggaga tcgagaccat 78840
tccggctcac acggtgaaac cccgtctcta ctaaaaatac aaaaaaaaat tagccgggtg 78900
tggtggcggg cgcccatagt cccagctacc tgggaggctg atgcaggaga acggcgtgaa 78960
cctgggaggc ggagcttgca gtgagccgag attgtgccat tgcactccag cctgggcgac 79020
agagcgagac tctgtctcaa aaacaaaaca aaacaaaaaa aaaaaaaacc aggctgcaca 79080
ggaagaagtg agcaagcatt accatctgag ctctatctcc tctcaggcca gtggtggcat 79140
tagattctca taggagcgtg tatgagttcg ttctcacact tctgtaaaga catacctgag 79200
acatataaag aaaagaggtt taattggctc acagttctgc aggctgtaca ggcttctgtt 79260
tctgggaagg cctcaggaaa cttgcagtca tggcagaagg tgaaggggaa gtaggcacat 79320
cttcacatgg cccacaggaa aaagagagaa ggagagagag agagagacag agagagagag 79380
agaaaaagaa agattgagag ggagagagga gggagaaagg agagtgcctg tagggggagt 79440
tgctacacaa aggagcacca gggggatggt gctcaaccat tagaaactac ccccatgatc 79500
caatcacctc ccaccaggcc ccacctccga cactggagat tacaattcag catgagattt 79560
gggtggggac acagagccaa accatatcag agcatgaacc ctattgtgaa ctgcacattt 79620
gagggatcta ggttgcatgc tccttatgag aatctaatgc ctgatgatga tttgaggtgg 79680
aacagtttca tcccgaaacc atcccccgcc aaccctggtt tgtggaaaaa ttgtcttcca 79740
cagaaccggt ccctggtgcc aaaaagtttg gggacctctg cacatatgca tgcacctgta 79800
catggacaca taatacatgt acatatgcat actttatatt ctctgccact tctggtccag 79860
actgatatac tatctcattt ggattactgc actagccttt tgttttggaa acagcatttt 79920
ttaaaaaatt taatttaatt tttttgagat agggtgtcat tctgttgccc agcttggagt 79980
gcagtgtcat gatcatagct cactgcggcc tcgatctccc aggctcaagt gatccttctg 80040
cctcagcctt ctcagtagtt gggactacag gcatacccac catgcccagc taattttttg 80100
attttttttt ttttttgaga cagagtctca gcctgtcgcc caggctggag tgggttggcg 80160
cgatctcagc tcactgcaac ttctgcctcc caggttcaag tgattctcct gcctcagcct 80220
cccgagtagt tgggattaca ggcgcctgcc accacaccca gctaactttt tgtattttta 80280
gtagagacgg ggtttcacca tgttggccag gctggtctcg aacttgtgac ctcgtgatta 80340
gcccgcctcg gcctcccaaa gtgctgggat tacaggcgtg agctaccgct cccagccagg 80400
aaacagcatt cttgagataa ttcatataat tcacccattt aaagtatata attcattctc 80460
tttagtatgc ccacagagtt gtacagccat caccagaatc agttttagaa cccataaagg 80520
aactctgtac tctttaccca aaacctccat gcctccagct gcaggcagcc actaacctgc 80580
cttctgtctc tgtgactcta cgtcttctgg acattactgt ggatgggctc atacagtcag 80640
tgagcttgtg actggtgcct tctaccaagc agggttttca gtgtagcagc ctctctgttt 80700
ttcttttttt tttaaattgt gacggaactt ctgcctcccg ggttcaagcg attctcctgc 80760
ctcagcctcc cgagtggctg ggactacagg cccatgtcac catgcctggc taattttttt 80820
tttttttttt tttagtagag atgggtttca acatgttagc cagggtggtc tcgatctcct 80880
gacttcatga tccgcctgcc tcggcctccc aaagtgctgg gattacaggc gtgagccacc 80940
atgcccggct aacctttcat ttactgtctg catttcttcc ctgatgcctt ccagtccatg 81000
cacccgattg tagccattca tcctattatg gtttaaggtg actgtcttag tcagcatggg 81060
ttgccataac aaaataccat agcctgggtg gcttcaacaa cagaatttac ttctcacact 81120
tctggaggtt gggaagtcca agatccagga ctttcgcctt gccctcatgt ggtgaggggg 81180
tgaggaagct ctgtggggcc tcttatatat ggatgctaat ctcattcatg aggggtctgc 81240
cctcatgacc cagtcacctc ccaaaggccc cacctcctaa taccatcacc ctggtaatta 81300
agtttcagtg tataaatttg ggggactata gacattgaaa ccataacaag cacttttcta 81360
agatcaggga gtgagtaagt agcagagcta ggacctcaat tccacatgtc agtcatcttg 81420
ccttcactct gctccatgat ggctgcctcc tagagcattg ggagtctcga tgttctatat 81480
gctctcatgt gttgtgtatt ggagatagtt gaggctttat gaatacatct ggatttgttg 81540
acttctagct ttgctggtaa ccagctgtga ccttgaataa gttacttcat ctctgagcct 81600
gtttcctctt ttagaaacag gagtttaaaa tgctgctttg ggttgggcac ggtggctcat 81660
gcctgtaatt ccagcacttt gggaggctga gatgggagga tcactggagc ttggagttcg 81720
agaccagcct gggcatcata gtgtgagatc ctgtctcctc aagaaattaa aaaattagct 81780
gggtgatgtg gcgtgtgcct gtggtcccat ctactctgga ggctgaggtg ggaggattgc 81840
ttgagcccag gaggttgagg ctacaatgaa atatgattgc accccatcct gggtgacgag 81900
tgagaccctg tctcaaaaaa gaaaaaaaaa atgctgcttt gtaccccttt catgtcatgg 81960
cgtcatggcc aacatagaat gccctggttg tttgctgttg gagggcatgg gcctgggggc 82020
tccctgaggg ctccttccat cttcaactca ttctctgtgc acctgttagg aagttgtggg 82080
ccagtcccta ccatgtatca ttgtgtgggt aaaagtaaat aaaatgtgta cagtgtctga 82140
actgtacata tcagggtcca agaacaaaat gagtgacatg ggttagctct ttttaataaa 82200
tggtaaaacc aaatattcta attttcagtt ttgttatact tccatcacat gtttttgttt 82260
ttttgttttt tgtttttgtt tttctatttt aggcagcctt gccttctcta acaaaccccc 82320
cttctctaag tcccatccga cgaaagggga aggagaaaga accaggagaa caagcatctg 82380
taccgttgag tcccaagaaa ggcagtgagg ccagtgcagg taggaaacag cgtggggaag 82440
ggagggacat gagtgcagca tctgtcatgt agaaacatag gatttaagta acttggtgtt 82500
ttagagaaat aaatataata cacatcagta aagtgagaga aagtttctcc aggtgcggtt 82560
caagatatta gaaactaatg actgatgtac acagaccacc ttttggtctg aagcatttct 82620
aagtgccact ggctgacatg cagcccctac agcctccagg cttccagccc tagcatggag 82680
catcactctc ctatgcttcc ctggttgcag gtgatggctg gagaggcctc ctgattttca 82740
gtaagggaag tggtgtagat gcttaggaat agatgtagtg agtgaaaaaa ctgattctga 82800
tatgtcaaaa attctgattg gaaatggaat atttacattt ggaagagcta aaggcgagag 82860
aaagtgggga taaagtcatc tgagttggag gagcttaaac cattcacaag tttggaggac 82920
ctttttttac ccatgaaaag gtcagaacag aaggggctag gatttaggtg tgactgcagt 82980
ttattgaatt cccatccata ctgctctcgg tgggcagtgg caggggcagg agaggagcct 83040
ggcaaagcat gaagtgactg ctgctgcctc tgctatctgg gacgcctggc cacctgtctg 83100
tacagtctcc ctccagaccc attctcacgc tgtctcttgg cacccagggg ccagtgatgg 83160
ttctcccatt tgttttgtgt atatagcatt tatatcaagg ctatttattt atttatttat 83220
tttatttatt tatttttttg agacagagtc tcactctgtc acccaggctg gagtgcagtg 83280
gtgcaatctc ggctcagtgc aagctctgcc tcctgggttc aagcaattct cctgcctcag 83340
cctcctgagt agctgggact acaggtgtgc accaccacac ctggctaatt ttttgtattt 83400
tttattagtg gagacggggt ttcaccttgt tggccaggat ggtcttgatc tcctgacctc 83460
gtgatccgtc cacctcagcc tctcaaagtg ctgggattac aggcatgagt cactgtaccc 83520
ggcctattta tttattttta attgacaaaa ttgtatatat ctgtaatata caacatgatg 83580
tttgaaatat gtgtacattg gccaggcgtg gtggctcaca cctgtaatcc cagcactttg 83640
ggaggctgag gtgggcggat cacgaggtcg ggagttcaag accaaactgg ccagcatggt 83700
gaaatcctgt ctctactaaa aataccacaa aaaaaaaaaa aaaaaaaaaa agccgggcat 83760
ggtggctcgc gccagtcgtc ccagctactt gggaggctga ggcaggagaa ttgcttgaat 83820
ctggcaggtg gaggttgcag tgagctgagt tcatgccact gcactctagc ctgggcgata 83880
gagcgagact ccgtctcaaa aaaaaaaaaa aaagaagaaa tacatatgca ttgtggaatg 83940
gctaattaac ctgtgcatca cctcacgtat cattgttttg tggtgagaac acttaaaatc 84000
tactctttca gtgattttct tgcatatggt acattgctat taactgcagt caccatgcta 84060
tacagtagat ctcttgaact cattcctcct gtctataaat gaaattttgt atccttgacc 84120
aacacattca aggttttttt tgagatggag tcttcttcac ccaggctgga gtaccatggc 84180
acgatctcat ctcactgcaa cctccgcctc ccaggttcaa gcaattctcc tgcctcagcc 84240
tcctgagtag ctgggattac aggcacatgc tactgcacct ggctaatttt tgtattttta 84300
gtagaagtgg agtttcacca tgttggccag gctggtctcg aactcctgac ctcaagtgat 84360
ccgcctgcct tggcctgcca aagtgctggg attacaggtg tgagccactg cacccggcct 84420
caagcgtttt aaaagatgct cttttctaag gattgactgt agtacaggag gaagattgac 84480
ctgttgaaaa gcctcagcct ttacaagtgt aaaattatca gtatattact atcatctttc 84540
tgatgaatta aataaactaa ggactccaag tcaaaagtct tcaaactgaa gtagaatagt 84600
tgtatatagt gcttggcact ttaatattta gtatcggttt aatgataatg tttgtgcctt 84660
tgccgtcttt aaaacatttt tacatcatcc ctgtttgatt acttggtgtg ctcatgaagt 84720
tgttggccac taaggaatct taggctcaga gaggttctgg aattggccag tggtccttga 84780
atcagctgct cctatgattc tctaactgat ttctcacaaa gcaaacaagc aatcataaca 84840
aaacaactgt gcacactgct cttcttattt tgttatttaa aaagtactta ggctctactt 84900
atgtttgtta gtcaatttct cattacttct agttaatcaa aaggtcagag gaaatacttg 84960
aatattttca tactagaata ctttaaaaaa tcatgatttc cagtaatctc tttaaaactt 85020
ggcaagttat tttgatctaa aagtttatct tttgtgtgca tatttttaaa gcttctagac 85080
aatctgatac ctcaggtcct gttacaacaa gtaaatcctc atcactgggg agtttctatc 85140
atcttccttc atacctcaaa ctgcatgatg tcctgaaagc tacacacgct aactacaagg 85200
tatgggcctc tgcatctttt aaaaatatat atgcacacat acttacgtct aatggatagt 85260
tgatgttttt cttatgattt gtaggatgta taagcccttt gagatatgag ttacatttag 85320
ttttttcaag tttgtttgtc tttcagcttt gtttatgata gcttctatca tacaggtgtt 85380
ttggattttc atattgtttg tactcacagc taagattgat tacagtgaca gagctaggat 85440
gtgcagccag gttatagggg gaagtggccc tggtggagtc tggagggatc cgtgtacagg 85500
cttccttccc tcccgtgagg ctcacacaaa aatacagcaa catgctggtc ctgcaggtac 85560
cctctgccta acatgagcca caattccaga ctcacagaag aaaagcaggt gttcggcata 85620
aaccatgtgt ttcaaatagt ctgggcatgg tgagccactt gttatcagct agggaaagtt 85680
tatgtcagcg taagaaactg ttcaccagat acccccaaga gccagccttt ctgtctaggg 85740
atgttttagt tttttagttc attttttttt ttaactttaa aattttctgt tcatctgcaa 85800
tttgttagat atgaagtatg tgtctaattt aatttttgtt tttggttgtc cccaataatg 85860
tttacagaag aatttttctg cactaattgg cttgagttac ttacattctc atagttctct 85920
agtttcagta gtttcattta ttattttgtt atatcaatct atctgtctgc tcatctatta 85980
gaagcatcct tgtttttttt ttttcttttt tagacagagt cttgctctgt ccccaggttg 86040
gagtgcagtg gtgcaaccat gcctccctgc agtctcaggg ctcaagtgat cctcccacct 86100
cagctcctga gtacctggga ctaccggcat gtgccaccac acccagctaa tttttacatt 86160
ttttgtagag acagggtctc cctaagttgc ctgggctggt ctcaagctcc tggcttaagt 86220
aatcctccct ccttggcctc ccaaagtgct gggattacag gtgtgagcaa ctgcacccgg 86280
ctacaagtat acttcttaat tattgtagct taatggtatt tatgagggga tcagttcccc 86340
tgttgttctt tagaattttc tggatattct tctttattga ttttgggatg tgaacaatag 86400
aatcaacttc tacttgtaga ttgatttagg gagaacttat acctcagatg ttaagtcacc 86460
ctgtccagaa tgtgggatgc tttcctattt gttcagaact ttttaaatta cctcagaagc 86520
acatgaaatt taaaggattt taaaaaaaac ttaaagatta tttcacatag ctcttgcaca 86580
tttcttgata aatgaatcct caggtattcc tctgtttttg ttactaatag ttacttctta 86640
tgggtttttt ttcccctgaa aatcatttat caaacgtatg tggcttattt tctgaaggat 86700
gtttgataat tttggaagat atgaaagtct tcatatttta caaggtttga ggtctcttta 86760
agctgcatgg ttctcatgtc agctcccaaa gcagaagacg gcatgttgaa aaatgccgta 86820
gagaagatac ttcttttcca cctgttttca actcatatca tcttgaattt cagggcacct 86880
ttccatgctc ctagtgcttg ctatctgttt attattttcc ttcctgaata ccctgaactc 86940
cagcatgttc tgctgtaatt ctggcctccc tggcatcttg gactcctgtt tcctttgctc 87000
tgtcatcccc gcggtcagct cctgctgcgc agcttctcag ctgaagtgcg tttggagtgc 87060
ctggcgtgtc ttgctggatc tttgagtatt gcctctggtt tccttggttc cttctgctga 87120
gttgctcagc gtctccactc cccatttctt gtgtggccct tcctgcactc ctctgattcc 87180
ttttgtcttc cctggtttct tgctttggtt tcgagtctcc acagaacttt tgcagctctt 87240
ctgaagacct ggaagctttt tcatcttaat tctcatctca tgacctcttt tcccttcttt 87300
gagagctaga acttcccatg gtgaacttct ctttccagaa ttccatgcct tcttttccct 87360
cccacttacc tgttgtccag gagaggtcag attgctgtgc atattggagg agaacccttt 87420
cttccctggg ctcttcatct cacatgacat caccacatca cctcgttcct tggaccctca 87480
gtggtgtcac tgctggattt ttctttcctt tggctggcct tagggcacac ccaggttgac 87540
tagcgtagtc atggtattta gatccactca cattttcagt ttctgtgtct gtctcttgcc 87600
tgcttctgac ttcgcccaga gaaagcttct ctttcacaag ggttcttaga tttatgttca 87660
ctgagcacct tcttttctga ggcagtgttt taccaatatt tattttccta gtcagtctcg 87720
ccttaccttt cttgttatgc atgtctttgg tcctgaccca ttctctgagt ctgtaaaata 87780
gaattgctgt ataatttaat tacatgaaat cctttagaat cttaacacat cttacacctg 87840
atttaatatt ttattgtatc caaattgaac caaccctatg tgaatttgac agtgatttct 87900
cccagggatc ctagtgtata aggaatagga cttagtattt tctatttttt gatataccac 87960
ataccagata ctgattatga tggacattta accctttttt ctcattatga aagaaagtta 88020
ggaattattt cttccagtag cgccagtgta acctgaaagc ctttgaaaga gtagtttttg 88080
tatagctatc tgaaaggaat ttctttccaa aatatttttc cagtgctgac aacaaacacg 88140
cagacacacc ctgcaaggtg agtgtacggc gccgcacagt ggaggcatct gctgcagccg 88200
tcgatgtttg tgtctttggt tgtacattat gagatcgtga cagggccagt aaccgtgtgt 88260
tctctccttc accttcccaa ggtcacgctg gatcttcaga acagcacgga aaagtttgga 88320
gggtttctcc gctcagcctt ggatgttctt tctcagatac tagagctggc cacactgcag 88380
gacattggga aggtttgtgt cttgtttttt ctccttgggt tgtggctggc acacttgatg 88440
tgcgtcttct gggctgagtt catctaggat ggagcctggt tctccagggt gcctccggga 88500
gactcctccc tgccccacgt gcttgcgtca caggacccaa gtctgactct gccttagcca 88560
tgaagtttag ggggaagttt ctatttgtat tctatttttg tctgttatca tgtattagct 88620
tagacccagt ttagtttgga aaatcagtgg gtttcaaaat gtgtttgtag agtcctttat 88680
ttcttaactt gaccttttca agtggaaagg ggcaaaacag acgggtaagg gggcggggcg 88740
ggaggtgtga cttgctcttt tgtgcctgag gaagtaacag agctggggtt gacagtcata 88800
ttctctgaca cagatagtct ctgacttatc tcacagaaag tcagcggcag agcctgagtt 88860
aaaagtctcg tagattttct ttttcttttt tttggtggct aatttcagtt ttatttatat 88920
ttgtttattt atttattata ctttaagttc tgggttacat gtgcagaatg tgcagttttg 88980
ttacataggt atacacgtgc catgatggtt tgctgcaccc atcaacccat cacctacatt 89040
aggtatttct cctaatgtta tccctccccc agtcccctca ctccccatgg gccccggtgt 89100
gtgatgttct cctccctgtg cccatgtgtt ctcattgttc aatttccact tgtgagtgag 89160
aacatgcggt gtttggtttt ctgatcttgt gatagtttgc tgagaatgat ggtttccagc 89220
atcatccatg tgcctgcaaa ggacatgaac tcatcctttt ttatggctgt atagtattcc 89280
atggtgtata tgtgccacat tttcttaatc cagtctatca ttgatggaca ttcgggttgg 89340
ttccaagtct ttgctattgt gactagtgcc acaataaaca tacatgtgca tgtgtcttta 89400
tcgtagaatg atttataatc ctttgggtat atgcccagta atgggattgc tgggtcaaat 89460
ggtatttcta gttctagacc tttgaggaat cgccagactg tcttccacaa tagttgaact 89520
aatttacact cccaccaaca gtgtaaaagt gttcctattt ttccacaacc tctccagcat 89580
ctgttgtttc gtgacttttt aacgatcgcc atcctaactg gcgtgagatg gtatctcatt 89640
gtgattttga tctgcatttc tctaatgacc agtggtgatg agcatttttt cgtatgtctg 89700
ttggctgcat aaatgtcttc ttttgcgaag tgtctgttca tatcctttgt ccattttttg 89760
atggggttgt ttgctttttt ttcgtaaatt tgtttaagtt ctttgtagat tctggatgtt 89820
aatcttttgt cagatgggta gattgcaaaa attttatccc attctgtagg ttgcctgttc 89880
actctgatga tagtttcttt tgctatgcag aagctcttta gtttaattag atcccgtttg 89940
tcaattttgg cttttgttgc cattgctttt ggtgttttag acatgaagtc tttgcctatg 90000
cctatgtcct gaatgttatg gcccaggttt tcttctagga tttttatggt cctaggtctt 90060
atgtttaagt ctttgatcca tcttgagttg atttttgtgt aaggtataag gaaggggtcc 90120
agtttcagtt ttctgcatgt ggctagccag ttttcccaac accatttatt aaatagggaa 90180
tcttttcccc attgcttatg tgtgtcaggt ttgtcaaaga tcagatgatt gtagatgtgt 90240
ggtggtattt ctgaggcctc tgttctgttc cattggtcta tatatctgtt ttggtaccag 90300
taccatgcag ttttggttac tgtagtgttg tagtatagtt tgaagtcagg tagtgtgatg 90360
cctccagctt tgttcttcta gcccaggatt gtcttggcta tgcaggctct tttttggttc 90420
catatgaagt ttaaaatagt tttttccaat tctgtgaaga aagtcagtga tagcttgatg 90480
gggggatagc attgaatcta taaattactt tgggcagcaa ggccattttc acgatattga 90540
ttcgtcctat ccatgaacat ggaatgtttt tctatttgtt tgtgtcctct cttatttcct 90600
tgagcagtgg tttgtagttc tccttgaaga ggtccttcac atcccttgta agttgtcttc 90660
ctaggtgttt cattccctta gtagcatttg tgaatgggag ttcactcatg atttggctct 90720
ctgtttgtct gttattggtg tataggaatg cttgtgattt ttgcacattg attttgtatc 90780
ctgagacttt gctgaagttg ctaatcagct taaggagatt ttgagctgaa ccaatagggt 90840
tttctaaata tacaatcatg tcatctgcaa acagggacag ttttacttcc tctcttccta 90900
tttgaatacc ctttattgct ttctcttgcc tgattgcgct ggccagaact tccaatacta 90960
tgttgaatag gagtggtgag agagggcatc cttgtcttgt gccggttttc gaagggaatg 91020
cttccagttt ttgcccattc agtatgatat tagctgtggg tttgtcataa atagctctta 91080
ctatgttgag atacgttcca tcgataccta gtttattgag agtttttagc atgaaaggct 91140
gttgaatttt gtcaaaggcc ttttctgcat ctgttgagat aatcatatgg tttttgttgt 91200
tggttctgtt tatgtgatgg attacgttta ttgatttgcg tatgttgaac cagccttgca 91260
ttccagggat gaagctgact tgattgtggt ggataagctt tttgatgtgc tgctggattc 91320
agtttgccag tattttattg aggattttca catcgatgtt catcagggat attggcctaa 91380
aattctcttt ttttgttgtg tctctgccag gctttggtat caggatgatg ctggcctcat 91440
aaaatgagtt agggaggatt ctctcttttt ctattgattg gaatagtttc agaaggaatg 91500
gtaccatctc ctctttgtac ctctggtaga attcggctgt gaatccatcc tggacttttt 91560
ttggttagta ggctattaac tattgcctca agtttagaac ctgttatcag tctattcaga 91620
gattcagctt ttttctggtt tagtcttggg agggtgtatg tgtccaggaa tttatccatt 91680
tcttctagat tttctagttt atttgggtag agatgtttat agtattctct gatggtagtt 91740
tgtatttctg tgggatcggt ggtgatatcc cctttatcgt ttttattgag tctatttgat 91800
tcttctctct tttcttcttt attagtcttg ctagcggtct acctatttta ttgatctttt 91860
caaaaaacca gcacctggat tcattgattt tttttggagg gttttttttc gtgtctctat 91920
ctccttcagt tctgctctga tcttagttat tttttgtctt ctgctagctt ttgaatttgt 91980
ttgctcttgc ttttctagtt cttttaattg tgatgttagg gtgttaattt tagatctttt 92040
ctgctttctc ttgtgggcat ttagtgctat aaatttccct ctacacactg ctttaaatgt 92100
gtcccagaga ttctggtatg ttgtgtcttc gttctcattg gtttccaaga aaatttttat 92160
ttctgccttc atttcgttat ttacccagta gtcattcaag agcaggttgt tcagtttcca 92220
tgtagttgtg tggttttgag tgagattctc aatcctgagt tctaatttga ttgcactgtg 92280
gtctgacaga cagtttgttg tgatttctgt tcttttacat ttgctgagga gtgttttact 92340
tccaactatg tggtcagttt tagaataagt gcaatgtggt gctgagaaga atgtatgttc 92400
tgttgatttg gggtgcagag ttctgtagat gtctattagg tccgcttggt ccagtgctga 92460
gttcaagtcc tggatatcct tgttaatttt ctggctcatt gatctgccta atattgacag 92520
tggggtgtta aagtctccca ctattaccgg gtgggagtct ctttgtaggt ctctaagaac 92580
ttgcttcatg aatctgggtg ctcctgtatt gggggcgtgt atatttagga tagttagctc 92640
ttcttgttga attgatccct ttaccattat gtaatggcct tctttgtctc ctttgaactt 92700
tgttgattta aagtctgttt tatcagagac taggattgca atccctgctt tttttttgct 92760
ttccatttgc ttgttagatc ttcctccatc cctttatttt gagccaatga gtgtctttgc 92820
atgtgagatg ggtctcctga atacagcaca ccaatgggtc ttgactcttt atccaatttg 92880
ccagtctgtg tcttttaatt ggggcattta gcccatttac atttaaggtt aatattgcta 92940
tgtgtgaatt tgatcctgtc attatgatcc tagttggtta ttttgcccgt taactgatgc 93000
agtttcttca tagcgtcagt agtctttaca atttggcatg tttttgcagt ggctggtact 93060
ggttgttcct ttccatgttt agtgcttcct tcaggagctc ttgtaaggca ggcctggtgg 93120
tgacaaaatc tctgcatttg cttgtctgta aaggatttta tttctcgttc acttatgaag 93180
cttagtttgg ctggatatga aattctgggt tgaaaatact ttttttaaag aatgttgaat 93240
attggctccc actcttttct ggcttgtagg atttctgcag agagatctgc tgttagtctg 93300
atgggcttcc ctttgtgggt aacccgacct ttctctctgg ctgccctttc cttcatttca 93360
atcttggtgg atctgatgat tatgtgtctt ggggttgctc ttctcgagga gtatctttgt 93420
ggtgttctct gtatttcctg aatttgaatg ttggtctgcc ttgctaggtt ggggaagttc 93480
tcctggataa tatcctgaag agtgttttct aacttggttc tattctcccc atcactttca 93540
ggtacaccaa tcaaacgtag atttggtctt ttcacatagt cccatatttc ttggaggctt 93600
ggttcatttc ttttcactct tttttctcta atcttgtctt ctcgctttat ttcattaatt 93660
tgatcttcaa tcactgatat cctttcttct gcttgattga atcggctgtc gaagcttgtg 93720
tatacttcac aaaattctcg ttctgtggtt tttagctcca tcaggtcatt taagctcttc 93780
tctacactgg ttattctagc cattagtcta acattttttt caaggttttt agcttccttg 93840
tgatgggtta gaacatgctc ctttagctcg gagaagtttg ttattaccga ccttctgaag 93900
cctacttctg tcaattcatc aaactcattc tccatccagt tttgttccct tgctggtgag 93960
gagttgtgat cctttggagg agaagaggtg ttctggtttt tggaattttc agcctttctg 94020
ctatggtttc tccccatcat tgtggtttta tctacctttg gtctttgatg ttggtgacct 94080
acggatgggg ttttggtgtg ggtgtccttt ttgttgatgt tgatgctatt cctttctgtt 94140
tgttagtttt ccttctaaca gacaggcccc tcagctgcag gtctgttgga gtttgctgga 94200
ggtccactcc aggccctgtt tgcctgggca tcaccagcag aggctgcaga acagcaaata 94260
ttgctgcctg atccttcctc tggaaacatc gtcccagagc acgaaggtgt ctgcctgtat 94320
gaggtgtttg ttggccccta ctgggaggtg tctcccagtc aggctacatg ggggtcaggg 94380
acccacttga ggcagtctgt tcattatcgg agcttgaatg ccgtaccggg agaaccactg 94440
ctctcttcag agctgtcagg cacgtatgtt taaatctgga gaagctgtct gctgcctttt 94500
gttcagatgt gcccttcccc cagaggtgga atctagagag gcagtaggcc ttgctgagct 94560
gcagtgggct ctgcccagtt cgagcttccc tgctgctttg tttacactgt gagcatagaa 94620
ccacctactc tagcctcagc agtggtggac acccctcccc cagccaagct cctgcatccc 94680
aggtcgattt cagagtgctg cgctagcagt gagcaaggcc ccatgggcgt gggacccgct 94740
gagccaggca caggagagaa tctcctggtc tgctggttgt gaagactgtg ggaaaagtgc 94800
agtatttggg caggagtgta ctgctccttc aggtacagtc actcatggct tcctttggct 94860
tggaaaggga agtcccccga ccccttgtgc ttcccaggtg aggcaacacc ccgccctgct 94920
tcggcttgcc ctccgtgggc tgcacccact gtccagcaag tcccagtgag atgaactagg 94980
tacctcagtt ggaaatgcag aaatcacctg tcttctgtgt cgatctcact gggagctgta 95040
gactggagct gttcctattc ggccattttg gaagcatccc ttgttttttg aggtggagtc 95100
ttgctctgtc gcccaggctg acgtgcatcg gcacaatctc ggcccactgc aacctttgcc 95160
tcctggtttc aagcgattct cctacctcag cctccggagt agctgggatt acaggcacct 95220
gccaccatgc ctggctaatt ttttgtattt ttagtggaga tggggtttca ccacattggc 95280
caggctagtc tcgaactcct gaccttgtga tccacccacc tcagcctcct agagtgctgg 95340
gatcacaggt gtcagccacc acgcccagcc atattttcag atctccctct ctttgcccta 95400
aaccactgtg cttaataagt agtttttagt ggccagcagt ctccatgtat aacacatttt 95460
agcaaaatgg aaaatactat atgttttaaa tttgaacgtg agattatact gaaataaaaa 95520
tcatctaact gggattcttt aaatagtaag attttctttt ttgtatgtgg gttttttttt 95580
aaccttatta ttatgactgt catatataga aatggctgtt tttcagttac agtcagtgaa 95640
tgtatcaaat gctgccttat ccaaataata aaagtaaatt attaataagt cacaatttaa 95700
tgaagattga tgttagttga tctttatatt cttgaaatca gccatatggt tgtgtgtgta 95760
tgtatatatt tttaaaggta cataaagata ataagctcat ctctgaaaat ttttacattt 95820
ggcataagaa taactggata attaagcatc ttattctctg gcctgtgtct ttacagttaa 95880
aggtagattt actcacctct ccttttttgt ttttctaagt tcatcttttt tgctgtttca 95940
agacagaggc ccattttagc tttctcgcat atccttttgt ttgtactttg gaagcctcac 96000
ctgcttaatt gttgagtttt tatccgtggt cttttagagg gggatatgta gggtagaagc 96060
tttcacaggt tcttgtttgc acttggcccc tgactgtttt gaggaatctc cctcactgac 96120
tcacagcatg gcaaggtttc agatctcttt ctgccacaca gcagttctga ggcagctgga 96180
aagatatcca gatgcttaga ttgtcaggcc aggcttgaga tatacaaact attgagcctt 96240
atctgtgacc ttgcttaggt gaaggcatca gagcccctgc accaacatgc ataggcctct 96300
gcatgtgtgc ggggctgggt gttgaggtct gagcacaagt gtagctggag aggtgagctt 96360
gatgtggcga cgggtatgag caggttttct tcagacttct gtgagtttac ctagttccag 96420
gatttaaagg cacagagact ttagaattaa aatagaatca ttttcttttt ctaaatagca 96480
acactaggaa taaaaaataa taattccaca ttcttgacag gtaatgtttt ttcttgtctt 96540
ctaatcctta tttattccat actcattttt atacataatt gaaatgtatt atgcattgga 96600
tttttctttt gcattatatt atagacgatt tttcatgtaa ctccttactg ttccatttta 96660
tatgttttgt ctggtttaag actttatctg caaaccggga aactgtctct acaaaaagaa 96720
aaacaaaaat agttggccgc agtggcatgc gtctgtggtc ccagctactc ggggctgagg 96780
tgggaggatt gcttgagcct tgggaggttg aggctgcaaa gagccatgat catgccattg 96840
cactccagca tgggtgacag actttatact gtctgttttg ggtgatttga taatgatatg 96900
ccctgatgta gtttttttat atcttgtgtt tcttgtgcct gggtttattg aggttgggtc 96960
tgtggcttca tagtattttt aaagtttgga aaattttagg ccattctttc tttctttctt 97020
tctttttttt ttttttgaga cagtgtctcg ctctgtcgcc tgcgttggag tgcagtgaca 97080
ctatcttggc tcactgcaag ctctgcctcc tgggttcacg ccattctcct gcctcagcct 97140
cctgagtagc tgggactaca ggcgcctgcc accacgcctg gctaattttt tgtattttta 97200
gtagagacga ggtttcactg tgttagccag gatggtctca atctcctgac ctcgtgatct 97260
gcccgcctgg gcctcccaaa gtgctgggat tacaggcgtg agccactgca cccagctagg 97320
ccattatttc ttcaaagatt ttttttctgc cctgcctccc tccttttttc cctctcttaa 97380
aggggctgtg atttcctgaa tgattgctta gtgttgtccc atagcttact gatgctcttt 97440
tcagtgtttg attgttttat gtgttttctg ttttgtatag tttctattat tgtgttttca 97500
agttctctga tcttttcttc tacagtgtct actctgttgt taatctgtta atctgttgtt 97560
aatcctgtcc agcgtatttt tttttttgtt tttgaaacag tctcactctg ttgcccaggc 97620
tggagtttag tggtgcgata tcagctcact gcaacctcca cctcccaggc tcaagcaatt 97680
cttctgcctc agcctcccga gtagctggga ctataggcac gtgccaccac acctggctaa 97740
tttgtgtatt tttattagag atggggtttc accatgttgg ccaaactggc cttgaactcc 97800
tgacctcagg tgattcatcc gcctcggtct cccaaagtgt tgggattata ggcatgagcc 97860
accgtgtctg gcccctgttc agtgtatatc actaattttg tttttatctc tagaagtttg 97920
atttaggtct tttaaaaatg tctccctgtg tttctgttta gctttgtgaa cacaattgta 97980
ataactgttt taatatcctt ctctgctagt tctaagatct tctaataact tcccagttct 98040
tggtgtttct cattggttga ttgatactcc tcgttttggg ttgtattttc ctgcctcttt 98100
gtatggctgc caatttttta ttggatgccc aaccttgtga attttacttt gttggatgct 98160
atatattttt gtgttcccat agatcttctt gagctttgtt ctgaggttag ttgagttaca 98220
tatagatggt ttactctttt gggtcttgct ttataatttg tcagatgggt tggagcagtg 98280
cttagtttag gactaatttt ttttttggac taattattcc tctttaggaa taattaggta 98340
ccatgcttag gaggcaagac catcctgagt actctaccta atgaaccaga aagtttgggt 98400
tttccagtcc gcctgctgag aacagtgact ttctagccct gtgtgagcgc tgagctctgc 98460
tccttctaat cctttccaat gcttctttcc ctggcctcag ggagttttct cacacacata 98520
tctctgctga gtactcgaga gggaccttcc ccagatctcc agagctctct ctgtcttgtt 98580
ttctcttctc tggtgctctg tcttatgaac tgtggctgtc ttggtctcct tagattctca 98640
gcacctcttc aattcagagg gttgcctgtc cctcctcctt gtgccacagc ctaggaactc 98700
tctcaaagca gcgagttggg gcagccatag ggctgactta gtctctcgtc tcccagggat 98760
cactgtcctt cattgctcat gtccagtgtc ttgaggactc tgggttttgt ctgttttgtt 98820
ttttggtttg ctttggttgt ctcaggcagg agggtaaacc cagtccctca ccctcattgt 98880
gctcagtagt ggaagtctca ctctattaca ttagatatta gtatttgtag cagagccctg 98940
gttccctggt acttggggag ctcttgaaag gccagaaaca gcatgctttc tcaccttttc 99000
cagggcttca gtttctggtg cacatcaagc attccataca catttgttaa agtcctttgt 99060
tagacaagta gtgattcaca ggttctattt gtaatttttt cagttaacat gtattgggta 99120
tctgctggga gctagtaaaa acaaaaagtg gtgtgtgaca aattcaattc tgacaagaac 99180
aaccttaaac acttagaata tactttgagc atatcagaat tttaaaaatg tgtggccctt 99240
gagtatttga aaccaacaag aatctattgc ttattagtag aggatatttt gttaaacaag 99300
tggagagaga ggcattttca gtctaattgg tgttggcttt tagcagctga tggaaaccag 99360
ttcgtgatta gccaggcagt ggtgaaacag gctgtgcatt ctgaatgcct aggtatctag 99420
gcattcagaa tggtggcgct ctttgagtta gcatcttctt ctttcttgat tctttttttt 99480
ttttttttga gatggacttt cgctcttgtt gcccaggtaa caactccagt gcaatggcgc 99540
catctcggct cactgtaacc tctgcctccc tggttcaagc gattctcctg cctcagcctc 99600
tcaagtagct gggattacag gtgtgcgcca ccacgcctgg ctaattttgt atttttggta 99660
gagatggggt ttcactatat tggtcaggct ggtcttgaac tcctgacctc aagtgatgca 99720
cctgcctcga tctcccaaaa tgctgggatt acaggcgtga gccaccactc ccagcccctt 99780
cttgattctt gaaaaggaca ttgggtgctg tacatctcgt tatagatgtt gataaaaatg 99840
cttgtgagaa gagtaacatt aaggtagtta tttggtcatt tttgcagatt attttaagac 99900
aattctagga ctgatttgtg gtaaatcaca cattgctgta tcatagttgt gttcactgaa 99960
catattcagg ggctctacag atgcagggct cttagctgct ttgcacactt ctgaattcct 100020
gccctgcgaa caggactgga tacctaatag acaacaggta cttgataaca gtttattgaa 100080
ttaatgagtg aatgaacaga tacataaatg catgaaagaa tggttgtaat gtatataact 100140
tggatttcaa gactttttac tgactgttca aaataagaaa ttgaaaactt tcctctgatt 100200
ttcctctact atttacacaa tttaaatgga agttatcttg taccttcaat ttctgtctag 100260
gattcgtaca ataacgggtc atctctgagt cgcttaatgt ctcacttgtc tttctacagt 100320
gtgttgaaga gatcctagga tacctgaaat cctgctttag tcgagaacca atgatggcaa 100380
ctgtttgtgt tcaacaagta agagcttcat tcttttcctc ttctgttaag acgttcgggt 100440
atgacagcaa aacgctgcta ctccttaaga ggcaggcgct gttggcataa tcagctggga 100500
ggattgtggg gtccagcgca gcactttttg gctcagtcca tgattgagcc aagaggccat 100560
ccttcccttc actccccagg aggacgaggt ctgtcactgt ggagggcaga ggacaccaga 100620
agctcctctg caacctcgct agttaacttc cagtccctcg gagtttctgt ttagaatgct 100680
caatctcatt tagaattgca aggaaaccca aaacgcctat ttaaggtaca aacagcactt 100740
catacaatat ctcatgaggt attaatagtg attcacagga agaatttcac gctgtgagtc 100800
tttgctaaca tatccagtta tttacagatg gatttgatat ttgtgtggga gattcttaaa 100860
agtgttgttc acgccacatt gttgatgcct catttttttc actgtagttg ttgaagactc 100920
tctttggcac aaacttggcc tcccagtttg atggcttatc ttccaacccc agcaagtcac 100980
aaggccgagc acagcgcctt ggctcctcca gtgtgaggcc aggcttgtac cactactgct 101040
tcatggcccc gtacacccac ttcacccagg ccctcgctga cgccagcctg aggaacatgg 101100
tgcaggcgga gcaggagaac gacacctcgg ggtaacagtt gtggcaagaa tgctgtcgtt 101160
ggtggaagca cgaaagagca agcaggaaat actttgtaaa agaataaaaa cgaaaaatgt 101220
tagcgaacat cttctaatag tctgctgtat tcagagaact ctaggagata tatatggttg 101280
atgcaaagat gatttaaggc atagcccggc cttccaagaa gtgtgtggcc agtgagtgag 101340
atgggcttgg gacttacaca tctcagaggt gggggtagag gaggaggaac actgagtggg 101400
ctgagaagca gccagctctc attgccaaag tgtgtcagca aaccagaatg cagttcataa 101460
tgtccccacc cattcaaagc acaggacctg tagagtggtg tggcatgtgt tggtggcact 101520
tttcaggcct gtaacaagga tgaaagaaca gcttcatagc agcacagtag tgctggtgtt 101580
cagaggtgtg tgaaggccat agaagcatct tggatatatt accttgtgtt ttgtcagctt 101640
tatgactaga agtctctttt cacttaaatt tgtttttttt ttttttgaga cggagtcttg 101700
ctctgtcgcc caggctggag tgcagtggtg caatctcagc tcactgcaag ctctgcatcc 101760
tgggttcatg ccattctcct gcctcagcct cccgagtagc tgggactaca ggcgcctgcc 101820
atcacgcctg gctaactttt ttttgtattt ttagtagaga cggggtttca ccatgttagc 101880
caggatggtc tcgatctcct gacctcgtga tctgcccgtc ccggcctccc aaagtgctgg 101940
gattacaggc gtgagccacc gcgcccggcc tcttttcact taaatttatg tttgtgtttt 102000
taatgcctag tatacaggac ttcttaaatt gccttaagta tgaacaggta tttgagttgc 102060
taatctgtat agtagcaata atagaatccc ttgtttttcc ttttataaat ttagcgatta 102120
aatagctaca attaaaacac tagagtcagg agtcaaggaa aatacccatg ttccaggctg 102180
tatgttagtg atgtacttac tatatattgg agtttcagga gtaagtctgt ttcaatgctt 102240
tctgtaacca tttggggtat taataagcat gtgagtgtgt gcatgtttgg gttaatttca 102300
tatatgtttc ttagaaggga tatcattgat gtaaatattt taaaggcttg tcctccaaaa 102360
aaatcatgta atttcttcta aattactgat cttttaaatg accttcacct ttctctcaaa 102420
tctcacttaa gactgggctg agtagtcagt ttcctgtagc agaaaaaagc tcagacttga 102480
gtagccttct gcgagtgagg agacttgatg gctgtcaggc agctgtaaac tctaaataga 102540
gtgtcattat ctgaagaggg cgatgctgcc acactgagtg gcctttcaag ttgtttctca 102600
atctgacacg ttctgatcgt gtgaatgtga aattggtttg agcaggagta tatctgagtg 102660
cagaggagat tatttaaaga tattctcatt ctctgcttcc cttttattcc catttggcag 102720
atggtttgat gtcctccaga aagtgtctac ccagttgaag acaaacctca cgagtgtcac 102780
aaagaaccgt gcagataagg taaatggtgc cgtttgtggc atgtgaactc aggcgtgtca 102840
gtgctagaga ggaaactgga gctgagactt tccaggtatt ttgcttgaag cttttagttg 102900
aaggcttact tatggattct ttctttcttt ttttcttttt tatagaatgc tattcataat 102960
cacattcgtt tgtttgaacc tcttgttata aaagctttaa aacagtacac gactacaaca 103020
tgtgtgcagt tacagaagca ggttttagat ttgctggcgc agctggttca gttacgggtt 103080
aattactgtc ttctggattc agatcaggtt tgtcactttt atctttcatc catcatacct 103140
gttcctaatt tagtacaaat taccctaaaa gacactgaaa tctactttaa agaaatgtgg 103200
tctgcatgtt tccctcatca gttgctgctg cttatctttt tcatgcacct agctggtgca 103260
gaaggcctgg ggcatagcca gcctcagcaa gtcagcatcc ttgccccagc tccctggact 103320
caaggctaac ctggggttgg ctgttaggga tttccaaagg tttgtcccat ccacttgcct 103380
cccctccaaa ataagtttga atttaaattg tgagatacaa ttaagattta ttgtttgggg 103440
aacatttttg caaaatctag agttagttta aacagattat caattattac cataattgat 103500
catctgcagt ttcaagctat ctaacaggtt cacttacctc tttaaaaagg aatggaattt 103560
agcaggacag taactgagac ccgtgctcct ggagtccatg tgggagctgt gtggctctgc 103620
acaagcattt gcacgcttcc cctcttgact gcattacctt cctcctatag ttgctgtggg 103680
caccagattc tggctagtcc tgtcccttca tgatgcacat tttcctcaag attcgtccca 103740
gttaaatcac tgcagatgaa actgcctttt catcgtcaaa atttaactgt catttttgag 103800
ccgtgatctt gggctacttt cttatgtggg gtaggaatat ttgtgagtta gaaatattac 103860
acttctctat ttccttctag acgtaaatct gttaatcctg tcagcactgt tactcacctg 103920
aaagggtctg tttccctagg agaactgagg gcactcggtc aacactgatt ttccacagtg 103980
ggtattgggg tggtatctgc ttgttttttt tgttgttgtt gtttgttttt ttttgttttt 104040
tttttgagat ggagtctcgc tctgtcaccc aggctggagt gcaggggtgc gatctcggct 104100
cactgccagc tccgcctcag aggttcacgc cattctcctg cctcagcctc ccgagtagct 104160
gggactacag gcacccacca ctacgccagg ctaatttttt gtatttttag tagagacgag 104220
gtttcactgt gttagccagg atggtctcca tctcctgacc tcgtgatctg cccgcctcgg 104280
cctcccaaag tgctgggatg acaggcgtga gccaccgcgc ccggcctggg gtctgctttt 104340
aatgaaggag gcatcaaggg gtgggctttg cgttggcctg atgctttcat ctttctttca 104400
caaaacctgt ccgaagaaaa tccgtctaaa tgggccattg ctctcctcag gaaatagtca 104460
ttgggaactt cttttccttt cctttgacac taggaggctg actggggaga agccctggtc 104520
tatggctgtg ggcagcaggg gctgagagga gcaggctctc aggggggcac gggtacccca 104580
agggaagcca gagccctgat ttgttccatt ctagtaagaa caaagactgc tctggtttca 104640
tgtttgttct gattgccttt catcaaccgg tcccctttct cccagttctt aagattcagt 104700
acagtgacag ttttatgaac aagaatagaa cactagaaca gacaaaccat tgaactctat 104760
gctgataaag atttattgag ctcctgctgt atgtttgcat tctgcccaga ggctctgaga 104820
aaaccaggcc atatgctcca tgctttatcc atggaagctc cccgtcaggt tgggaaagct 104880
gacagctgca gggaatacag tgtgacacaa aactggctcc catgcagccc ttacgtgtcg 104940
cctctcagat ggttggggga cgaaggtcga ctcctttggg tatcttatta ctaaaccagt 105000
ttcagggaat ctgtgccacc ctatctgcca ttaacgtgaa cagatgagtc cccaaggtgt 105060
aattttgggt attgtctgat gtctcttgga atttattatt tgtttttcca atgagatttc 105120
acctcagggt atagtaaagt tgttgagggg attcctggat gtgttctgca attatctagg 105180
ctgatttcag aatagagtta tgcttatagt caaatttatc agctgtcaag aattttattt 105240
aaaatttatg cagataagca ggaggaaaag aagcctggtt tttacatttt aatcctatta 105300
ttgatgtgaa attttatttt ccttcctgta ggtgtttatt ggctttgtat tgaaacagtt 105360
tgaatacatt gaagtgggcc agttcaggta atagcatttt attattttag atttttttct 105420
tcttcttgtg tacttacatg taatttaggt tattaagtga atgtttaaac tactgttagg 105480
catttttgct gttttcttta aatggaaatc tgactaacat actgtgcatt tttgcttctc 105540
ttaaaaatta atgtatatct caagacttgt ttggaagtag ttatgtatct gaaaattcca 105600
tatgttgtca gtattcattg cacatttcaa agcatttaat tgtgttgaca gatggtggaa 105660
tgaaatcttg tggtggagca ctagttttta aatcttctta gagaaagcag ttttatataa 105720
tgttgtcttt agtaattatt atgcatttgt attctctgca gctttttctt gctagatgtt 105780
gaggttttaa tacttcttgc tagtccatta caggtttata attattaaaa gttaaaattc 105840
ttttagtacc taaaatgctt aataaacatt gtaattagga aaatttagtg cagaaggaaa 105900
gtgttcccag attccctggg gtctggaaac atagtgttta ttctaattac atgacacctc 105960
cactgtgttt tggggcaagt tactgtttct cttttgagtt tcaatttctt caagagcaaa 106020
gaggcagagg agagctagga agatcgtagc tgctgtgccc ctgtgccgtc gggtgccttc 106080
tacctgctgc ctccgaacct ttacacatgt ccctgctctg cgcgagggca cagatgggat 106140
gcactgtggc aggggtgggg ttagagtaga tcacggacac ctgttagctt gatgtgtgct 106200
tgctgtcaag gttgaatcat gaattatttt atgttgctta tattgatatg tatcttaatt 106260
ttaaaagaaa ggtctaaatg gatgtttttg tttttaggga atcagaggca atcattccaa 106320
acatcttttt cttcttggta ttactatctt atgaacgcta tcattcaaaa cagatcattg 106380
gaattcctaa aatcattcag ctctgtgatg gcatcatggc cagtggaagg aaggctgtga 106440
cacatggtaa cgggacacac ctttcactgt cgtcttcggt gtcgtgatgt gcttggcagt 106500
gttcgttttc atatacccac tttgaacgtt gtcagtggca gccatgtgct tctcaggctc 106560
tgcatgtgtg tctgtgtatg tgaaggtact ggttagagac gtttcaaaag agaagagagc 106620
atattcttta ctctcagcaa tttgtaatct tctcagggaa aaaaattcaa gaaacagtaa 106680
gataacctaa ggtacagata gattctgaat ataaagttcc tgttcattca catgaaacgc 106740
taaaagttct tcacttgatc ttagccaaaa ggccaagaag cgatgcaaca ctaaaaattc 106800
ttaaatcgaa cttgccgtga attaaatttt gatctctcat ccagtggtat tggagatata 106860
gtttgacttg ggttcagggc tttctgtttt gcctgatgat tttgctggag cttaaataag 106920
gaacccagga gatggccagc tgtgcaagcc cccagcctgt ggaaggagct agtgtggttt 106980
tatgaatgag ttgcaaatct ttctttgagc tttttgaact gatcttccag cattgcccta 107040
ttgacccctc cctgactcct ttgctggaat ctgtaggctt ttgaactttg acagggacac 107100
atcctaagac ccttgcaaac tcccagatgt gagaatggca ctactactta gagtcttttc 107160
gactcagcgt gtgtgcagaa gagcatcaac cgggctgtgt tgcgaggcag ggccttggct 107220
gacctctcag tgtttacata gctaagccag ttagtgtttg ccacggcctc acaagggctt 107280
cagattcaca cagccaaagt atagattatt aaaggcatag gtgtttggtt tcctggactt 107340
ggagggtctt tggacagaaa atcagtaggc aaccacaccc agtactttgt gctgggaagc 107400
ttggtcatct gtgagagggt cagagagtat acccatgcgt gcatgccacc gaagggtcag 107460
tgagtattcc tgtgtgtgca tgtctcaggg ccggagagag tatgtgtcac tgagaggtca 107520
gagtgtttgt gtgtgtgtca aagagggttg cattgtgccc ttcactgagg ggtcagaggg 107580
tgcctcgcgt gtgtgtgtgt gtacgtgtgt gtgtgtcact gaggggtcag agtgtgcctg 107640
tgtgtgtgct tgtgtgtgcg tacatgtcac tgaggggtca gagtgtgcct ctgtgtgtgt 107700
gctcatgtgt gtgcatacgt gtcactgagg ggtcagagtg tgcctctgtg tgtgctcatt 107760
tgtgagcgta tgtgtcactg agggggtcag agtgtgcctc tgtgtgtgtg ctcatgtgtg 107820
agcgtatgtg tcactgaggg ggtcagagtg tgcctctgtg tgtgtgctca tgtgtgagcg 107880
tatgtgtcac tgaggggtca gtgttcctat gtgctcatga cattgagggt cagagtgtgc 107940
ctgtgtgcca atgaaaggca tttcttatat ttttttatat gtggtcatag tagaccagtt 108000
aatttatttt gactcctgtg ttagaccaaa ataagacttg ggggaaagtc ccttatctat 108060
ctaatgacag agtgagttta cttaaaaaag cataataatc cagtggcttt gactaaatgt 108120
attatgtgga agtctttatt gtcttttcag atgaatcaag tagattattc ttgagaccag 108180
gaatgttgct gttttggtta tttggaaagt tttatcattt tcaaattgac ttttgaattt 108240
gagtcacctt ttttcagaag tggtgttaaa ttataggagc cctaggtttt ttttcttttt 108300
ttagaagtca tcacaaaatg atcagtgttc agaggaagag ctttgacctt ccacatggta 108360
taatgattga taaccttaat tcatctctta ccataaacca agtatgtgta agggttttct 108420
ttatttcttg aaagcatttt gtagatgttg agagcagttt tccaaatgta atttccatga 108480
aatgcctgat aagggtaccc ttttgtcccc acagccatac cggctctgca gcccatagtc 108540
cacgacctct ttgtattaag aggaacaaat aaagctgatg caggaaaaga gcttgaaacc 108600
caaaaagagg tggtggtgtc aatgttactg agactcatcc agtaccatca ggtaagagga 108660
atgtatgttg gaactgtcgt ggatacttta ttgacccgtg cagatggaag gaagtgccat 108720
gtggtaacgc tcactgttaa ctgtgttact ttgaaccagg tttgggcttt ctggggcctg 108780
ggtagatgcc ggtgcagggg gatggggagg gaggcggggg gtgggggggt gtggtggagt 108840
tggggaggtg cagtggcagg aggtgttgtt ggtgtgtatc cttttttttt ttttgagatg 108900
gagtctctct ccgtcgccca ggctggagtg tggtggcacg atcttggctc attgcaagct 108960
ccacctcccg ggtttaagca attctcctgc ctccacctcc cgagtagctg ggattacagg 109020
catgcaccac catgcccagc aaattttttt ttttgtattt ttagtagaga tggggtttca 109080
ccatgatggc caagctgttt cgaactcctg acctcaagtg atcctcctgc cttggcctcc 109140
caaagtgcta ggattacagg cgtgagccac catgcccagc ctggtgttta tctttaaagt 109200
gggcacagcc acaggagttc acctgactcc tggtctgaga gtcacgagat cgttcaagat 109260
agtgaggccc tcttttccaa aacgaggacc aaaaatcaat tgacagtgtt ggtcaagatg 109320
gtagaaacct taaaatgata gaaatctcaa ctctgaaata aaaactttat ttgtatattt 109380
atttaccact attttgacat agggctaagg tctttttctt tgagctgatt tctggttttg 109440
ttttcttaaa gtggcataag aattcaaaga cattttgagg aaggctgagt gcagaaatct 109500
ctctttttaa atgacttctc ctttctttta acttgcactg ttgtctagcc ctcacttatt 109560
ttgtcaattc tttttagctg tttgtctttg aatcttcata aagccatagc ttttctcata 109620
agaagcagca ctttctttgt tcattcatat tttaatgaac ccctgtagta tttaattaaa 109680
tacttaatgc ctaattaaat cacataattg caatgcaaaa gtacatgtat cataaagagg 109740
tctgaaaatg agcaactggc aagcaggtgg tggcaggcag agctgcttgg gtgggtgggt 109800
gtcatggaga ggagttcatc agccacatgt tcagtgagct ctggatatgt ctgtttagaa 109860
atgatcacta ataaacttgt gctcaaccat gtatacctct gggaagcagg tgctcttcag 109920
tagattgcct ctgcagagaa cacagaattg aagtgaatgt ccacaaaggc aatgagccac 109980
ctgcagaata gtttagtcaa ggctgtgttt gaagtttgcc aaagattaat atacatttga 110040
ttttcatgtt gtgccttttc tctgattgtg aaatattaca aattctatac aaataacaat 110100
gatggcaaat cctcctgagc aaagtgtgca ccttgtatgt gccctagagg aacttgtgtt 110160
tcgttctgat tcccctacat ttctcatgtc atagagtggg ggttgcatta gtgtccccct 110220
gtcctcgctg ggatcacatc tgtttggatc ctagagtctt ccagctgaac tgggacaagt 110280
ataacagacg gacacgtagg ggtggaaagg cgtctcttgg cagcagactt tctaattgtg 110340
cacgctctta taggtgttgg agatgttcat tcttgtcctg cagcagtgcc acaaggagaa 110400
tgaagacaag tggaagcgac tgtctcgaca gatagctgac atcatcctcc caatgttagc 110460
caaacagcag gtttgtcccc gcagccttgg cttgttgttg catagtgatg gtagcttaag 110520
gtccttgtga aaggtgggtg gctggaatca gctcttcctt cagtcctaat ctgtgccttg 110580
atagcagttc tccgtgctag tcatgggaca gctgacttca tttcttctca caatgccatc 110640
tcaggttggt attgcccacc tactttacag gggggatccc acagctccga gaggttatgg 110700
aggtgatcag gcagcacaca gctttagagt gctggggtga gggcgggcca aggctaactc 110760
taaagcccga acccttacct cctacactgc ctcctgcatt ctggtcaacc cagtgtttta 110820
tttggtggtt agatttttgt ttttgttacc ttactgcttg taatttagca gttttccttt 110880
cctttccctt cctttccttt ccgacagggt ctcactctgt cacccaggct agagtgcagt 110940
cgtgtaatct cactgcaaca acctctgcct cccaggttca accaattctc ccacctcagc 111000
ctcctgagta gcaaggacca caggtgtgca ccactacgcc tggctagttt tttgtatttt 111060
tagtagagat gaggtctcgc tgtgttgccc aggctggttt taaactcctg ggcgcaagtg 111120
atccaccaac cttggcctgc caaagtgctg gcattacagg tgtgagccac ctcgcctggc 111180
ctattcatca ctaatcagaa tttctatgat caaatgacat gaatcattgt ttccacaact 111240
gcagtggaag gaaatggcct ggcagtgcca gtttcagaag cagcctgccc ccagtcaggc 111300
acaggccact gtgcccccag tgtagcagca cctctgtagc tcacagagaa gggtggtggg 111360
gacctccttg aggcagctct gccagaaaat ctcatgagct gcctggcaca gcttgaggtt 111420
gccttttaag tggactcagc aaatacatgt ttgttcatct tgattataca caataaacaa 111480
ctactctgta tagtacgagt agtccgtggt ttttggcatt tgatttaaac ttagaggcat 111540
gtgatattga tgttactgcc ttcatgactg cacccccatt ctgatttcat aatggaatgt 111600
tatcttgaga ccagttagac aacaggacag ggatcttggc ttctggtgag attgacagca 111660
gttttagtgt ggtcagggtc tccctgccta cagatggttt tagaatggtg ccctggaagc 111720
tttatcccat tcttttctgt gcgtaatctg agtagagtgg agatcgaagg cctgaataca 111780
tagtaaatac ctgacttaat atctgccgca atggaaattg tgtgatacaa catttatgaa 111840
acgcttagtg cagcacctgc caggtagctc accacaggtg catgttgcat tcagaagtag 111900
tgctagatac tatcctgtta ctggcagtgc atacatcagt gatcaaagca gattaaagaa 111960
agaccccctg ccttcttgga gtgaagattt tgttgggatg cgggtaaggg gacagacaat 112020
agaaaagcaa gtgagtgaag tctataccat ggcggctgat caggaacacc gtacagaaga 112080
atccaggagg gaagagagtt aggtggtgtc tgcggtggga gtggcattgt tcagctggtg 112140
atgagaagaa gctttggtga tctggtgaca tttgagtgaa tttgcagaaa ggaaagatac 112200
aagcctagga gatacctggg gaaggaacat tccaggcaga gcaaatagca gtgcaaaggc 112260
cctggcgggg ggcggacatg ctgttagggt acaagcaatg agggtggagg agtggggcag 112320
ccatggggag ggaagggagt gaggcctggt ggggtgaggc cagtgtggag gagccttgag 112380
agggtttgcg ctgatgtggt gtaggtttta gcaggatcat tcttattcct gagttgagaa 112440
tagccttgag ggggaggtga gggcagagca gggccaccca tgtgagaccc ggcactggag 112500
tggaatggcc caagtcagca tcccttggca gcatgaaagc aaaaccagca aggtttgctg 112560
gtggcttaga tgtggcatgt gagagagagc agggctttgg gggtgatttc agggtgagga 112620
cagggtggct gtggacaagg tagggcagac attgggggca gcaggaggtc agagcctgtc 112680
tggatgtagc agttgagacc ccataggtgc ctaatgaggt gaggccagca tcaggtgtat 112740
gagcctggag ttgtcgagag actgtggggc agggggtcag catctgagat gtccactcac 112800
agtggaccca gactggctgg agaggaggag gagcttgaat accgagcctg ctgagtccca 112860
gctccaaggt caggtaggtg aggggagcca gtgctggggc agggggagta ggcaggtgtg 112920
gggttcctaa agccaagatt ttttttaagg cattttgtgc aggagggcga catctgctgt 112980
cagcaccttg ggaacttggc ccaggtttgg cagcaccgag ggcactgatg agtgcttttg 113040
gaggagcaaa gggagccaaa ccctaatggg aatgtgttcc tgaaaggaca ggagagagac 113100
ttgggaaaag gttttacttg aagagggaac ggagaaatag ggcagtagcc agaggaggag 113160
aggagtcggc aatgggttaa gttggcagaa atgaaggcct gtttacgcac tgagggcaga 113220
agcaacaggg aggatcagtt catgacacag gagacacaaa tcgccgttgt ggtgttcaca 113280
gacatgggtt aggattggct gcatggatga cagagcactg tgggttctcc cagagttgct 113340
ggggaggagg cagagttggt gagcacaggc gagggtccag gatgcaggaa tcctggagct 113400
caagtcagtt gttcccttgt tgtaagatgt ggccagtgtt gtgagcttca catctgtgcc 113460
ttgaaaaaca ccacatctgt ttgcagagtt gtttactatg tatacacact cagtagaaac 113520
aaaaattgga aacagtcagt gcccaccatc aataagtaat ggttgaacac actgtggtat 113580
aagcttagac tattttagct tgggctattt tgcatgatta aaaatgttct ggccaggtgt 113640
ggtggctcat gcctgtaatc ccagcacttt gggaggccaa ggcaggcaga ttgcttgagc 113700
tcaggagttt gagaccagcc tgggcaacat ggtgaaaccc tgtctctact agaaatacaa 113760
aaagtagctg ggtgtggtgg tgtgcgcctg tagtcctggc taactcagga ggctgaggtg 113820
ggaggatcac ttgagcccat tcgtgcgcca ctgcactcct ggggcacaga gtgagactct 113880
gttagaaaga gagagagaga aagaagagag agggagggag gaaggaagga aggaaataaa 113940
tggaagaaat ggaagggagg aaggggaggg aggaaggaag aaaggaagtt cagccagttg 114000
ccttgggagt tctccattgc actgggttaa gtgagaagag cagagacgtt tatgattttt 114060
caaaacaact aaaacaaaac ctctgtgggt gagggggcaa ggatatggct ataggaacat 114120
ggggcagatt aagaaaggga tatacacaca ccacttagca tttgttacaa ctgttgtggg 114180
agggatggag tgcagaaaaa gaaaaaaaaa agtgcacacc atcccatgta tgtgtataca 114240
aagggacgct tggaagactg gtccccaaaa tgttggtaat gattgtgtca gggtgctgca 114300
gtgctagttg attttttttc acacttttgt atatttgagt cttttacaga aagcatttat 114360
tatttatgta ataaaaatct aaatgacaag atttctgtta tgggaaaaat gtagctatac 114420
agtgttgttg taaaaatgtt tgcttggttc accactgaac ttaaaatgct tttaaatgag 114480
ggaaggtgac gatgagatga ttatgatgat ttgcccttga gttacatagc tggtgtacag 114540
gaagctgtcg tttcttttgg cttacgtaga aatgtttgtg gtgtctaatt ccacagatgc 114600
acattgactc tcatgaagcc cttggagtgt taaatacatt atttgagatt ttggcccctt 114660
cctccctccg tccggtagac atgcttttac ggagtatgtt cgtcactcca aacacaatgg 114720
tgagtctctc gcctggctca gcagatgaat ctggacggct tgttcaggct ctgattactg 114780
ggaccacccc cagaatgtct gagtcagtca gtttgggtag ggcttcttga gagtttgctt 114840
tttttttttt tttttttttt ggtgtggggg tggtgcggaa cagagtctca ctctgtcgcc 114900
caggctggag tacagtgtca tgatctcggc tcactgcaag ctctgccttc cagcttcaca 114960
ccattctcct gcctcagcct cccgagttgc tgggactaca agcgcccacc accacgcccg 115020
gctaattttt ttgtattttt agtagagatg gggtttcacc gtgttagcca ggatggtctt 115080
gatctcctga cctcgtgacc cgcccatctc agcctcccaa agtgctggga ttacaggcgt 115140
gagccaccgc acccggcctt tttatttttt ttggagatgg agccttgctc tgtcacccag 115200
gctggagtac agtggcgcta cctcgactca ctgcaacctc cgcctcccgg gttcaagcaa 115260
ttttcctgcc tcagcctccc gagtagctgg gactacaggt gcgtgccact gtgcccggct 115320
aattttttgt atttttagta gagacggggt ttcactgtgt tagccaggat ggtcgcgatc 115380
tcctgacctt gtgatccgcc cgcctcggcc tcccaaagtg ttgggattac aggtggctct 115440
cgcaccaagc caagagtttg catttttagc aaattcccag gtgaaactaa tgcctgcttt 115500
tctgggagca cactttggga ctcagtgata gagaggttta ttggtaggat agtaaaatag 115560
gagttatttt ctttcacaaa attggcaatt gggggaaatt taatcttcct tttttcttca 115620
gctgtgactt atgtattatg tttattttag gcgtccgtga gcactgttca actgtggata 115680
tcgggaattc tggccatttt gagggttctg atttcccagt caactgaaga tattgttctt 115740
tctcgtattc aggagctctc cttctctccg tatttaatct cctgtacagt aattaatagg 115800
ttaagagatg gggacagtac ttcaacgcta gaagaacaca gtgaagggaa acaaataaag 115860
aatttgccag aagaaacatt ttcaaggtat gctttctatc tgagcctata actaacccat 115920
gccttttggg aagtcacgtg atgtttcaca gtcagtaagt ctggaataat acctggtctt 115980
gcttcacttc tgagttgggt aaagaagtct gtatcagtgt aattttctaa tccgtcctgc 116040
attatctatg gctcttggtt catacctgtc ttgaagttct gtcatgttct gtctcttgtc 116100
ctcagtagag atgctacagc agtggctcgc ctcaggcagg gcagggcagt ggggtggctg 116160
tcctgggggc aggcagtagg ggcacgctga cgtcagggaa gttgaaaccc aagagaagcc 116220
agtaaaagtg agtctcagat tgtcaccatg tgctggcagt tttacacgct gtcagtaata 116280
aaagtcttct ccctgcaggg cagcctgcct ccaataaata cgtgtagtat caaatcctgt 116340
cttccctcat aaattgtttg gaagctcccc aaggacagtg atgaggcact cgtaagtgct 116400
tgctgcctag atgggtccct ctccaccttt gctagattct gagcattcac tgagttagag 116460
ctgcttctgc aaatgtgctg cttctgctaa gtggctgtga cttcatgcag ccttcacttg 116520
gtttgtcatc agtggagatg ccctgtgttg tcgaaggaga taagcccagt aagcctgctg 116580
ggcacctttt ggtttgcagg ttcagcaggc agcccatggc tttccctgtg tcgcattgaa 116640
gcagctggct aaaattgatg atacattaaa ttcctgtgac agatgatcag cttgtatttg 116700
tgtaatggtg tacagttcac aaagcttaaa aaaatgctac ctgccatttc atcctcagtg 116760
aggaaggtga tacacagaga gaccaagtga ctgtgtccac ggcgacggcg ctctgcattt 116820
cactttagcg gttaatgtac tctacctata tttttacttt atatttacca tatatctttt 116880
catgtatact tggcgtaagt gctttatagt agtcacctaa ttcactgtca tcttttttgt 116940
ttcttggaag gtttctatta caactggttg gtattctttt agaagacatt gttacaaaac 117000
agctgaaggt ggaaatgagt gagcagcaac atactttcta ttgccaggaa ctaggcacac 117060
tgctaatgtg tctgatccac atcttcaagt ctggtaggtg aatcacatta gtcttcctgg 117120
agtgtctcgt tccccattct gcactataca ctctcagagt gtaggagctg tgctgcccgg 117180
tagaaactct gccttgccca gtgtgccagt tgaaaatatt tgttgctgta agagtacacc 117240
tgataccatg tgacccagca gttccactct tgggtatata cccaaaagaa tggaaagcag 117300
ggtggtgaaa agatatttgc atgccagcat tcatagcagc attattcacg atagctaaaa 117360
tgtggaacca actgaagtgt ccctcgatgg atgaatggat aagcaaaatc tggtgtatat 117420
ttacagtgga atattattca gccttaaaaa aaggacattc tgacacatgc tacaacatgg 117480
gtgaccctta aggacattat gctaaatgaa ataagccagt cacaaaagga caaatactat 117540
gtgattccac ttacatgagg gacctggagt agttaattca tagatataga aagtagaatg 117600
gtggttgcca ggggctgcag gggaggggag ttatttttac aagatgaaga gagttattct 117660
agaaatgaat ggtggtgatg gttgtataac attatgaatg tacttaatgc tactgaactg 117720
tacagttaaa aatagttaag aggaccaggt gtcatggctc atgcctgaaa tccaagcact 117780
ttgagaggcc aaggcaggag gattgcttga gccaaggagt ttgagaccag cctcagcaac 117840
atggtaggac cccatctgta caaacaaact agccggggat agtggtgtgc atgtggtccc 117900
agctactcag gagactgagg ctggaggatc gcttgagccc aggaggttaa gtctctagtg 117960
agatgtgttc atgccactgc actccagcct cggctataga gtaagaccct gcctcaaaaa 118020
aacaaaacaa aacaagacaa gagccaaaaa tggttaagat gggccaatca cagtggctta 118080
tgcctgtaat cccaacactt tgggaggtca aggtaaaagg atcacttgaa gccaggagct 118140
tgggaccagc ctgagcaaca tatcgagacc cctatctcta caaagaaaat caaaaactag 118200
ctagatatgg tgggcacatg cctgtagtcc cagctacttg ggaggctgag gtgggaggat 118260
ctcttgagct caggagttcg aggctgcagg gagctattat tgcactccag cctgggctac 118320
agaatgatac cctgcctctt attaaaaaaa aatccaaaaa aaaaaaaaag taaacctgag 118380
agcttcctcc tcctgtgtta aatttggagg ccaagatgtt tttgttactt ttacaaatga 118440
tcaaggacgg tgaaggttgg gcatggtagc tcacacctga aatcccagca ctttgggagg 118500
ctgaggcggg gtgatcgctt gagcttgaga ccagcctgga caacatagca agagacccca 118560
tctccacaaa aataaaaaaa taaaaaaaaa tagccaggag tagtggcatg agcctgagcc 118620
caggaggtca agctgtagtg agccatgatc atgccactgc actccagcct gggcgagatc 118680
gagaccatgt ctctagagaa agaaaatgac aaggacagtg aacccaagaa agtcataaga 118740
tgccagctgt gcagcaagca tggaaagcag ccagtccaaa ttaggacagt gtgttttcca 118800
agaagaacga tcgtttgtaa tgagaatgct ttgctttaaa taaatgacta aatagctaga 118860
agcctagttc taggggatag gcacgtcttt cttctctcaa gaaaatagaa aggcaattct 118920
aatttctagt aacagcaaac agcattaagt catggtccaa atatgaggca aaccaaaatg 118980
tggcttgatt gttcagcagt tgatctgttg gaagcccttg atattaaaaa ggttctcctt 119040
taagcggctt aggagtcacg atcaaagacc tatagaaaga gatgccatcc ttctaggatc 119100
cttggctctc ttgggaacta gattcagata gtcataatgt aaatactgct tgagctttct 119160
ttctttcttt ctttctttct tttttttttt gagacagagt ttcactcttg ttgcccatcc 119220
tggagtgcaa tggtgccatc tcggctcacc gcaacctctg cctcccaggt tcaagcaatt 119280
ctcctgcctc agcctcccga gtagctggga ttacgggcat gcaccaccac gcctggctaa 119340
ttttttgtat ttttagtaga gacagggttt ctccatgttg aggctggtct cgaactcctg 119400
acctcaggtg atccacccgc ctcggcctcc caaagtgctg ggattacagg tgtgagccac 119460
cgcacccggc ccgagctttc atttttgaaa tcaatgtatg actgaaacac tgaagactta 119520
ctgacttaat tatggtttca gaacagaatg aaaatgtctt cggttctgat gaatataaaa 119580
ggaaaactaa ccaagttaat ttggcaagta gatggtagag atagaggtgg ggagtggaag 119640
gggaactaaa atcttcacct agcattgttg ggattatatg gttacatcat ctgaagttga 119700
cagaccaaaa tatagaggct tcagaggtct ccaaatagaa ctaaacatgt aattcagatt 119760
gttaggaggt agtataaatg agctaaatct catctttatt acggtagagt taatgggtga 119820
tgtctaaagt tgtctgaagt ctataaatca tgacaaatta tgatgtggtg attgtattca 119880
acagtctttc agttgcaggg ataaaacccc agtttaaact agagtaagag aaagaatgtg 119940
ttggtttaag ctcctggaaa gtgcaggcaa gggtagttgg taggactgca tctagtgttg 120000
taattctgtg gtctgcattg tatatttatg catctcagct ctgctttctt cttttcattt 120060
atataatttt taaattttat tttaaagata gggtctcact ttgtcgccta ggctgaagtg 120120
cagtggcatg aagtgcagtg cgaggctcac tctagcctcg aactcctggg ctctagagtt 120180
cttcctgcct cagccttcta agtagctgag acaataggca tgtaccaaca tgcctggata 120240
ggttttaaaa tttttttgta gaaatggaag tcttgctgtg ttgcccaggc gggtctttaa 120300
ctcttagctt caggcgatcc tcctgcctct gcctcccaaa atgctgaggt tataggtgtc 120360
acccaccacg cccagtctca tctctgcttc ctgtgttagt tttgttctct ggtgggctgt 120420
tttcacatga ccgaagatga cctctagcag gctgtgttct cagcccctca agtaggccta 120480
tgtgattggc cttgcatgag taatatgggt gaccataaac ccctgaatgc tctggtccac 120540
atgggccaaa tgggagactg gacagcattc cattgatgag gaggtggggc tggtctccgg 120600
gagtaaggga gaggagcaca tgcagtaact gatggtctgc tgcaagggat agcagcacag 120660
cagttagaat tttggaggta actaccagaa ctgaaaacag aaatgataac aagtagttgc 120720
cttaaaaagg gatgggagca gggtgctttt gtgatcaaag ctcctttctc ttactggatt 120780
tttgtacaca ttttgcatac atatcttaga gtaaaagata gcattttcag ccttggtcca 120840
tttgaggata ctcttggcgt ggcccgcctc catgctagca ggctctggtt gtgccaagtt 120900
cagttgagca tcctggctct tgcctgcacg gaacttccag tcagtgcgtc agtatcacaa 120960
gtcttgatat ttcctatgaa gaagaacagt agtgcagtga cagacgaaat gggtgggcag 121020
gcagaggcag gatttctgag ggagagaagt agctagcttt ttgcagagaa gagttccggc 121080
acccaagaga gcagctgaga gtacaggcag gcaggcagga tgccggtagg gcccggccgc 121140
acggcgccac agaatcctgg agaaaggggc ctcttcatgg cctctgcatt cagctgctgt 121200
caccctccgc acaggccatg gccaaaattt aattttcata gtggactcta gtttttgagc 121260
cttacttgct attattgaaa taattttctt gtttcttttt aaagatcttc ggattatgct 121320
tcactgacca ctgtaataag tttaaagttg agaaaatatg gcttgttaat gaatgatagg 121380
tcaattttag tatgttggtc attttaatat tttgccacca gttggtttgg atttgatgcc 121440
aggaggagac agcctcattt ctaaggacta gtcttgcctt tgtgggataa gggtggtgtg 121500
ttctgtgtcc ttctacatgt ccgagcgatc tctgtgcagc tcaaatgtgg tcactgtctt 121560
attgcgctga tttcctctcc ttccatctca caattgaggc aaaatattgt tactgttgaa 121620
gtgttgtcca ataggacttc cagcagagac aggatgtctg cactgtctaa tttagttgcc 121680
tttagccaca tgtggtgttc tgtacctgaa atgtggctgg tctgattgga tagcttaatt 121740
tataatttta tttaatttta attaacttaa atttaaacag ctctgtgtgg atagtggctc 121800
ctgtatgaga cagtgcaggt ctgttgagaa gcagctttac tggtgggagt ggagggcttg 121860
gagagggcac gtgggtttcc tgctggtatc ttttgacctt atttaatctg cccaacattt 121920
gcaagtaagt tgtgtgtgtg tgtatatata aatgtgtgtt tctgtcttct tgtttccttt 121980
gactgcattt atttgaaaga cactaggtgg cagaattact gtatttgatt ggtttcaaga 122040
taagagttga aataattcat ctcgtgtttt tatataagta aggtgtgttt agcatgtaaa 122100
attggtaata tgtattcacg tactgcttaa acaaaggcta tgaattccac ccataaaccg 122160
aaaatgaaga cctttaaatt tgtccatttc aggcgtgggt acttcttaaa taatacctgg 122220
ttcaggaact agtcagaatg gcacccttga ctttttgttt cctgcttttc ctcttgttgg 122280
gagaggaggg tattcatccc aaagtggttt gcctatttca cattccatct aggataagca 122340
gaatagccaa gaaagatagc tgtcctcctg tttacaacat ttggggtaac cagcatccct 122400
ctcttttggt ccaagataga ctggtttaga aacagatgat ggcaccagag gcccaggagg 122460
tggaaacatc agctttgttt gttgtccatg tggctgaatt agagctgtct ggccttgtag 122520
cctcaacacg gccttccagc tttgctcacc gtgattttca aggacacatc ttgtgctctt 122580
ccctgcctgc catccagact atacccagtc agggtggcag gagctgctgc cccttcctcc 122640
ctgagtcctg gtcgtgggtg gtggagatgt gccatgacgc tcacggaggc atgctcaccc 122700
cttcctctgt ggcagagggg atggctgcac gacagctctt ccctgtcctt tccaaagcgt 122760
ctgtggttcc actttttggg gcaaagcagg aatactggaa gagagagaaa gtggtccttt 122820
ctatagtaat aaagttgaca ttgattcaag ttcatgcttg gggaaaggac agggctacta 122880
acaattataa tgctgggagc aatggaattt tctcatgggt atgtggtagg tttaatttta 122940
attatcccag ttaattctta gaactgctct gtgaagtatt tcccgctttg tgcttaagtt 123000
ctaaaagatc ctgtgccaaa accaagaatg aaaacccaag cattctttct tgcccatcga 123060
tctttctctc atcaggccac ttcttgggtt gatagtggtg agtgtagccg ctgccacttt 123120
cagaataccc accatgggcc ccagtcactg tgtggcgtgg agaagagatg gttctctctg 123180
tgtcatagct gaacaagccc agcccagaga ggtttctgcc ctaggagctc tcgatggtgg 123240
aattgggatg cgatcccaca tcctgcctgt tttgaaaaca gcattcttta tttccaattc 123300
ctgcttccat tgttcctttt aatatttctt tgtttagctc acaaaaacac ggcttgcgga 123360
gctgctgcgt gcagctgtag ctgtttctct gggtgcagcc tgcatccgcc ttcctgcccg 123420
cctcctttcc tgcactgcca tcgtggtctc cgggcacttg gtccctttct cttcccctga 123480
gtccctttgg ctcccctgtg ccacccttgt gatccacagg ctctgccttc tttctgtctc 123540
agactgctgc tcatcactac tcgggaccct aggaagggag gttccaccga gaagcatctt 123600
ctcatctcag ccacgttctc agtgccactg ttgtctttgt taggtaatgg tagctactgt 123660
aacaaataaa ccaacatttc catggcttca caccagagaa ggttgtttct tggttttatg 123720
acaatgtatt gagggtgttc ttggttcacg gatggttttc ctccatgtgg gaattcgggg 123780
acccaggctc ctttccttct tttggttctg ttctccaggc cttcacatcc tctgtgtctg 123840
gttggggaca aggagaggga aggtaaagaa ggctttgtgg ccttggataa gtgacaggca 123900
tgcctttgct ggtgttctct cgtggtgaca ggtcacagcc ccaccctgta aaaggggact 123960
gagagacgtc gtcctgctgc ttcccagcag cagcactgtg gtctctgatg tgttttctgt 124020
gaggataaaa acaggtgatt ccaggatgag gaaagtcagg gaaacccttg gaaggagggg 124080
accaggcggg tgtcaccatg ggattagtgg tggcttcaga atgagctgca gcgagtgcca 124140
tgccttctaa agcttttgct attctgatat gcccacacca tgcccagcag gtgtctgcct 124200
tgctctccgc agagagagtg atgaatcctt ctcatgagcc tctgtccagt tgttcctccc 124260
tccacctgga agggaccctg ggttcctcat aacatcccag cggaacaggg gaccttctat 124320
cctgtcccca agttcatcct catcctcctg ccggcttcct ggcccctctt atgtctgctt 124380
cctgacgcca catccttctg gattctctgg aattgaattt tgcctttgat gcttatttaa 124440
aaatatccat tgcaggccag gtgtggtggc tcacacctgt aatcctgtgc actttgggaa 124500
gccaaggtgg gcagattgct tgagcccagg agtttgagat tagcctgagc aacatgttga 124560
aatcctgttt ctatagaaaa tacaaaaatt agctgggcat ggtggcgcac acctatactc 124620
ccagctactc aggaacctga gacaggagga tcaattgagc cccggaggcc aaagctacag 124680
tgggctgtga tcgtgccact gtactccagt ctggtcaaac agagtgagac cctgtctgaa 124740
aaaaaaaaaa aaatccattg catacttcac cgtagcgaaa catgtatgtc ttacctttcc 124800
tttcctgcct gtagctgctc ttttacactt aacagccaca ctaagccagc cttaaatgaa 124860
aaacaaacca gcacttcctg tgccctcctg cttccttcat gaggggtccc tccctctgtg 124920
tacactccat tctcattgcc catggtggtt tgtttccctc ttgtttctca agccatggca 124980
gcctgcctct tgccctcttt actaaaaagg cctttgcaga ggctgcctgt gttctttctt 125040
tctaggtctc tctcatccta ggccctccag cttgattctg tggagctgcc ctcttgtcac 125100
tcagtagctt gtggggtctt ctctgtctag ccacttaatt gattgtgttc ctcgagttgc 125160
tgtccatggt ctctcgttac tgttttctct gtgtttctgc ctctctcctt ggccttggta 125220
ggtccatccc ctttgtgacc ttggctgttg ctctcatgga caactttctc ttgctggtcc 125280
ttgtagtcct ggcatccagc ttctcgacac gggacttgtc ctgccagtac ctcagacttg 125340
cacttaaaat tgaactagca ccactgtcac tctccagggc ctcttcttgt taattagatc 125400
attagggatg ttcagaatcc cagcatcata gtatgttcct cctcccgcta ccccaggaac 125460
cctaacctta cctcctcctc tctatctact aggaggtggc cctcagagtc cgtctcatct 125520
tccacctgaa cttccctaat aggctccagc agctgccacc ccgggggctg agtacttcct 125580
ccatgccttg tgcagtgctg agccctttac ctgggttctc ctgtttgctc cttattacag 125640
ccctgcgaac agatactgct cttaattcca tcttacacct aaggaagctg aggccccagg 125700
taaggtgcat ccaaggtcac ccaggtagta gacagtagag ccacgatctg aaccaggcag 125760
tctgattcag agcctgtgtt gacactcagc cacctagaac acagcttgga ttgtgggttt 125820
ctattacctg ttcaaaaccc ctacatcccg ggtctgtccc tgcacgtgct ctgtggcctg 125880
gctgcatctt ccttgaaggc agtgcatgcc tcttcactca gggggcccat gcaggaacag 125940
agggccccac agaaggatga ggccagtgca gaatgggctg gaggggacaa tgctgaccag 126000
gaagcaagtg tagagaaatc ccaggaaacc tggaggagcc agagacaagg cattagaact 126060
cctcgtcgtg acctggtctg cattctctga gtgtgctgct tctgttagct cgcttccttg 126120
gtctcaggtt atagtttaag gcattgtgga gccctaaaaa gcctgtactc tgtttttacc 126180
tgttttagga ccctttcact ttggggatgt gttgattttt tttttttttt tttttttttt 126240
tttgagatag agtctcgctc cattgcccag gctagagtgc agtggcacga tcttggccac 126300
tgctgcccct gcctcctggg ttcaagcaat tcttgtgctc ccgcctccca aatacctggg 126360
attacaggca cccgccacca cactcggcca atttttgtat ttttagtgga gacagggttt 126420
taccatgttg gtcaggctgg tctcgaactc ctgacctcaa gtgatctgcc caccttggcc 126480
tcccaaagtg ctgtgattat aggcgtgagc caccacaccc ggcctgaaat ttaaatcaga 126540
aataaaattt tgatcccaac agtgatgcca ggcagcccag atctggggga gagggtggcc 126600
ttggccagct gggcctttct ctgtttccca agtcttgctg cctctccctg ctgggctttg 126660
cagcctgtgc atgtctctgt gcctttgacc ttgtttatcc aaaggagagg atagaatgaa 126720
gtcatgattc ctggagccct gagaaggatg ctgtggagaa atttgccggt agaatctagc 126780
tgagtgtgtt gctgaggtgc cagcattgtg tgtggggagg ctgaccgctt ggcctgccta 126840
ggcccaggat gctccatggc cgggcacaga ggccacttgg ctgtcaggtg tcaggagcct 126900
gcagagggca cacagagcct ggaccgcagg ggggtcctgc tttctcacct ggcctccttc 126960
agcatttctg tccctcagtc cttagcaagc ccaggagctg ttgagtttgg caggtgccga 127020
gtgctgttcc tgcctgtgta gctgtggctc agtcctgtgg gggccccgct gtggcccgag 127080
tgcagtgatt cgaggcgctg agtgttccct gactccttct ccaggagctg tgttcagact 127140
ttcgcagctc ttggcttgga gctcctggag ggcttggcat tgccgaccaa tgtggaggtc 127200
gacagtgaga gaggaggaat gctagctttc ttgaccagtc cattaaataa gtgggatatt 127260
ggccaggcac ggcggctcac gccttaatcc cagcactttg ggaggctgag gcgggtggat 127320
cacgagctca ggagttcaag accagcctgg ccaacatggt gaaaccccct ctatactaaa 127380
aatacaaata ttagctgggc gtggtggcag gcgcctgtaa tcctagctac ttgggaggct 127440
gaggcaggag aacagcttga aaccggaagg tggagtttgc agtgagccaa gattgcgcca 127500
ctgcactcca acctgggcaa caagagcaaa actctatctc aaaaaaaaaa aaaaaagtag 127560
gatatctgtt tctgcttaga aaaatcagaa ttttctaaat gccaggtgtt ctgaatacgt 127620
aagtatggga gacgactcag cctgtttcat ttttatgtaa aatcttcgcg tagccatgtg 127680
gcactggacc gagatgaaag caaagacatt tctccttaac tttgtttcta ggaatgttcc 127740
ggagaatcac agcagctgcc actaggctgt tccgcagtga tggctgtggc ggcagtttct 127800
acaccctgga cagcttgaac ttgcgggctc gttccatgat caccacccac ccggccctgg 127860
tgctgctctg gtgtcagata ctgctgcttg tcaaccacac cgactaccgc tggtgggcag 127920
aagtgcagca gaccccgaag taggttcata atgccccaca gcccagggcg ccagcccagc 127980
accctgtcct gagactccca gtaacctgag ctttggccac cgttaaagca ttttcatttt 128040
ccattttttg tgagggcttg tgaaatttct gctgcatatt aatattcctt tcatggacag 128100
catattattg ggacaaacat gcggtccagc taaaggcatt caaaatagca gttgctttct 128160
aaatgcgatt ttctttggca ggttctttga caccattgca tcttgtggga tatgcttgtc 128220
atgctctgtg gctcctacta agttctagtc cttaaattgg ttccatagcc agacatgttg 128280
caatgtctta acctcattat aaagtaaatg tggttctggt tatccttaga taatgaagta 128340
acagtgtagc aaatttcaaa acctcttgga aatgttattt taccattcaa aaaggcttac 128400
taaggttctc gttatgggtg gccctctttt tgcaaaaggt tttcaggctt aagctccatt 128460
tctaggtgct ccaacactcc attatttgta tatgtatgga aataaaagct gtgaccaccc 128520
ccaaccctgg cccccgccca gctgaatcct cagcacagta tttctggaag gctcaagatc 128580
ccacgctggg gaaaagaagt tctggagaca aaagagggca ggtgctgccg tgcctctctg 128640
ctcagtatgg atactggacc ttgtgctgcc agggctccca gtagggccag ttcatggcac 128700
tcagctggaa agtccactgt tgggaggcat tcttaaccat ccactctgtg ccgtatgtag 128760
tggggtctgg tcattctgtt ggaggagaca gaccagtgac gacatttgaa atgcttggtg 128820
gatgtcttag gcctgttacg atgactgagc actgtggggg caggagacag aaagtcagtg 128880
tctcctagtt ctgtgctgct ttaacgtgca tagaaatcag ctgcggattc agcagatcac 128940
tccttttctg acagatgggc ctgcttactc tgatgttata tcagaaagct ctgaatctgg 129000
gaattgtgtc ccctgaattg gagtaacaga aatgcttaga tgatgagtgt ttaaaagaaa 129060
taaaccaaag gtaaatttag tttggaattc agcaagcgtc ttcattcagc cctctgaggg 129120
caaactacag ctttttgtaa atgtaggtaa attctgtgac tgtttcgtga ccccctctga 129180
tccagttttc ctttataacc ttctgtattg ttccttctat tatcctgaaa taacattaat 129240
agattaggct gggcgtggtg gctcatgcct ataatcccag caccttggga agccaaggcg 129300
ggcagatcac ctgaggccag gacttcgaga ccagcctggc caacatgatg aaatgctgtc 129360
tctactgaaa ataacaaaaa ttagccgagc atggtgacag gtgcctgtag tccctgctac 129420
tcagaaggct gaggcgggag aatcgcttga acctaggagg aaaaggttgc agtgagctga 129480
gatcgcgcca ctgcactcta gcctgggtga cagagtgaga ctccatctca aaaaaaaaaa 129540
aaaaaaaaaa aaattaatgg atcaatggat ttttaaccta ataattaaat ttcaaaaaat 129600
atcgttcttt aatggtaatg taaaggtaaa attaagataa tatgtaacaa gcatgtgagt 129660
gtctaaggtg tccccgtggt ggaaggaaaa aataaatccc cataagtgtc caagatgccc 129720
atagagagca gagctgttct ggtttaaacc cctgctctta gcactgtgtt tttccagctg 129780
tgggtggtgg gggatgagta tctttttatt tccatgagat gagaaaaatg aattactaga 129840
agtgtgaaat acaaaacaca gctgctcttt ttttagccat agactcagca gccataaaat 129900
tgctgtatcc agttgcagaa attcctgctg cttactcttg accctctctc ggtttgtgtg 129960
catctcctct caggctggct cccagatggg agctggctcc aggcgacact gggtgctctg 130020
ctccaggagg tccttatgtg ggtcctgccc tagcctagcc cctctcttat ggactctgtc 130080
actgtgggtt tatgattcac tctcaatctg tcttacctct tggtgaactg ttagagtcct 130140
gcctatactt tggcgcttgt gggtgtgttg tggtacacat gatgtgttgg tcacttccca 130200
gctcatcttg ttctgagtca ccctagattt gggacattca ttcgccacca gtaccgggcg 130260
gtgtatggcc tgagatttgg gggggcttgt gctgctacaa attggggctg aatttgagtt 130320
gacagtggac cttctttatg tctactgctc atatttgaat tgcaaatact gcctcttctc 130380
tttcagaggc tcattaccct atagctgtat tattgcaaag tgcacaatta cagcttgagt 130440
gtaagtcaca ctgcgctggc aggacggccc actgagaaag ggcacgtttc ctgttcgtta 130500
gttttcacat tgacacataa tttacaatac agtaaaatgt acttttctat caactgtagt 130560
cagtaacagc ccccctcccc caaccacatc aagatataga ggagtgctgt cacttcaaac 130620
agttccctct tcctctgcca catcctgccc ctccccaggt ctaaccacca atccgtgctc 130680
tgtccctctg ttcagcccat tgcagaaggc catagaaata gaatctatag gctaggtgtg 130740
gtggctcatg cctgtaatcc cagtattttg agaggctgaa gtgggaggat gacttgaggc 130800
tgggagttca agactagcct gggctgccta gcaagacccc atctccagaa aaaaaaaatt 130860
taaaaattac aatcacgtcc ctgtagttca gctgcttggg aggctgaggc aggaggatca 130920
cttgagctca ggagttagag gttacagtga gctatgatcg tgccactgtg ctccagccta 130980
ggtgacacag caagacgttg tctctgggga aaaaagaaag aaacggaacc acgcggtgtg 131040
cagccttctg agtctggccc ctttcggtga gcagtgtcta aagttctgtc gcgtgttgcc 131100
cacgcgtcgg tggctcgctc cttgcaactg ctgagcattg tatggctagg ctgtagtttg 131160
ttttcacttc accagttggg aaacagagaa aaggcacttt ttaaaaagtt taaatctgta 131220
gaattttggt ttttaccagt tctcttctaa atcctgaggg attacaggaa aagttgttgt 131280
atttcagaat attcttagct tgatgtgacc tctgtccccg ttaaggccct ttgccgcaat 131340
gggaaggacg tcgctcggtc agaccctgaa ggtcagaggg gcagtttggg agtgtgtcaa 131400
cattttaact gtatggacta gagccaagag tctcaaggtt tataattccc acgtattcaa 131460
aaagaaaaaa acaataaagt gagaagtcag tgtagagtga aataacctgt gttagtgggg 131520
aagaagtgtt tttaaacagg atttccataa cgtataacat caacatgttt agagtggtga 131580
tgtttcattg ggaaacgaac agtaaaacat gaaagcaggg aggttttcat tctggcagtt 131640
ggcaactttc acggcagatg gagaatttca aaagcaattg ctcaattatc aaacatagcc 131700
agtgtgagtt ctgaaataaa ggtgctgatt gaatgtgcag ctttatggtg gattttgcta 131760
ttcaggcaag cattttaatt ttctgcctgt taaattctgt tttctttagt ttttcatatg 131820
tggtttattg tagcttagga atagataact gagagtatat attacacata caacattctg 131880
atatggcaat atttaaaaca acttgtctgt tttagaacta gaattaaaca taatcatctt 131940
cagtattttg caaataagct cactgccatc cagaaacatt gtcaatgcat ctgttgctcc 132000
ttctagaaga cacagtctgt ccagcacaaa gttacttagt ccccagatgt ctggagaaga 132060
ggaggattct gacttggcag ccaaacttgg aatgtgcaat agagaaatag tacgaagagg 132120
ggctctcatt ctcttctgtg attatgtcgt aagtttgaaa tgcctgtaaa cggggttgag 132180
ggaggtgggg accaggagaa catcctgtgt agatgacact tgcatggacc ctctggaacc 132240
cagaccgccc ggtgtcctgc caagctccat cgaaactaaa tctagaatga atgtttactt 132300
ctgctgtgac atataattgg agaccaggcc tggccttcca gtcactggat tctaagttgg 132360
actgtgagag tttttgcagc tgactcattt atcaaatgcc cggctattgg ctcacgccta 132420
catgatgctg ggtatgtttg ttaatttgag ggaagcaatg gaataataat aactaatgat 132480
ttaaaaaaca aagtaagtgc attgactgta gtggggttct gattttaaat ttttttaaaa 132540
attaatacca ggagcagtgg cttatgccta aattccagca actcgagagg ctgaggtagg 132600
aagatcactt gagcccagga gtttgagaca agcctgggct atggtgtgag acacccatct 132660
ctaaaaaaat aaaaaataaa aaattatcca agtgtggtgg ctcgtgcctg taatcacagc 132720
tctttgagaa gctgagggcg gaggatggct tgagcctggg agttcgagac cagcctggca 132780
acacagagaa accctgcctc taccaaaaaa agaaagagag gaagaaagaa aaattagcct 132840
ggcgtggtgg tgcatgcctg tggtcccagc cacctgagag actgagaagg gaggattgct 132900
tgagcccaga agtttgaggc tgcagtgagc tgtgactgtg tcactgcact ccggcctggg 132960
tgacaaggcg agacccctgc tctaaaataa tttttttaag ttaatttgta gaaaaggtgt 133020
tagatgttct ttgtcacatt ttatgatgga ttcctgttta aatgccgttc tctttaaaga 133080
aaaaaaaata acttgtggga gtttttaacc ataaaactag catcacatat ttaccatgga 133140
gaatttacaa aaaaacaaat aaacggagga aaataaaacc tcctgtaatc atactactca 133200
gagataactt gctgttagat tttggtctag atttaatact ttttctatat ttatattaaa 133260
aatatttaaa acatatgcat ttctttgtca caaacatggt atcttataga tactactgtc 133320
acatagcaaa acagtgttaa atattctgaa tcagaaaagg aagccgactc tccaactgaa 133380
agaggtgtta tcctagagac tttttctggt gatgacaatt tattaatagt cactttttgc 133440
tttactttct ctattgaagt agtttttcta ttttgttcta cttttaagga taatataatt 133500
tataatgctg tttttcacag aaatataaga aaaaagatac taattttata agttaataaa 133560
gtttgatcat cccaaatcca aaaatctgaa atccaaaatg ctccaaattc tgaagctttt 133620
tgagtgctga cattatgttc aaaggaaatg ttcattggaa ggtttcagat tttcggattt 133680
agggagctca acaaataagt ataatgcaca tatttcaaaa cctgaaaaaa atcctaaatt 133740
cagaatactt ctgatcccaa acatttcaga taagggttat tcaacctgta ctgtcagatg 133800
atcccaaatg aaaaatatta atcgttaacc aaatatcaag gaattgatca cattttacag 133860
tttctgccta ggattatgaa tcaagatgaa aaggctctgc atgtttaaaa atatatattt 133920
ttattttctt ataaatctta aatatctaca cttaagattt atttgatatg tgggatccat 133980
tcatattttg gattcaacag ttctgtcaaa actgtggcag tgatagggga ttcttttttt 134040
cccactgaac tatcacaaaa ttggaaaaag agtaattgga gaaccccact ggcttagccg 134100
gcccgaagcc cgggagaggg caggcagtgc tgtggatggg gtcatcccag cgcaacgctg 134160
cccctgctac ctgcggatct cgctgaggcc tgcctttgtc ctttgaccct tggccatttg 134220
ttagtgtctc tgagagctgg actgctgtac cctacttccc cagggggcct aacttcacac 134280
agcctctgcc gcagtgcgtg gttggaggtg acggccttgg taaatcgagt ttcctacctc 134340
ctcaattatt tgtgctcata cactgtatat ttttagtgag gtttatattt gggatgtgtt 134400
ttctccttct taccctttct ggcctttcta tggcattaat acctggtctc ttcttgtgta 134460
cttgaaaatg aatctctcat catatttttc cttagtgtca gaacctccat gactccgagc 134520
acttaacgtg gctcattgta aatcacattc aagatctgat cagcctttcc cacgagcctc 134580
cagtacagga cttcatcagt gccgttcatc ggaactctgc tgccagcggc ctgttcatcc 134640
aggcaattca gtctcgttgt gaaaaccttt caactgtacg tcttcatcct gccgactatt 134700
gccagttgca gttttccctg ccttaaaaat ggagtattga aatttttaac tttaatttct 134760
gatttgcaaa atagtcatct tttgttcttt tccttcttgc tgttagccaa ccatgctgaa 134820
gaaaactctt cagtgcttgg aggggatcca tctcagccag tcgggagctg tgctcacgct 134880
gtatgtggac aggcttctgt gcaccccttt ccgtgtgctg gctcgcatgg tcgacatcct 134940
tgcttgtcgc cgggtagaaa tgcttctggc tgcaaattta caggtattgg gaagagaaac 135000
cctgatattg atttatattg aaaatttagc aggccaagca aaacaggtgg ctggcttttt 135060
cctccgtaag tatggtcttg acatggtcac cgatagaaac atggaaacat ctgcaaactt 135120
gccgttactc gtgtgtccga tctgactgtt tcttgtattt ttttctagtc tgcccttact 135180
aggatgaact gtacacatca gttcatcctt tttaaatgag catgaggtta ttttgggttg 135240
ttaggtgtta caaacacact aatgtgtttt tgtctattag agcagcatgg cccagttgcc 135300
aatggaagaa ctcaacagaa tccaggaata ccttcagagc agcgggctcg ctcagaggta 135360
atgctggaaa cacaggtcgt ccttgtgtta ggacaaccca ggatataaag gatatagatt 135420
tgtacgggaa taaattcaca ggacaagaaa tcgatgtgcc ttataggtgg gtttactgca 135480
gaagtgccat aatagaacct tcctactttt aaaacaacca gatctcactt tctaaagagt 135540
aaaggatgac cggcaggatc acgtctgtga cgtgagtgga ggcagtttgc actcctggtg 135600
gctgtttgag aggtagcatt tagaatgcct gtattcactg tcctgtgatg agtgggaaaa 135660
taggttatca ggtttatctt agcaaaatca aagcatgtca tctaattgct aaacaagagt 135720
tggcaaatct gagagacatt actcaatcct tggcatgcag gacttacatc tgcatcctgt 135780
tgccatttta tgtcttcaaa gcatttaatc atttagttgt gtttgcaaag tctttgagaa 135840
gcctttgtca gaaatcccta catctcctat gtgagtgtat ttccatgact gcagaataag 135900
ttaaactttt acctttttcc ttcccttgcg gggcggggtg gggggcaggg attgtgtgtg 135960
tgagagggag agagagacag cagagaagga gaatataatt atcatgctgt gtactttgag 136020
ctgaaactgc aaaaaaggaa aaacacacaa aaattattat gcttttcagt ctttagagta 136080
ccttgtctat tatgcttttc agtctttaga gtaccttgtt gatggtgttt ttaaatggga 136140
ttgggcacaa ttaggtggac agtttgggat gatttttcag tctgtagggc caagctcttt 136200
tgtaatttgc attatgaagt tgtcactctc atagcagatg gcgggagata aactattatt 136260
actttttgac cctagactta gtcttcagtc cagatgaggg agattaaaag attataaata 136320
tcttgtgcca gatgaggtga ttttattttg aaatgaccat gaattcctat cagttgtctt 136380
actgggatat ttgatagtgg aatttgtgca tttgagtctt agatgatctg ttttacattt 136440
attaagaaag cctttattag cttttatact gtgtattgcc tgttgcagtg tttgagtata 136500
aatgaaattt ctggaaaata ttaatggagt acaaactgtg atacttaaaa gtaaactagg 136560
gcctgcattt gtatcatgac ctgtttgagt attgatgaga agatagctgt gaagaaaaag 136620
gtttaaacaa gtgtattttc ctttaagaag ccactaatag tgcatctcct tagagtgtat 136680
atttctagaa tcctagtgtg cagagtttag actaagacta aaaaaaaaaa aaaacaaatt 136740
atactgtaat ttcattttta tttgtatttt agacaccaaa ggctctattc cctgctggac 136800
aggtttcgtc tctccaccat gcaagactca cttagtccct ctcctccagt ctcttcccac 136860
ccgctggacg gggatgggca cgtgtcactg gaaacagtga gtccggacaa agtaagtgtc 136920
cagcgtgtct gcatgggagg cacagggcgc tgagtgcctc tgtcacctgt ggcagataca 136980
gagagtgcag aggaggtgcc gtggacccaa ggagttctgg cgctcggctc ggctcagtga 137040
agctgtggtt agagacgtgg ggggccatca aggtctgagg gagccaagca gtgctgatgt 137100
gggacccttt tggtaggagt gtggggtgag tagttagtgg gtgaatcaag gaatagtcgg 137160
ccgtggcctg caggcccctg actgcacagg ccttcaagca catgtcaatg ccgttagcct 137220
ccctccatct cctcatacct tctggccacc tgtgagttgc actgccactg ccagccattc 137280
tggtatgttg tcagcacctc cactgctcat acctcatggt tagggaccac ctggagcctt 137340
ggtagagcct tggtagagcc ttggtactct actttcctgg acaaagttca gcttatgaat 137400
atgaatttag atttcaaaaa ccagcagccc aagtataaga aagcgaaggt tcagtcctgc 137460
cttcttaggc tctattcgct aagcacctgc cctgccctgg ttgctgggga gagatgagta 137520
aagcagacaa cccaggagag gatggcaaag gggccgctaa cccttagtgg tttagctata 137580
tttggaaggc ctattggaag ttcaccaggt gaagggggag gctgtgaggg tgcccaggca 137640
ggtaacagaa gtccaaaggg gaaaacctgt ggtgtggtga gccgtatagc cacagcctgc 137700
cggccggcag ccctctcagc ctagtgcggt gttcccaagc actggcctag gcctgtagct 137760
ccagggatgt gaagtcccct tgaacgccgc ccatcatgtt ccccttatcc atttttttct 137820
tcccaggact ggtacgttca tcttgtcaaa tcccagtgtt ggaccaggtc agattctgca 137880
ctgctggaag gtgcagagct ggtgaatcgg attcctgctg aagatatgaa tgccttcatg 137940
atgaactcgg tacgggggga gcagtggagg caaggaatcc tcagcttttc ttgtgacttc 138000
caagtgggat ttgtctcatc atcatgtgac ccacttgttg acaacacatg ttggggactc 138060
cagtctgggc agggacggga tgtcggagag actccactct gaatggggcc gggaagtggg 138120
gaggactcca tttcagatgg ggtcgggaca tgggggttat gctgatcgag acagaaaagc 138180
acattgtttc agccacatta gaatccacgg aggtgttgtt ttgaaatcca gctggcccca 138240
aggctgggtg tatggtttgg gatgagaact atctggcctc cactggagga acaaacacag 138300
gatgttatca tctaagctcc atggccaaga cagaatggaa gtcaaggttg cgtatttgcc 138360
gtagacttca acacagtgtc gtaatgcgtg acgtcaataa cttgtttcta gtgtcttgga 138420
agttgatctt tagtcgtaaa agagaccctt ggatgcagcg agatttcctc tactcacacc 138480
tctgttagat gtagtgaggt tcttcacccc ccaaccccag atgtcagagg gcaccctgcg 138540
cagagctagg aggccatgca aagccttggt gtccctgtcc ctcacccgtg ggcaggtcct 138600
gtgagcagtg ggggggccac ctcttgggta tggtgcagcc atggcccaag cagggcttct 138660
tctcagacct actaggacgg gagaaacctc ctggtgcttt agccctgcgt tgatatgcag 138720
caaatgggag ggaagtgggc acctgggagg acaaatgcct gtagaggccg ggagtgacgg 138780
caggtgttca tgaaaagaga ccttgtgggg agggcaacac aacagtgtgt tctgatgtac 138840
tgaagagctc aactgaaaac aacaggagaa ttagcccaaa atccatttac taaaattgtt 138900
tatctttttt tttttttttg agacaaagtc tcgctgttgt cccccaggct ggagtgcaat 138960
ggcgctatct tggctcactg caacctccgc ctcctgggtt catacgattc tcctgcctca 139020
gcctcccaaa tagctggtat taacaggcat gcaccaccac gcccggctaa tttttgtatt 139080
tttagtagag acgggatttc accatgttgg ccaggctggt ctcaaactcc tgacctcagg 139140
tgatccgccc acctcggcct cccaaagtgc tgggattata ggcctgagcc accacgcccg 139200
gcctaaaatt gtttatctta agattcatgc agtgaaagct aacttactga gtgataaatt 139260
tgcttagtga tctgtttatt aggttttcca aatttgctaa ttgggctttg aacagctgta 139320
aaagttctga ctgtaaaaga aagcttcaac ttttggcatt catgatgctt ttctgagtat 139380
taaactaaga tagatgtttt acctgaagga tcggccacca atctttaaat ggctaaacaa 139440
aagggttgct aaaacataat ccaaattgac ataagaaata ccatttttcc aaccaaaatt 139500
ttggcattca tatggctact tttacgtatt tcagctgcat ttgaacatct ttttcaaact 139560
ttagggtggt tggtgtatca ctgaggtctt ggatgacact ttagctttga ttttgttttt 139620
atgaattaaa attgtcatac caaaattttt atttcaagca aatccaagag cataaaaaat 139680
taaaatatta cttaaaatac taagagagaa cagatatata ttttactaag catatgttga 139740
atgaaattgt tcaaatattt ataacaggca tagagtagaa ttttcttaaa aatatttttg 139800
atggtatacc aatttgtatt ttctcagaaa catttgcctt attctttttt ctgttgtgtt 139860
tttcttacct gattgaaagc tcataatctg ttgttattgt ttgttaacct ttaatgctct 139920
gatttcagga gttcaaccta agcctgctag ctccatgctt aagcctaggg atgagtgaaa 139980
tttctggtgg ccagaagagt gccctttttg aagcagcccg tgaggtgact ctggcccgtg 140040
tgagcggcac cgtgcagcag ctccctgctg tccatcatgt cttccagccc gagctgcctg 140100
cagagccggc ggcctactgg agcaagttga atgatctgtt tggtaattaa aattaaaatt 140160
tatcttattt ttaaaaagca ttccagggcc agtatagtac tttgcaccaa gtaaatgtac 140220
aataaaggca gtggatctaa tacattgaaa gcgtttacag aggtagctaa agagcagcac 140280
gggtgtcctc ggctcagaat ttcttcctgt gtgtttgcca ctttgccatt cattgacatg 140340
gtcatggaca tagggctcta agcccttgag gaaggctggg ccagacctca ggggagatgc 140400
agccccaaac cacgtgcagt cctgtggacg gatgtgtaga tgtgccactg aggaacaatg 140460
tcttgagctt tcatcagatt ctcagagaat tgcttgactg cctttcgaag ttgatgcatc 140520
tgtgctcacg tttgcaccca cccacgaggt ccttctgttt caggggatgc tgcactgtat 140580
cagtccctgc ccactctggc ccgggccctg gcacagtacc tggtggtggt ctccaaactg 140640
cccagtcatt tgcaccttcc tcctgagaaa gagaaggaca ttgtgaaatt cgtggtggca 140700
acccttgagg taagaggcag ctcgggagct cagtgttgct gtggggaggg ggcatggggc 140760
tgacactgaa gagggtaaag cagttttatt tgaaaagcaa gatctctgac cagtccagtc 140820
acttttccat ctcagcctgg cagtaagtct tgtcaccgtc aagttattgt agccatcctt 140880
caccctcacc tcgccactcc tcatggtggc ctgtgaggtc agccaggtcc ccttctcatc 140940
tgcacctacc atgttaggtg gatcctaatt ttagagacat gaaaaataat catctggaag 141000
tactttatgt cttaagttgg cctggacatg tcagccaagg aatacttact tggtttgtgt 141060
tagtgcttgt aattcgcccc cagaatgtgt acacgttctg gatgcattaa agtctggcct 141120
gtatccttaa agggccatcg ctgtgctgcc tgccctcagc aaggacacac tttgcagacc 141180
cacagaggct ccgcctccac ctcacaccaa agaaagggag gagtccaaag ggcatcagtg 141240
ccattactca caaaatgata aatacaccct tattctgaac cacgtggagt catatggttt 141300
gtgatccctg tccttcaggt ttcagcttag tggggaagtg ggaaagtcag cgtgtgatca 141360
cagcacaggg tgattgctgc tgattatatt atgtgcctgc tgtatgcagg atgaaatact 141420
ttatatgcgt catcttattt gactctcaca accccctgtg agataggctc tgttactccc 141480
atttgacagg tgaggaaagc aaggcttaga gaatttcagt gacttgccca ggtcctctga 141540
gctaggaagt agccattctg gcatttgaac ccaaggcctg ctatccctag aacccacgct 141600
ctcaaattca acctatgaca gaggcaagcc ctggtgctgt gggagcccca aggaagagcc 141660
tctggcctgg tggccacgta gcccaggaga gatttctaca ggagcccaca gcgctgaagg 141720
agagagaggc agcagagtaa gggggctttg tggcagagag gggactggca ctttggggaa 141780
taggtgggtc aggactgaat gtaatggagc catgtcagag ctgtccttct ggaagggcaa 141840
gggcacctgg acgcgctgcc cctcagtgct ttggacggtt ccacaactgt gattcacacg 141900
gcttccccaa acgaaggtac acgagtgggc attctgtgac tcggtacttc cctttaggcc 141960
ctgtcctggc atttgatcca tgagcagatc ccgctgagtc tggatctcca ggcagggctg 142020
gactgctgct gcctggccct gcagctgcct ggcctctgga gcgtggtctc ctccacagag 142080
tttgtgaccc acgcctgctc cctcatctac tgtgtgcact tcatcctgga ggccggtgag 142140
tccccgtcca tgaacggtgg gttcctatca tagttcctgt ctgcttcacc atgtttttat 142200
tttgtgctgc ctgtttgcca ggtactaagc taggaattgg ggatggagag gtagataaaa 142260
tatgcatcag gaagggctgg gccccatctc ttactctcca atatattgga gtctacactg 142320
gaatttaact ggaatttgct tttttagtca ttttatttag attttgaagt ttcagctttc 142380
atcaaaaata cctctaaact ttatgtctct gtgatctttg gtcttagctg ttttatgtat 142440
ttagtcttat atgatcataa gattaataac attacattca gaagattatt tgttttctgt 142500
cagagttaaa atgtttgttt ttatactgca ttgtaatatt aacgtactgt aaaataaaag 142560
tggcttgttc ttttcaagga acagtatcct caacaagggt cattagccac aatttttaaa 142620
aaattggacg tcatagttta catgttagag ggcgttttga agctttgtat ttttaaatta 142680
aatgttatag agtgatgttt tcatgtttca taattgtttt catctgtgca tttgtagcca 142740
acttgaaaac aaagatccag ggattactac ttaaaagcca gacttcttgg aggttatagt 142800
gatgattttg atagtatctt gagccgtctc ataataacct cagggtgaga gatggccaac 142860
aggagacagt cgagggactt agaaatctga atgaaatctg aagttcaaat cttcagacat 142920
ataccactaa ccaagagatt ggtacctcag tctagtattg tctgtttgtc taaaattggt 142980
tctaaggaat ctaggctagt ctgtctatcc ctttcaactt ttgtgaggct gcacaaatgt 143040
aaaatgttga ataaaaagca ctgatggaag tgtgtagaaa ttcttctctt tgttctgttg 143100
taattttagt tgcagtgcag cctggagagc agcttcttag tccagaaaga aggacaaata 143160
ccccaaaagc catcagcgag gaggaggagg aagtagatcc aaacacacag agtaagtctc 143220
aggacccatt tttttcttac atgttgttcc tccaggactt aaaaatcatt cacagagacg 143280
tgcaccgcgg tgagtgtgga ctcctggaag cgcaccgtag ctccgctgtg tcctgctgct 143340
cctccctagc tgtcagggag gctgtagtcc attgctttgc cagctctttt gtttccgagt 143400
gaacacctta tccgtacaca tgcggctgtc tctgacccta cagaccagct gggatgccac 143460
tgggggagcg ctcccttccc cccgcacttc ccacactctg cagttattct gagatccttg 143520
agggcaggga acaggtttgt cttctttgtg ttctcagaaa ttaatgctcg gcctctggtc 143580
agcaagcaac aaccttttgt tgagtgataa tgaataaata aatgtttccc acatgagtat 143640
tcagtaacct cagtgtcagg ttcagccatc tgttttggtg gatatttaaa agaaaattcc 143700
gcttttccta cagaaaaaaa aaaaaatcca aatcccagtg atttaagcca gttatagact 143760
tagacatata ctacggcttt tcatgcactt tcctcccaat tctagagtag gtattttact 143820
aggaaaatgg tggcagtgcc tgttgggagg aagattcttt ggccaagtgt cttttgttct 143880
tgccagggcc cctaggctgc tggggtgctt cagcttcttt agcccagtgt ctggtgggga 143940
atggcccctg ttgcctgtcc cacagaggtg ggggtgcctc acctggagcc tgtccacaca 144000
ttttacacag cacgcttacc tggagcatca ggcatctttt ccatgctctg tggctcagga 144060
aacacgcctt ttcaatcatg agtgcaccag tgcttttggg ctttttctcc ccgcttttgt 144120
gcaatcctgg ttgtggatgg agttttcctg tctttagtct tctgcatagt acttttctct 144180
tctggttccc ggttcaaggt tttgtaatta gagaatgacc cagaagcaat ggcattttaa 144240
tgcacagcca aggacttctc tgaatttgta tctcaaacct ctgtgggtcc ttcaggcttc 144300
agtttgtgat ttcatgattt cttgttgcta cctaaggaat atgaaaacac ccacctccct 144360
actctgcatc ttccagccga gtggcacctc aggctgtgga tcctgtgctt ctgtggtgag 144420
gataagaata gtgccaaccg tgtggattga aatcaatcag ttaatccctc catgtaaagc 144480
acctggaacg gatgacagtc ttgttatgaa tactcaacaa atgctatcat gatttttagt 144540
tagatttcca ttgctttaaa acagttgaga catcttggcg gtttgagtta gagcaacggg 144600
ccctgaagtg ggttctgttt gggtgaagat gattatgctt attccccatg gccctcttta 144660
ggcaagagtg ggaagctttc tttgtttttt taatcacctc gataggacgt tacttcttaa 144720
aggtcatcca ataaatatta ataggccggg cgcggtggct cacgcctgta atcccagcac 144780
tttgggaggc cgaggcgggc ggatcacgag gtcaggagat cgagaccatc ccagctaaaa 144840
cggtgaaacc ccgtctctac taaaaataca aaaaattagc cgggcgtagt ggcgggcgcc 144900
tgtagtccca gctacttggg aggctgaggc aggagaatgg cgtgaacccg ggaggcggag 144960
cttgcagtga gccgagatcc cgccactgca ctccagcctg ggcgacagag caagactccg 145020
tctcaaaaaa aaaaaaaaat attaataaag ccaactcgtt agcgtggggc ttaattgctt 145080
aagtccaatg agaagtcctt ctctatccta ggaagttgcc caaactgtag aatctcgtgg 145140
cctgtgggta atagccacgt aatacacact cactgcctca acaaatcata ttttagtagg 145200
tatgatattc tagactcaag acaccattct gtggatcttc ccaagggtgt gaagtgtcca 145260
cagcgtctgc cttgggagtt tccatgccca ccagaaccat gccccaagcc cctcaagcac 145320
tctgacctag gaaagccagt gaagcaagga tgacaacatg gccctttgat actagctgag 145380
ggacagacac aggtcctggg agaccagaga aagacgaggg gcagaggagg tgtcctaaag 145440
gaagtctgag gctgaggagc cacaggatgg cttccagctg tcacaggctg ctgctggcct 145500
tatcacagag agtgggccag agggctggga accaaggcca gagctcaggt tcaggaccat 145560
tccagcaatc ccagcagaaa atggggagaa ttgtatggta taggcggata tgaaggtaga 145620
atctgcaggc cttcagtggc caactcagag tctaagtgga ttccacagtt acagcttgag 145680
cagctggttg taggtcatgc tttctacact gggcatatag gatgtgtttt ttaaaaagtc 145740
ctctcttaac cgttgcttgt ttagatccta agtatatcac tgcagcctgt gagatggtgg 145800
cagaaatggt ggagtctctg cagtcggtgt tggccttggg tcataaaagg aatagcggcg 145860
tgccggcgtt tctcacgcca ttgctaagga acatcatcat cagcctggcc cgcctgcccc 145920
ttgtcaacag ctacacacgt gtgcccccac tggtgagtct gctcgttcct tgcagaagac 145980
caagtacggt gaaaggcacc ggtaggccct gggctgggca cacgtgagag ggcgggacag 146040
aatccccgca gcccagaggc tgcctgctgt ggttctggtg cccactgtgg ttctggtgcc 146100
aggctgcttt cctcaggcac cacgtgtgga ggtcgctagt agaaatactg ggttttctaa 146160
aatgaactga ggccctacat ccctaagaga ttagtgttag acctgattct agagcaacta 146220
gaccactttg cttaatagca gaccagaaac cacaccccct cgagtgagtg agattttcct 146280
ttggagataa ttcatgtttt tctacacagt tttgcagttg tcttcagaat tggtttaaag 146340
taggtgttat tgccaggcgc agtagctcat gcctgtaatc ccagcacttt gggaagccaa 146400
ggtgggcgga tcacttgagg tcaggatttc gagaccagcc tggccaacat ggtgaaaccc 146460
catctctact aaaaatataa aaattagcca ggtgtggtgg tgtacgcctg taatcccagc 146520
tactcaggag actgagacag gagaatcgct tgaacccagg aggcgaaggt tgcagtaagc 146580
cgagatcgcg ccactgcact ctagcctggg caacagagca agactccgtc tcaaaaaaaa 146640
aaaaggtagg tgttattgat cagaaccctt gtttcagata acatgaggag cttagcttga 146700
ggagagtgag ggttgatgga gggggactga cttctgccca gtgaaatggc atcatctccc 146760
accagcccgc tgaaataaga tgatggggcc tgttccttag ggcctgcagc atcctcaggc 146820
aggaaagaaa ggccgacctg gcagggtgtg agccagcagg tgtaggtcag ggagaatgga 146880
gccaggtccc agggaagagg cttgtggctg cctgagaagg gtgcgtgcct gcctgtgtgt 146940
gtgtgtgcac gtgtgtgtat gtatgctgga gagtctaggg aggcttgctc caaggacgca 147000
gtattgtttg atcctgagag ataaggattc tgccgcaggg aatgaaggta ttccagatgg 147060
cgggcttatt ccgaagaaga ggccagtgcc tggcggtgct ggaagcagtt gcagaacagg 147120
gagttgtagg ctttcctggg aagagagcag caggggtgct ggagaagcag gccacacttg 147180
ctgcatgggg ttgctctcgg ccccactctt ggtgcacagc gagtcactgt gggttcatta 147240
gcatctggtt atgagacagt aactgctcct ttggaggggc tcgtggagac catgcaggag 147300
ggcacggtct tgaggtcatg ccgtccagag cacacctgag gataggccag gacgggctgc 147360
acgctgtagg taaaattcct ccagcaagct cttcactggc attgaggagt tccctgagtg 147420
cggtcatctg gaaggcagct gtaacaggca ctgcagtctc tccctgggtg ggtaccagag 147480
aggagcatag gggagcataa ccgatttaaa gagagggctt tcctgtggtg aggtaagaga 147540
ttagctggtc attatcatag agccccctct gcctttgtgc agatgggctg tgggaatcct 147600
ggggttccgt tgggtccttt gtcacctcac tgaaggcatg taagctgagc tggccagacc 147660
gtgagctgat cctgccactt gaacagcatc aagcctgcct ctggattctt ctgtgcatgg 147720
cacttgtctg agcacctcac gcacagagaa ctggacttca gagtttacag aaataagctg 147780
tatggttcat tttcatgcct gcttgccaat aaacatatct gagctgaacc tcattgaacg 147840
cctgccttta ttctagcaca gcacctgctg tttgtgggcg aggggtgctg tctctaactc 147900
ctgcctgctt ctcccagcac tccctgagtg gggtgtgcca gcagcctcag gatgaggaca 147960
ggaagtggga gggcagagca gatttgggag ggccacttga tggggaagga agtcccagga 148020
agcagttgga gctgttttct gggggagaag gtgccagctc tgggacagtg ttggggtagt 148080
gaggagggag cccagtggag agaagtcggg cttcctgctt cctcacagta tgtctgtcct 148140
gactcaactc ggatgatgtc acttcctttt catcttctca ggtgtggaag cttggatggt 148200
cacccaaacc gggaggggat tttggcacag cattccctga gatccccgtg gagttcctcc 148260
aggaaaagga agtctttaag gagttcatct accgcatcaa cacactaggt actcttgggg 148320
cctctccttc aggtcaccat tgtcggacat ctaccgggag gaaatccaga gcccccagta 148380
ctgggatctt ctcatttgac tccagaaaag atttaagcat gataataata caaacctatg 148440
tgaatacatt ttgcagtgtt ggcaaaactc cttttatact gagaaaatag atcccagttc 148500
ctgtgttttg tggcttgaat cccagctttg tgtattccgg gcttgtttga agtcaggaaa 148560
ggttcatgtg tagtggacaa cgtgagacca aattctgcct tagattttgc atttaggcta 148620
aacagtggca gcacttgtct cagaatgttt tcttgtgttc accagtctga tcctgttgtg 148680
tctcagtggt ccattttctc atatgggaac aagcagacgg gagcagatgg agtcaggttt 148740
cttggcactc gccttcccca gagcctagag gcagcatggg gagaaagcag gcttggggct 148800
cagacagtcc tggtctgctt ccagccctcc tacctgagca gcgcagggca agtccgtcta 148860
acctctagag accctcagtt ttgtcatatg taaaatgggg gtcgtgtcta tttcatagaa 148920
ttgttgcaga tttagaaatt acatttctaa acaaatgtta ccccttattt ctaaataagt 148980
gtctaaatga ataagtcacc acttttgccc ctatttgatg gcaagaggtg tgatcttgtg 149040
gtgggactgt aatcagtcag ttctcagtga ctgtgccctg ctgtggtgtt tcctggaatg 149100
ttcctgtctt gtcctagaaa gtctggcagg ggcaccctga ctccactgtc cagtcctctc 149160
cccagtccct cgggcttctg cagatttgag gcttgtttgg atcccagaag gttgtggcag 149220
gagacacctt gcctctactt tcccctttat aattcaatgt ccaaagagag ccctgagcag 149280
gtacctcacg ccagctgcct cacggagctc ctcctcttcc tggctgtgag gatcggtatc 149340
agtggcctcc tgctctctcc cccttgccta acacgagcac ctttgcttac ttgggtgccc 149400
ttgctcttga actgcccatc ggacgtgcgt gacccaagac tgtgccgcag tccttgcctt 149460
gtctgtgctc attttctttg ttcatttttt tccctgtaac gtaaattgtt atatttgtct 149520
gtatctgtgt ctgaatcagt cctgcacgct ctccttctct ctgtctcttg ttctttcttt 149580
accccgttta tcacggggac cccgatgtcc attgctctag ttctcctgtc ctaagcaccc 149640
catcccgtct ctctggcctt accacaagtg gcgtggctgc ctcagacatc atgatgggga 149700
catgaagcac agctgtcaga aacaactgtt cgttagatac actcgaatgc agctcatcaa 149760
tagggatgga gggtctgtcg gatgtatttt cactgaatcc ccgttcctac cttgatacac 149820
tctttttaat ctattcttct agacaggtca gaggaaccat tactttgact tttaaatttt 149880
tagcagcttt attgaggtag aattcacata ctacagattt cacccactct aagcggacag 149940
cttggtggcc attagtttta tccacagagt tgtgcagcca gctgcacagt ctcagggctg 150000
gactccaggg aagattttag cccatttagt gagtggggca gaagtggccc tggccctgca 150060
cgaggttgcc tgcatgggcg tccctgccct gtccctgtgt ctgctccact gggggttgac 150120
caggctgcca gggccgactt gggcctgtgc cacctgcctc tcatgtgtct cggacagtgc 150180
agccgatgtc tatacttcgg tttcctcaat gatgaaatgg aggggatagt gttccccgca 150240
tcatagaact gtgtgaggtt taagggactc actgcccttg gcgtggagcc ttctccaggg 150300
gccgtgctgt gtcggcgtag ctgtcagctc tccgttacag gcttgagaag ggttgacact 150360
ctctcatgta acatttatat ttctaggctg gaccagtcgt actcagtttg aagaaacttg 150420
ggccaccctc cttggtgtcc tggtgacgca gcccctcgtg atggagcagg aggagagccc 150480
accagaagta aggccacacc ctgtgctggt tggcacatgg gcagttatgg ccgcttgcag 150540
gcctttggtg gggaataaaa taaggcagca agctggtgtt ctttttttct cttaccttat 150600
ttttgaaaga gtagctgaat ggtgtcttga ctgatattcc agagcaggga caaagcctgc 150660
tgaggtctgg gggctgcgat taccaatggc tggaatgcat tttattacgg tgcattccat 150720
gttaaggatc aatacgattg tgccctttct ggaaaatatc ttttagttta tcaatattca 150780
gaggagtgta ggttgaatta aaatgaaaag gcactttata aaggccatga gtagtacctg 150840
gtttcatttt tctaatgtct tgcagagatt ttatcaggct tcttgaagtg ttcacgtaca 150900
ttacgctaac acgatattaa taataactgt gctctggtac agcggagcca gcagaatggg 150960
aagttgtgga atgcaggccc ttgattctga tagaaggtgt ggtttgaact cacagaaatg 151020
acagtttgga gggtagacat atgtcacaag tcatcaagat tgtctttaaa ttcatgcata 151080
gaagctaaca gggtgtcata agcaaggcct gtaaaatgta tgagggaatt caaagataat 151140
ttattaaaaa gtaattcatg tttggagttt tgtgcccaaa ggagtccttg atttgaaaaa 151200
tgggcttttg cccatcagat tgtttcaggg cccgtgtgtg cggaggccct gccttgtgcc 151260
ccgtgagctc agcctgacag aaatcctttg gtagcactta aggctcctct tcctcccatt 151320
gaggcaggga agactctggg ttctgcaggc agaggtggtt gtgggtgtct tgctgctctt 151380
gttgacatgt gggctctcct tccaggaaga cacagagagg acccagatca acgtcctggc 151440
cgtgcaggcc atcacctcac tggtgctcag tgcaatgact gtgcctgtgg ccggcaaccc 151500
agctgtaagc tgcttggagc agcagccccg gaacaagcct ctgaaagctc tcgacaccag 151560
gtttgcttga gttcccacgt gtctctggga catagcaggt gctggggaca gtgggttccc 151620
cgctgaagcg tccagcagct tcaaccaggc cgttttcctt cattgctaga attgaaaaca 151680
ccgtccgtgt ggcctgtgca ggagatgcag acccaaaggt ggcctcctgg tcagtgagaa 151740
gctggaaacg tgacaggaac tgacgtgggg ttattgagca tttaggggaa gacgttagca 151800
gagcaggaat gagcaggcaa ctagtagaac acccacttaa gggctcacgg acaggtgctc 151860
acttaggaag tgagtttcat ttggtattac accaggttcc tttaggcaaa gcggagggaa 151920
agttctggtg tttttcactt gtaagatttt gaaggaaaca aaacactctt tacctttttt 151980
ctaaaatgta ggtttgggag gaagctgagc attatcagag ggattgtgga gcaagagatt 152040
caagcaatgg tttcaaagag agagaatatt gccacccatc atttatatca ggcatgggat 152100
cctgtccctt ctctgtctcc ggctactaca ggtacctgag ggaaagggtg cgggggagcg 152160
gttgtacttg ggctagaatg agagaagact ggcatgctca ccacaccagt gatgcgggaa 152220
gacctgagtg tggtctgagt tggaggctgt ggtgctaaat acgctgcccc tttcataagc 152280
aggagtctta gtcaggccca gggaggaagt aaaatctgga aatgaatgag aagcattctc 152340
tcctgccagt caagaaatga gaagcgaaag aattctcacg ggctgtaaga ccagcaggat 152400
ttaaaagttg aattagttgc ttatgttaag aactcaacca agttcatcta cacaagctga 152460
atctccagct tttcctaaga aaccatgtgt ggcagtggct gcagggcagg gcacagctgg 152520
gcctgagcac cccgctccct gcacctctcc cctccctggg ccctgcctgt cactgcccac 152580
tctcccacca agccttccgg ttgtgtgcct gccctatcac aggcatcgga gcttgtcacc 152640
tggtttaaaa gaagagagtt gtgtggggat ttgggatgca cgtttttcac tcaaaagtat 152700
tttagcgtag agctctgtga ttccgtagct atttaggagt ttaagcacct tgaaggcttt 152760
aattgcagaa agttctatgt ggacgtgcaa tgtgttatac gcagtgtcta tgagactcaa 152820
atgtttatta gggcgttgaa gtaaactgag cacttggagg gccatggatc cagccttcaa 152880
ggagctcata agtcaggagg acccaggagc aatgacctgt catagaaggc agaaaagagg 152940
ggcacagagg tgggtgggag gcatacacag gcagctcctg gagctccaag gggagcaagt 153000
gcttccaggg aagggggcgt ggaggcccct ttggaggagg caagttgatc tggggtctgg 153060
cagagggtta gctggggaca tttagcggga ggctggtgcc cgggaattgg ggggatgccc 153120
agcagaaaga catgaggagg ctggcctggg gcgtgggggg gtgtgaaagg ttaagtgggg 153180
gcattatcct gctcccgctc ctgccggctg tatctggtca gcctgggcac cgaggtgggg 153240
ttctggaagg cactgttcac caaaatgctt atctgggtcc cccagagagc ttgcctgcct 153300
ggactgtcgg ctcgcctgca actgctgact cctaagcttt tgcagctcag cccacaacca 153360
gttcctattc acagaggtgg gagctgaggg gtgacaagtg actgctgcag tcttatttgt 153420
catagagaaa aagtgacaga gtccagcttg cccactggcc ctgccagctt aactggttat 153480
aaagtgacaa atccccaaga cccacagggc tctgcacaac ctgggccctc ctgccagtgg 153540
cggcgagggc aggtggctca cggctgggtg cctgtctggg caggagctgg gctggtatgg 153600
ggtgggcctg cggccctgcc cccctgtgca gatcaagact cagggtgctg gtgttcacag 153660
gtgccctcat cagccacgag aagctgctgc tacagatcaa ccccgagcgg gagctgggga 153720
gcatgagcta caaactcggc caggtcagtc tcgcgccccc gccgcctggc ctctgtccgt 153780
ttctgtcctc agactttggc gcttgacaca cccaggagaa aagctcagtg cactttttaa 153840
atgaaaggaa gttttccttt tttttaaaaa aaaatttaat gttcattgtt tttatctgtt 153900
ttattcctag gtcccgcaag cagaggaagc attagttttg tttttattta tgttctgtat 153960
tccagaaagt agttaagaga cctcacatgt agcgatagag atgtgtgtaa gagacagtga 154020
gagggcgtga cttggactta agcaaggacc gtgagacaca aaaagggggg tgaggacaga 154080
gtggagtcag ctgaaatgct caggaggaag tagacgccat gaagggccat ggtatggggg 154140
gccgcaggcg tggccgtgag tgtccctggg gccagctctt ggggggctcc ctgagtgtcc 154200
ctgtccctgt ggccagttct gggtgggagc cccgtgtgca ggcagacagc tcggccactt 154260
cctagcaggt cacattggtc tgtgcttctg tttcctcctc agataagtga agggattcaa 154320
gggtctgggt gtggtggcta acacctgtaa tctataacat tttaggaggc tgaggcagga 154380
ggcttacctg agctcaggag gttgaggctg cagtgagcca tgattgcacc actgcactcc 154440
agcctgggca acagaccagt actctgtccc ttaaaaaaaa atgtaaacag aaacgtaggg 154500
ccatttgcat atgatggcac atggcgtgga gccctacagg tgtatgctgg gcggggcccg 154560
gctgtgctgg ccgacttgca cctttccctc caccccggtg ctgtgtcttt cgctcaccgg 154620
gttcctgatt tagtgaaagc agttgtgcag gacagttctc tttgtagctt ttgtttctgt 154680
ggaaatgggt cagaatatgg tgtttagaaa cacttatgag ctctgagagt ttcctcttct 154740
gagttcctgg cctgcagcct tcacagcaga aaccctgtga tgtcacaagc ctgtttctgt 154800
tccctgctct ctgcctgtac tgtcctgttt tgtgcctgcc ggtttcagtg acaggaagca 154860
gggagctact ggaccagcct gtatttttct agacatagtt ggaaaaagaa gtcccactct 154920
tctgtccttt cacctttgac agatgtttcc accccaagat aagtgaaaat gaccaatagg 154980
atgcactgta tttttcatga aagtgtttct gaagggcagg ctgagagtga gaggcctggg 155040
gctcactggg tgcctctggc cttgtcctgg gcccagggac actggtctgt gcccgaggta 155100
ttccctatcc ccccaacccc gctgcatttg gccacatcct tcaatgtttg cgttgtgtcc 155160
agcgtccgca aaccaactgt catgggatca tactggggct gaagtacggt cccacccctg 155220
ccctgtctgg ggctgaagta cagtgccacc cctgccctgt ctggggctga aggacagtgc 155280
cacccctgcc ctgtctgggg ctgaagtaca gtgccacccc tgccctgtct ggggctgaag 155340
gacagtgcca ccccttccct gtctggggct gaaggacagt gccacccctg ccctgtctgg 155400
ggctgaagga cagtgccacc cctgccctgt ctggggctga aggacagtgc cacccctgcc 155460
ctgtctgggg ctgaaggaca gtgccacccc tgccctgtct ggggctgaag gacagtgcca 155520
cccctgccct gtctggggct gaaggacagt gccacccctg ccctgtctgg ggctgaagga 155580
cagtgccacc cctgccctgt ctggggctga aggacagtgc cacccctgcc ctgtctgggg 155640
ctgaaggaca gtgccacccc tgccctgtct ggggctgaag gacagtgcca cccctgccct 155700
gtctggggct gaaggacagt gccacccctg ccctgtctgg ggctgaagga cagtgccacc 155760
cctgccctgt ctggggctga aggacagtgc cacccctgcc ctgtctgggg ctgaaggaca 155820
gtgccacccc tgccctgtct gggatgttta gcccctagat gccactggac tgagccgcta 155880
cttgcttttg ggaaagaggg gtgggggtta ggggtctggg cgaggggagt gcaggggctc 155940
ctccttggcc tgagagctgt tcatacagac tcctcgccca ctccctgcag ggtgctgggt 156000
cccagggggg aaatggccct tggtgccaag aacgtgagtt ggggctagtg ccagtgatga 156060
tggagaacag ctttttatgg gcacacagcc cacagcactg tgccaagtgc tcgaggcttc 156120
ccgagaacca ggcagaaagg aggacagtcg aggtgtgctg actgcgtggt ggctgcgtga 156180
tctagagcgc gggtcacaaa ggcgcgaggg agctctggcc ttgggtttac cgcaatgact 156240
gccagtgcgg gagactggaa aaggaatctc acgtattggt tccgtgtttt ggggactcca 156300
ttcagatgtc acttaggagt gaaagcatcc cttcgtagag cctctttctg tgtcaccctc 156360
ctcagctgct cctggggttg actggcccct gattcatgcc tttagcatgt gctggagctt 156420
cccagcagct gtccagcccc tgccccaccc tctctgtggg ctcccttgcc cgtaacctgg 156480
ggtgtctgaa cgacccttgc taaggggcag actgttagac ggtaggcatg tgctgagtcc 156540
cagtggccac acccacccac caggagcctg gcactgtggc cgcagcactg agcagtgccc 156600
cgtttctgtg gcaggtgtcc atacactccg tgtggctggg gaacagcatc acacccctga 156660
gggaggagga atgggacgag gaagaggagg aggaggccga cgcccctgca ccttcgtcac 156720
cacccacgtc tccagtcaac tccaggtttt ccaatggcct ttttcttttt aacagaaatt 156780
tgaaatttct tatcagtcat ttgatttgtt tgaggtgctt cttgaaatga gcctctcatc 156840
tcatgtactt ggaaaatacc catctcgcat attccacagg aaacaccggg ctggagttga 156900
catccactcc tgttcgcagt ttttgcttga gttgtacagc cgctggatcc tgccgtccag 156960
ctcagccagg aggaccccgg ccatcctgat cagtgaggtg gtcagatccg taagtgagcc 157020
ttcccattcc cctcacacct gcacgtgcca cacgcaccac acacgccaca caccccacac 157080
acacacaccg cccacacaca tgccacttgc acacacaccc ctcatgcatg caacacacac 157140
acaggccaca cgcaccatag acaccacaca cacatgccac atgcacacac atacacggca 157200
tgcaccatac acacaacaca cacagcacac atgccacaca cacacgccac accacatgca 157260
ccacacacat gccacatgca cacacactcc acatgcatgc accacacaca cacacacaca 157320
ccacacacac cacatgcacc acaccacaca ggttacatgc acacaacaca cacatgccac 157380
gtgcacacac cccacacacc acatgtatgt gccacacaca gcacacaacc acacacatgc 157440
accacacaca tgccacatgt gcatgcacca gacacatggc acacactaca cacacgccac 157500
gtgcacacac cccacacaca tgtacgcacc acacacatgc cacacacaca tgcaccacac 157560
acatgccaca tgtacacaca tgtatataca caccccacac cacacacaca ccacttgcac 157620
accacgcaca cacaccacat gcgcacacac acaccacata cgccacatgt acacaccata 157680
cacacaccat acatgcacca cgtgtaccac gcacccacac agacacagca cacgcataca 157740
ccacacacac acgcacacat gcgtcccgca cagtaatgtc tcttgggtgt aagaacacga 157800
cttgccagta gtagcgttct ggatgcgttg cctggattct aacagcgcga ttctcccctt 157860
gccctcctgg ttttccacat ctccagcttc tagtggtctc agacttgttc accgagcgca 157920
accagtttga gctgatgtat gtgacgctga cagaactgcg aagggtgcac ccttcagaag 157980
acgagatcct cgctcagtac ctggtgcctg ccacctgcaa ggcagctgcc gtccttggga 158040
tggtaagtga caggtggcac agaggtttct gtgctgaagc cacgggggcc catctgcctt 158100
gggacctggt gttggccaga ggtgccgggt gcggctgcct ccttccaaga gttgacccga 158160
accggactcc acggcccacg tgagctgcag tgcttctcag atggaggggg ttcagcgacg 158220
gtcagtgcca ttcacaggtc actgtgatgt gggttgtggc ggccaagcca tggtttgggg 158280
tcccgtatcc ctgggcttat gacatcattg tagtagccca tccccacaga accacggtgt 158340
gtggtggcgc tgaggcatcg tagatggtgg aaatgctact ggcttcccca tgctctgccc 158400
tgaggcctga ctgcctcact ccccttctca gttatgttcc aggccccccg agcttcctgg 158460
ctggacagct tctctcctgg gggccgtttt gtcacagtga ccctgtgttt ctagtcccaa 158520
atctgggtgc tatagtctct ttttagcgtg gtggttgtct tagtcttttt tggctgctac 158580
cacaagttac cttagactgg gtaatttata aacagtggaa atttacttct caccgttctg 158640
ggggctggaa gttttcatgg tcaaggtgcc agcagatttg gtgtgtgatg agggctgctc 158700
tctgcttcat agatggcatc ttctggctgg gtcctcacgg tggaaggagt gaacaagctc 158760
cctcaggcct tttagaaggg ccccaatcca caagggctct cccatcatga cctcatcacc 158820
tcccaaggcc ccaccttctt gtactgtggc actgcaaatt aggtgtcagt gtaggagttt 158880
caggagggat agaaacattc agaccatccc agcggtcaag tgttcatcct cttgagttcc 158940
tccttattct gcttctggtt tatcaggatt cagccagtgc agcatggtac ctgtattctg 159000
tggcacatca ccacatggta tttgccaagt atccatcacc tgcacacgtg aaatcattgc 159060
ccgtgggtcc cgacatctgg cgaagcatat tcaaggatgg cagaactgtc agagctggca 159120
cctctggttc cttgtcatgt ggcattacct agtaatccat tttatgatag caatggaaac 159180
tcatttcttc aacaaacacc tgagtggctg ccgtgtgcca gccgtctggg gcccttggtg 159240
agaatggcat ggtggtgccc atcagggcct gcctagcccg tgctctggac gggctcctgt 159300
gtgtcaggaa cgacaatgct gtcatgacgg tgaatgattt ttttttttgc catcactcca 159360
gccgctaaca tttgcggagc tcttcctccc gcacccccac ctgacaaggc caagggtgac 159420
cttggcccca ccctaggcgg ccaaggtcag aggttagctg gcttgtctgg gtcacacaaa 159480
atgcagcaga ggttgaggtg agcacatgtc cgtgacctgg agcctgactc cctctctgcg 159540
agtcttgact gctcttgcct agactctgtc ctccccgagc ccaaacgcca gtcatcttcc 159600
cttgtgggtg tccttcagcc tggtgccatg ctggtgactc agcagccgtc cagggagtgg 159660
aaacaattga gtgtgtgggt tccctgtgtg ggcatctctc ttcacggcga acaccctctg 159720
ggtgttgccc acacgatgtc aaagcggctc ttggaagggg tccttctcct ttgtgggaag 159780
tttcagctgc tgggctaact tgaattgtaa ctgtggtttt gtgctcaggc ccagatcccc 159840
ctaggcaagt gttgtgccat cagtaatcaa atgagaaata atcattttga aaagcagatc 159900
ctaaggcagg atggtcatgg acactcactc ccagctcttt gtgcactcat gctttctgga 159960
agatggccat cctctgtgaa ggttttcagc gcgtcatgct tggtacccac gtatccagag 160020
catgtcgttt tgaggtattt gcccaccgtt gtgaaatccg tgccacccga gagcaggtcc 160080
tgatgtgggg ctttcagaag tgggacctgg ggccgtacgc agtccttagg gaggggccgt 160140
gtggcgttgt gcgtgtgagg ggatagcaca gggtgaggtg ggggcccaag aaggaagtga 160200
cccacaaaga acagcctcct cttttggtcc ttgttcctgg gatggctggg agtggcttct 160260
gtgtcgtccg gccatttccc ctgcggagag gctcctacca ctgccgagaa cctcatcatt 160320
ccacaaaaac aagaggccgc ctggccatcc agcgctccat gggaattctg tgtccccata 160380
gtcttgggct gaaggagggt gacattcctt gctgacttct gcaggggtct cctcactgtt 160440
aaagagcaga ttgaaagtga agaacgtggg ctaagtgttt aggtcgatat ttaaccctgc 160500
taggttttgg atactaagtg aaattgaggc cattttggtt gaagttgaca gaaaccacta 160560
tcagggatcc ccaagactac cccaggcttt tctagaaaga ctctcagcta agatgtgtta 160620
tggtaaaagc acacaaaaca aaatcagcaa agaaaattag caagggcaga ggcccatggg 160680
gcgatgtccc gaggacacca ggcttgagct tccagaatcc tctcccagcg gggtcgtgca 160740
ggacgcactt aactccccgc acagtgagcc gtgacagcgc gtgtgcagtg tcgtcgccag 160800
gaaagcacac tagagactcg gtgccagggt ttttactggg ggctgggcac atgggcaccc 160860
tctgcctgcc tcgtgcccag actctggact cccggaggga aggcaagttc tcagcaccaa 160920
ccctggtgcc cacacaagca gctgagcaca gggagcccct cctcagtgag gatggtgggc 160980
accgtcccaa caccagccag gggccagcct tgcacacagg cctctcagga tggtctccgg 161040
cctgctgtgt agtctcttct gcacacaagc gtgagggcag cgcccccgcc tcggctgtgg 161100
ggaggagcca ctgggacgtg agctctggtg gcatgcagca gcttttgtct gtgtgtgcct 161160
aggacaaggc cgtggcggag cctgtcagcc gcctgctgga gagcacgctc aggagcagcc 161220
acctgcccag cagggttgga gccctgcacg gcgtcctcta tgtgctggag tgcgacctgc 161280
tggacgacac tgccaagcag ctcatcccgg tcatcagcga ctatctcctc tccaacctga 161340
aagggatcgc ccagtgagtg ggagcctggc tggggctggg gcgggggtct cagaatgagc 161400
tgtgaaggaa gcagcatcac cctctccaag tgcccaggct cctggccaga tggcaggcca 161460
ggtatcagtg ggaacccagg tgggtgccat ggctgaggtc agtgagacgc aagagcacag 161520
gtgcgtccta gaggcttcct cgggcacctc cagcgagctg gagctctcgc ctctgctgct 161580
gtctcatgtg gcgcttagca cactctccca cgtgcccatt cctgactctg ctctcgaggc 161640
catcggctct cattctctgc tcccagaacc ctgttattac ccaggctagc ctcctctctg 161700
caccttcccc gccctggccc agtacctccc tcttgtttcc actgtgattc cgacctcacc 161760
ttatcttaaa gctgctggac ggcaggttct gtacacacgt gtccttgaca aagcacggct 161820
ggtgccgcaa cccctcagcg agcaagtcaa gctcttcaca gcgatgtctt acaagcgcag 161880
agggctctgt gacaccctgg tctcaccgcc actcttccaa agtcgcagag gctttagcag 161940
agatgggccc agcctctctg agtcataggc ttctgcacac gggagctgtc tttagaggga 162000
gggtggaatt tcatcagcca cccacatggg ggagttgagg gcaagaatta ggagcaaaga 162060
tgggaagggg tctgggagga atggccagtg atcccctttg acaagtgggc aggaaacggg 162120
ggctaggtca aagttgagtg gaagacctgg agggagacgg gaaggtctct gtaggcacag 162180
ttcagacagg agggaggtgt gagccagggc acatgccggt ggccgtctgg caggatttgg 162240
gacatgctgg agcagggaca gcggctcatc aggggccatt gccctcatcc aggccagagt 162300
gtcacaagcc cgtggggagg cccttctcgc ctgtcatcct tgctgggcag tgggtgctgt 162360
gctagcagga caggcggacg gctggcaact gtctctgcat ccctggagcc tggcataggg 162420
ccaagtcaca cggggcacag gcctgcaaat caggcacata tgttggtgca gtgacgtgat 162480
tttggggggc agccccagaa caggccccag acacaggcca aagccctgcc tgtgctggtg 162540
tgttgggctg ttctatggct cttgctgtgg gcatggagga ctcagggaag gagagttgag 162600
gtggtccagg agttgcgttt gggatgcaga gagcttgtgg catccaggta gaaatggtgc 162660
gtggggctga cctcagcacc atgggcagag gggccgtgtc acgtgcctcc gaggtggagg 162720
tgggaccacg tggtgacaga tatacgcatc actgggcacg tttttgtggg tgttgggggg 162780
catcgtattg gctcctctgt tcacagtggc cactcattca gtccctggct accaggtcct 162840
cactgtgcca tggggaaggc cggcgctgtc gggggatcac agaaggcagc acgtcatgat 162900
ggcatgtgcc atgaaggaaa agcacagggc actcaggaag tagaggggac tggcctgggg 162960
tgtgggaatc tagggcctcg ttgagggaca gagagaggaa gtgtgtggtg gccagcatgg 163020
aggtggccac aggggaggct gagttaggcc gagagggcag ggcgttgggg aggtagacgg 163080
gctcagccac tcagggagtg gtcaagcaga ggctgaaggg tcaggccagg ttgcaggggc 163140
ctgggggagc cactcagggt aggcgctccc gggagcccgc ctggcccata gctctacact 163200
cccgcgtggg gccggacatg ctgtgaagcc ctctccacgt tggatggggg tggctgagcc 163260
tggatgctgt ctcccgtttt cagctgcgtg aacattcaca gccagcagca cgtactggtc 163320
atgtgtgcca ctgcgtttta cctcattgag aactatcctc tggacgtagg gccggaattt 163380
tcagcatcaa taatacaggt gagtgggccc tggctgtctt cctctgcaca cggggagtgg 163440
gcttcccttc tcttttcctt gcaggatcat accagtgggc cagttttgac ttggtcggga 163500
ggaggcatga acacctgaga ctgtgcagcg attctttgac acagaggcct ttctccctgt 163560
gcagatgtgt ggggtgatgc tgtctggaag tgaggagtcc accccctcca tcatttacca 163620
ctgtgccctc agaggcctgg agcgcctcct gctctctgag cagctctccc gcctggatgc 163680
agaatcgctg gtcaagctga gtgtggacag agtgaacgtg cacagcccgc accgggccat 163740
ggcggctctg ggcctgatgc tcacctgcat gtacacaggt gagcatgtac acggtgccca 163800
taaggccagc ccaagtcctg ttcaagggag gcaggagcat gctcactcaa gggacctcga 163860
ctaggtgccc tctgatttca cacttctggt gttgccccaa gccggcccca tcaccttgca 163920
agaaaggctc tggagccccc agggctggag tacctggtca gggttgaccg tccctgtggt 163980
cactcatccc atgtggctga gctgggctgg gtcctgggca agcaaggggc tgatatcacc 164040
tgctttcaga tctccaggga ctcactggac ccctgtgtac aaagcactgt ctacagagcc 164100
tattgggttg tatagaggta accttcgtac tgaacacttt tgttacagga aaggagaaag 164160
tcagtccggg tagaacttca gaccctaatc ctgcagcccc cgacagcgag tcagtgattg 164220
ttgctatgga gcgggtatct gttctttttg ataggtaaga agcgaagccc catccctcag 164280
ccgttagctt ccctagaact ttggcctgaa gctgtgcttt tgtgtgtgtc tgctgatccc 164340
ctggcgctgt tgctggagtc ctgccagtga ttccccacca cagcctgacc atgggctgcc 164400
ttggctcagg gttccactgg cgagctggtg gtccttggac cccagcactc aggtgtagcg 164460
ttgaccagtt ccaaggttgt cccagtgcct gcccatctct cctgagggct cagggacagt 164520
acctggcagt tgggggtgtg gcagggggca ggaatgacca gcctctggga gggtggggca 164580
gaagcctgta cagtgaggag gagctggctc agcctggctg cctatcgtga gaggggagcc 164640
cacggggctg tgggaggggg gccgtggtgc ctgtgagcag ggtgaggagc agcggcagga 164700
ggatgaaggt ggaacccaca catgcatctt tgagacccgt gtggtcagtg gcttctgccc 164760
cccaccaccc cccactgctg tgcgtgcata gaattggctt ccctcacctg ctctggaagt 164820
gggttaggag cttggtaggg ctttttctca aggacaaggg cccctgattt gctctcaggc 164880
ctcagtcctg gcgacatggt ggatctggag ccttgttgca ctgccttgcc tgtgctctcc 164940
aatcagggtg gccagtgggg agccatttgg cttttctcaa gagcatactc aggtggacct 165000
tgctccactg tttgaccaga tgaggcattc tgaacagcca agcctgtgct ggtctgtttt 165060
catgttgatt tttttttttc ttttcttttt gagatggagt ttttcccttg tcacccaggc 165120
tggagtgcaa tggtgtgatc tcggctcact gcaacctccg cctcccgggt tcaagtgatt 165180
ctcctgcctc agcctcccta gtagctggga ttacaggcac acaccaccat gcccagctaa 165240
tttttgtgtt tttagtagag acggggtttc accgtgttgg ctgggctggt ctcgaactcc 165300
tgaactcaag tgatccaccc tccttggcct cccaaagtgc tgggattgca ggcgtgagcc 165360
actgcgcccg gcccccatgt cgatttttaa atgcacctct gcatcgttct tcagtcccca 165420
tatgctcact gagcaccact gcgactggca gacgggcaca gggaggcgcc acgaccagtc 165480
ctggccttca aggggcttgt ggtctagtgg gcccaatgct aggtggcgag tgctccaaag 165540
agtgtggtgc acgccttccg cttgaccgct ctccagacgc cacagggagg cacctcgcag 165600
ctgaccacag atttctctct gtggagcagt gtcttcagag cggctgccat gccactgctg 165660
ggcgagggtc tgcgggcggg tagagccagg agcacctgtg aggaagtgca ctgccatttt 165720
cgtagctgct tcccgtgtgt ctcagttaca cacggctggc atgtgtgcac tgatgagacg 165780
ggaacgtgat ggttgctttt cagcactgaa agggatactg ctcagggggc gtgtttcagg 165840
atctggttag ggaagaagca gcgagagcac agatggggcc ctgtgtggta acaagaaaaa 165900
agtcctggtt gacaacagtg ccacgaagcg ttagaacaca tagggatgtt tgtggagcat 165960
ttgcatgtgg aaagcagcaa aaacataatg ggaacgggtt cttttgttat gatttttaaa 166020
aatctctttt gtaacatcct tcccgctgcg ccgtttctgc atattccttt atgtagcttt 166080
caaactcctc ttaggagttc tggtccctac agggcgtggg agcccaggct ttacgtagct 166140
ttcaaactcc tcttaggagt tctggtccct acagggtgtg ggagcccagg gcctgtgccg 166200
agcagcctgc ctccacgagc tagacagagg aagggctggg gttttgcctt tttagtctca 166260
aaattcgtac tccagttgct taggctctga ctttccccac ttggaaagtc cctcacggcc 166320
gagggtccct cccagccctg atttcacatc ggcattttcc ccagtattag agccaaggcc 166380
ctccgcgggc aggtggggca gctgtgggag ctggtgccag tctctgacct gcgtccctcc 166440
tcccaggatc aggaaaggct ttccttgtga agccagagtg gtggccagga tcctgcccca 166500
gtttctagac gacttcttcc caccccagga catcatgaac aaagtcatcg gagagtttct 166560
gtccaaccag cagccatacc cccagttcat ggccaccgtg gtgtataagg tgaggttgca 166620
tgtgggatgg ggatggagtg ggaaagcctg gaggtggagt tgcctccgac ttcccagcag 166680
attcgccagc agagcccagc tcctccgctt taaagcagca atgcctctgg cccccacccc 166740
acccccgcca cccaggcgca gcaggtgctt cccgtccccc cagccctgac actcaggcac 166800
ctgcttgctc cttgcaggtg tttcagactc tgcacagcac cgggcagtcg tccatggtcc 166860
gggactgggt catgctgtcc ctctccaact tcacgcagag ggccccggtc gccatggcca 166920
cgtggagcct ctcctgcttc tttgtcagcg cgtccaccag cccgtgggtc gcggcgatgt 166980
atcctctctg ggtccctggt gctggccccg tttcccttgt caacaccgag gctcatgttt 167040
catgataagg ttttgaaacc taacctttgc aaaaacccca cagatgccag ggtgacaggc 167100
cctcagcccc agggaagtaa aatgctgaca ggggtacaga aaggagcacg tccagacatt 167160
tgctgaccag ggcctctcag aggggccggt gtatggcagg agggtcgcag ctgaggggcc 167220
tttctgtgga gggcctgggt gaggggagcg agggtgggcg gtggtctctg cagacgtccc 167280
gcccactcgc gggctctgtg tggctgggct tctcctgaca ctgcttctca ttagctttgg 167340
tcattgtgcc tcgatcgccc tctcggggaa aggcttaagt aaagatccag ttcccacccc 167400
cagatgctgg ctgccaggag tttccctttc cacagccctt ccccaagaca gaccacaaga 167460
gcctccaagc agcacagttg tcctggtgct gacagcacag ccttgcccgg cgtgcctggc 167520
acggctctgc cctcactgca ttggagcagg gctagtggag gccagcggaa gcaccggcca 167580
ccagcgctgc acaggagcca ggccaggtga gtgctgccga gtgggtgccc tgcctgcagg 167640
gcatccagcc agccaagggt tgcaggaatg gaggtggagg cgctgatgca gctggaggca 167700
tccaggtggc ccttccgggg ctctgctcgc tctccaggct ccctggaccc ctttgtagac 167760
tgtttcagga gaggaactcc caggtgagga cagggaggca gcattcccct catttgccgg 167820
cctttttcct taactcctgc accagcctcc cacatgtcat cagcaggatg ggcaagctgg 167880
agcaggtgga cgtgaacctt ttctgcctgg tcgccacaga cttctacaga caccagatag 167940
aggaggagct cgaccgcagg gccttccagt ctgtgcttga ggtggttgca gccccaggaa 168000
gcccatatca ccggctgctg acttgtttac gaaatgtcca caaggtcacc acctgctgag 168060
cgccatggtg ggagagactg tgaggcggca gctggggccg gagcctttgg aagtctgcgc 168120
ccttgtgccc tgcctccacc gagccagctt ggtccctatg ggcttccgca catgccgcgg 168180
gcggccaggc aacgtgcgtg tctctgccat gtggcagaag tgctctttgt ggcagtggcc 168240
aggcagggag tgtctgcagt cctggtgggg ctgagcctga ggccttccag aaagcaggag 168300
cagctgtgct gcaccccatg tgggtgacca ggtcctttct cctgatagtc acctgctggt 168360
tgttgccagg ttgcagctgc tcttgcatct gggccagaag tcctccctcc tgcaggctgg 168420
ctgttggccc ctctgctgtc ctgcagtaga aggtgccgtg agcaggcttt gggaacactg 168480
gcctgggtct ccctggtggg gtgtgcatgc cacgccccgt gtctggatgc acagatgcca 168540
tggcctgtgc tgggccagtg gctgggggtg ctagacaccc ggcaccattc tcccttctct 168600
cttttcttct caggatttaa aatttaatta tatcagtaaa gagattaatt ttaacgtaac 168660
tctttctatg cccgtgtaaa gtatgtgaat cgcaaggcct gtgctgcatg cgacagcgtc 168720
cggggtggtg gacagggccc ccggccacgc tccctctcct gtagccactg gcatagccct 168780
cctgagcacc cgctgacatt tccgttgtac atgttcctgt ttatgcattc acaaggtgac 168840
tgggatgtag agaggcgtta gtgggcaggt ggccacagca ggactgagga caggccccca 168900
ttatcctagg ggtgcgctca cctgcagccc ctcctcctcg ggcacagacg actgtcgttc 168960
tccacccacc agtcagggac agcagcctcc ctgtcactca gctgagaagg ccagccctcc 169020
ctggctgtga gcagcctcca ctgtgtccag agacatgggc ctcccactcc tgttccttgc 169080
tagccctggg gtggcgtctg cctaggagct ggctggcagg tgttgggacc tgctgctcca 169140
tggatgcatg ccctaagagt gtcactgagc tgtgttttgt ctgagcctct ctcggtcaac 169200
agcaaagctt ggtgtcttgg cactgttagt gacagagccc agcatccctt ctgcccccgt 169260
tccagctgac atcttgcacg gtgacccctt ttagtcagga gagtgcagat ctgtgctcat 169320
cggagactgc cccacggccc tgtcagagcc gccactccta tccccaggcc aggtccctgg 169380
accagcctcc tgtttgcagg cccagaggag ccaagtcatt aaaatggaag tggattctgg 169440
atggccgggc tgctgctgat gtaggagctg gatttgggag ctctgcttgc cgactggctg 169500
tgagacgagg caggggctct gcttcctcag ccctagaggc gagccaggca aggttggcga 169560
ctgtcatgtg gcttggtttg gtcatgcccg tcgatgtttt gggtattgaa tgtggtaagt 169620
ggaggaaatg ttggaactct gtgcaggtgc tgccttgaga cccccaagct tccacctgtc 169680
cctctcctat gtggcagctg gggagcagct gagatgtgga cttgtatgct gcccacatac 169740
gtgaggggga gctgaaaggg agcccctcct ctgagcagcc tctgccaggc ctgtatgagg 169800
cttttcccac cagctcccaa cagaggcctc ccccagccag gaccacctcg tcctcgtggc 169860
ggggcagcag gagcggtaga aaggggtccg atgtttgagg aggcccttaa gggaagctac 169920
tgaattataa cacgtaagaa aatcaccatt ccgtattggt tgggggctcc tgtttctcat 169980
cctagctttt tcctggaaag cccgctagaa ggtttgggaa cgaggggaaa gttctcagaa 170040
ctgttggctg ctccccaccc gcctcccgcc tcccccgcag gttatgtcag cagctctgag 170100
acagcagtat cacaggccag atgttgttcc tggctagatg tttacatttg taagaaataa 170160
cactgtgaat gtaaaacaga gccattccct tggaatgcat atcgctgggc tcaacataga 170220
gtttgtcttc ctcttgttta cgacgtgatc taaaccagtc cttagcaagg ggctcagaac 170280
accccgctct ggcagtaggt gtcccccacc cccaaagacc tgcctgtgtg ctccggagat 170340
gaatatgagc tcattagtaa aaatgacttc acccacgcat atacataaag tatccatgca 170400
tgtgcatata gacacatcta taattttaca cacacacctc tcaagacgga gatgcatggc 170460
ctctaagagt gcccgtgtcg gttcttcctg gaagttgact ttccttagac ccgccaggtc 170520
aagttagccg cgtgacggac atccaggcgt gggacgtggt cagggcaggg ctcattcatt 170580
gcccactagg atcccactgg cgaagatggt ctccatatca gctctctgca gaagggagga 170640
agactttatc atgttcctaa aaatctgtgg caagcaccca tcgtattatc caaattttgt 170700
tgcaaatgtg attaatttgg ttgtcaagtt ttgggggtgg gctgtgggga gattgctttt 170760
gttttcctgc tggtaatatc gggaaagatt ttaatgaaac cagggtagaa ttgtttggca 170820
atgcactgaa gcgtgtttct ttcccaaaat gtgcctccct tccgctgcgg gcccagctga 170880
gtctatgtag gtgatgtttc cagctgccaa gtgctctttg ttactgtcca ccctcatttc 170940
tgccagcgca tgtgtccttt caaggggaaa atgtgaagct gaaccccctc cagacaccca 171000
gaatgtagca tctgagaagg ccctgtgccc taaaggacac ccctcgcccc catcttcatg 171060
gagggggtca tttcagagcc ctcggagcca atgaacagct cctcctcttg gagctgagat 171120
gagccccacg tggagctcgg gacggatagt agacagcaat aactcggtgt gtggccgcct 171180
ggcaggtgga acttcctccc gttgcggggt ggagtgaggt tagttctgtg tgtctggtgg 171240
gtggagtcag gcttctcttg ctacctgtga gcatccttcc cagcagacat cctcatcggg 171300
ctttgtccct cccccgcttc ctccctctgc ggggaggacc cgggaccaca gctgctggcc 171360
agggtagact tggagctgtc ctccagaggg gtcacgtgta ggagtgagaa gaaggaagat 171420
cttgagagct gctgagggac cttggagagc tcaggatggc tcagacgagg acactcgctt 171480
gccgggcctg ggcctcctgg gaaggaggga gctgctcaga atgccgcatg acaactgaag 171540
gcaacctgga aggttcaggg gccgctcttc ccccatgtgc ctgtcacgct ctggtgcagt 171600
caaaggaacg ccttcccctc agttgtttct aagagcagag tctcccgctg caatctgggt 171660
ggtaactgcc agccttggag gatcgtggcc aacgtggacc tgcctacgga gggtgggctc 171720
tgacccaagt ggggcctcct tgtccaggtc tcactgcttt gcaccgtggt cagagggact 171780
gtcagctgag cttgagctcc cctggagcca gcagggctgt gatgggcgag tcccggagcc 171840
ccacccagac ctgaatgctt ctgagagcaa agggaaggac tgacgagaga tgtatattta 171900
attttttaac tgctgcaaac attgtacatc caaattaaag gaaaaaaatg gaaaccatca 171960
gttgttgctg tgtgaggctt gctttgcttc atgagaacct agaccttgct gagctggagt 172020
cttaggaagc agtctcctaa gtgcttctcc agcaggggca gaaactgtcc caccagctaa 172080
catctggcat tatggagggt cccccaggca gctgccagca gggacaggcc ccgtgttttc 172140
tgtagccagg gatgaggaag tggccccagg gcatgggcct ggctgggtgc ttctgcaagg 172200
gccttcccaa accacagtac aggtggtctt cctgccctgc agatgggagc tgtgggagct 172260
gctggagctg ctggagcctt catggtcaag tgacatcata agcttatatg acatacacaa 172320
gcctcaggac ttggcccatg gcactgaagc aggtcatcag gcccagcaca gagactagag 172380
ctgtgttctc acagggccca ccacccttcc acctccttgg ccattgacac ctgcgtccct 172440
ggcccagctg ctcccaggta acccccaaag cagctggcac atcccacctc tggtgtggcc 172500
ggggctgctg tgtgtccgca gggcctgccc cgtctattct agcttgtttg tcctgtctga 172560
accagcgcct actccaagaa gcctctgctc agcccagcgg ggatgcttct aagctccgga 172620
cgagcctctc ggaagccttg gtgattggtg gtgtagtcat cttgggatgc agatgtctta 172680
ccaacctgca agaacaaaaa ccctgtggct tcctctggtg cagggtattt agtcaatgtt 172740
tgctgaggtc ccgtctggtt ctggctaatt ggcaggggtc gtccacccat tctttccctg 172800
ctctgctgtc tgtgccagga gagacggggg ccagtcggcc aaggggccag ctcctgctgc 172860
ctgctcctct tgggcacgtg cgggggcccc ctttctctga gcagggatag ggatcagtct 172920
gccggaggga tgtggtggac aggcctaaag catttggggc ggggcatgcc acttgagctc 172980
cctaaatctg tctcctcata ggtgacaccg ctccagggcc ccccagtggc ctctcctttc 173040
agagctacct aaattctggt cacttcagag aaatggagca cccccttctc cctggtccag 173100
gtgtggacag cctggcacac tgagcacacc tggcatggct ggtaatttca gaaagaagag 173160
gggccggggt ccagtgggaa gcagcggtga acccctcgtg agtgggcttt gcagtccctc 173220
cccatgccac ggcagagctg ccctcaacac agccttcctc ttcctcatcg gagagcacac 173280
cctgtcccct tgccgagctg tgccctgtgc cttcggtggt atttgatttt ggctgctact 173340
ggctttgttg ggatctggaa gtcgcttccc ctgcgtggtg cgtggagcac tgtaagtcag 173400
atgagggaag tagccagggt gaggtgagta ccgggtggag ccgccactga agggactggg 173460
taggggggcc ttgcctctac atgatgtgac acagccaacc gaggacagag gaagccccgt 173520
tcctgggggt gtggggtgca cccctcaggg aagcctgcag tggggcctga ggaaaggcat 173580
cctccgcgag cccacgagtc tggtccatga gcaccgtgac agtgtctgtg ggtagaggtg 173640
gacccggcct tgtgtcatca ccaggacctc ttttgggaaa ccatgtggac atcgcttgcg 173700
ggtcccccag gctctgcagc cccagcagcc tggctgcctt ttgggcaagt ggcttgagcc 173760
acagaggacc cagtcctgtt gcagccacat cctctggggg ggcccgccag tgtggccggc 173820
tttctccacc ctacaccagg cctccaggtg tcctggtcgg gggtgtctgg gccctgggtg 173880
ggccctgtgg acctgtgagg tcagggtcag ggcatcactg gaggcagagg gctgaagttg 173940
tgggtctggg ttccccttgt gtgcacaggc ccctgccctc catgcttggt caggcagcta 174000
cccccaaaac tgctaggaca ggctggtcct gaggtggatc ctggcccctg taccctctgg 174060
acagcccacc cgcccaacct tctaccctgc cccagcggcg gcagtgttgg ccacatcctt 174120
cccctcctgg ccccaattgc tctggggaag tccaggctcc ggagcctgcc caggggcccc 174180
ccgtgatttg ggcccaggac tccacgtggt tctctgcctt cacccaagcc ctgaactcct 174240
cagctgccaa atccccaccc atctgcacag gctgtgctca ccactgctgc tcctggaagg 174300
tgcccctcag tgggacgccc acctcctctc tgggcttctg tgtttgggag ccctgctgcc 174360
cccacccttg gtcagtcccc atgtcctgct ggcctgtcag gcagggcaga aaatccaccc 174420
agaaatgctg agcaggatga gagtctagtt gggcccagcc tcattattta gaagggatgg 174480
aggcctaggg agcatgcttc tagcctgagc ccagcagggc cccgcccatg tcccaggtct 174540
gcaccaggga cagctcctgc cgaggcctga cctgcccctt ctccctcagg tgctgctggt 174600
tgaccagcct ctggccctag gagaccccgt agcgactgag ggtcccagca ggccatgcag 174660
ctttgccaag gtacgagccc ctccccagca ggggacagat gtggggaccc tcccaggcag 174720
gagcagctgg gtgcctggtg ctgccatctg ctgcctgcct ggttcttgtc ctcacattgg 174780
aggtcagtgt gagggctctg cctcgggaaa ggccatggag cttgccctgt ccagggcctc 174840
ccatgtgcac tgagcctggg aagagagggt tggagttgag ccttttaccc tgggaatgct 174900
gcctggagga tggtgcgggt gtggggtggc accctgccag gcagggccct gcctccctgc 174960
gcccactgga actcgggcag gcaggggtgt aggtgcctcc 175000
<210> 2
<211> 13481
<212> DNA
<213> Homo sapiens
<400> 2
gctgccggga cgggtccaag atggacggcc gctcaggttc tgcttttacc tgcggcccag 60
agccccattc attgccccgg tgctgagcgg cgccgcgagt cggcccgagg cctccgggga 120
ctgccgtgcc gggcgggaga ccgccatggc gaccctggaa aagctgatga aggccttcga 180
gtccctcaag tccttccagc agcagcagca gcagcagcag cagcagcagc agcagcagca 240
gcagcagcag cagcagcagc aacagccgcc accgccgccg ccgccgccgc cgcctcctca 300
gcttcctcag ccgccgccgc aggcacagcc gctgctgcct cagccgcagc cgcccccgcc 360
gccgcccccg ccgccacccg gcccggctgt ggctgaggag ccgctgcacc gaccaaagaa 420
agaactttca gctaccaaga aagaccgtgt gaatcattgt ctgacaatat gtgaaaacat 480
agtggcacag tctgtcagaa attctccaga atttcagaaa cttctgggca tcgctatgga 540
actttttctg ctgtgcagtg atgacgcaga gtcagatgtc aggatggtgg ctgacgaatg 600
cctcaacaaa gttatcaaag ctttgatgga ttctaatctt ccaaggttac agctcgagct 660
ctataaggaa attaaaaaga atggtgcccc tcggagtttg cgtgctgccc tgtggaggtt 720
tgctgagctg gctcacctgg ttcggcctca gaaatgcagg ccttacctgg tgaaccttct 780
gccgtgcctg actcgaacaa gcaagagacc cgaagaatca gtccaggaga ccttggctgc 840
agctgttccc aaaattatgg cttcttttgg caattttgca aatgacaatg aaattaaggt 900
tttgttaaag gccttcatag cgaacctgaa gtcaagctcc cccaccattc ggcggacagc 960
ggctggatca gcagtgagca tctgccagca ctcaagaagg acacaatatt tctatagttg 1020
gctactaaat gtgctcttag gcttactcgt tcctgtcgag gatgaacact ccactctgct 1080
gattcttggc gtgctgctca ccctgaggta tttggtgccc ttgctgcagc agcaggtcaa 1140
ggacacaagc ctgaaaggca gcttcggagt gacaaggaaa gaaatggaag tctctccttc 1200
tgcagagcag cttgtccagg tttatgaact gacgttacat catacacagc accaagacca 1260
caatgttgtg accggagccc tggagctgtt gcagcagctc ttcagaacgc ctccacccga 1320
gcttctgcaa accctgaccg cagtcggggg cattgggcag ctcaccgctg ctaaggagga 1380
gtctggtggc cgaagccgta gtgggagtat tgtggaactt atagctggag ggggttcctc 1440
atgcagccct gtcctttcaa gaaaacaaaa aggcaaagtg ctcttaggag aagaagaagc 1500
cttggaggat gactctgaat cgagatcgga tgtcagcagc tctgccttaa cagcctcagt 1560
gaaggatgag atcagtggag agctggctgc ttcttcaggg gtttccactc cagggtcagc 1620
aggtcatgac atcatcacag aacagccacg gtcacagcac acactgcagg cggactcagt 1680
ggatctggcc agctgtgact tgacaagctc tgccactgat ggggatgagg aggatatctt 1740
gagccacagc tccagccagg tcagcgccgt cccatctgac cctgccatgg acctgaatga 1800
tgggacccag gcctcgtcgc ccatcagcga cagctcccag accaccaccg aagggcctga 1860
ttcagctgtt accccttcag acagttctga aattgtgtta gacggtaccg acaaccagta 1920
tttgggcctg cagattggac agccccagga tgaagatgag gaagccacag gtattcttcc 1980
tgatgaagcc tcggaggcct tcaggaactc ttccatggcc cttcaacagg cacatttatt 2040
gaaaaacatg agtcactgca ggcagccttc tgacagcagt gttgataaat ttgtgttgag 2100
agatgaagct actgaaccgg gtgatcaaga aaacaagcct tgccgcatca aaggtgacat 2160
tggacagtcc actgatgatg actctgcacc tcttgtccat tgtgtccgcc ttttatctgc 2220
ttcgtttttg ctaacagggg gaaaaaatgt gctggttccg gacagggatg tgagggtcag 2280
cgtgaaggcc ctggccctca gctgtgtggg agcagctgtg gccctccacc cggaatcttt 2340
cttcagcaaa ctctataaag ttcctcttga caccacggaa taccctgagg aacagtatgt 2400
ctcagacatc ttgaactaca tcgatcatgg agacccacag gttcgaggag ccactgccat 2460
tctctgtggg accctcatct gctccatcct cagcaggtcc cgcttccacg tgggagattg 2520
gatgggcacc attagaaccc tcacaggaaa tacattttct ttggcggatt gcattccttt 2580
gctgcggaaa acactgaagg atgagtcttc tgttacttgc aagttagctt gtacagctgt 2640
gaggaactgt gtcatgagtc tctgcagcag cagctacagt gagttaggac tgcagctgat 2700
catcgatgtg ctgactctga ggaacagttc ctattggctg gtgaggacag agcttctgga 2760
aacccttgca gagattgact tcaggctggt gagctttttg gaggcaaaag cagaaaactt 2820
acacagaggg gctcatcatt atacagggct tttaaaactg caagaacgag tgctcaataa 2880
tgttgtcatc catttgcttg gagatgaaga ccccagggtg cgacatgttg ccgcagcatc 2940
actaattagg cttgtcccaa agctgtttta taaatgtgac caaggacaag ctgatccagt 3000
agtggccgtg gcaagagatc aaagcagtgt ttacctgaaa cttctcatgc atgagacgca 3060
gcctccatct catttctccg tcagcacaat aaccagaata tatagaggct ataacctact 3120
accaagcata acagacgtca ctatggaaaa taacctttca agagttattg cagcagtttc 3180
tcatgaacta atcacatcaa ccaccagagc actcacattt ggatgctgtg aagctttgtg 3240
tcttctttcc actgccttcc cagtttgcat ttggagttta ggttggcact gtggagtgcc 3300
tccactgagt gcctcagatg agtctaggaa gagctgtacc gttgggatgg ccacaatgat 3360
tctgaccctg ctctcgtcag cttggttccc attggatctc tcagcccatc aagatgcttt 3420
gattttggcc ggaaacttgc ttgcagccag tgctcccaaa tctctgagaa gttcatgggc 3480
ctctgaagaa gaagccaacc cagcagccac caagcaagag gaggtctggc cagccctggg 3540
ggaccgggcc ctggtgccca tggtggagca gctcttctct cacctgctga aggtgattaa 3600
catttgtgcc cacgtcctgg atgacgtggc tcctggaccc gcaataaagg cagccttgcc 3660
ttctctaaca aacccccctt ctctaagtcc catccgacga aaggggaagg agaaagaacc 3720
aggagaacaa gcatctgtac cgttgagtcc caagaaaggc agtgaggcca gtgcagcttc 3780
tagacaatct gatacctcag gtcctgttac aacaagtaaa tcctcatcac tggggagttt 3840
ctatcatctt ccttcatacc tcaaactgca tgatgtcctg aaagctacac acgctaacta 3900
caaggtcacg ctggatcttc agaacagcac ggaaaagttt ggagggtttc tccgctcagc 3960
cttggatgtt ctttctcaga tactagagct ggccacactg caggacattg ggaagtgtgt 4020
tgaagagatc ctaggatacc tgaaatcctg ctttagtcga gaaccaatga tggcaactgt 4080
ttgtgttcaa caattgttga agactctctt tggcacaaac ttggcctccc agtttgatgg 4140
cttatcttcc aaccccagca agtcacaagg ccgagcacag cgccttggct cctccagtgt 4200
gaggccaggc ttgtaccact actgcttcat ggccccgtac acccacttca cccaggccct 4260
cgctgacgcc agcctgagga acatggtgca ggcggagcag gagaacgaca cctcgggatg 4320
gtttgatgtc ctccagaaag tgtctaccca gttgaagaca aacctcacga gtgtcacaaa 4380
gaaccgtgca gataagaatg ctattcataa tcacattcgt ttgtttgaac ctcttgttat 4440
aaaagcttta aaacagtaca cgactacaac atgtgtgcag ttacagaagc aggttttaga 4500
tttgctggcg cagctggttc agttacgggt taattactgt cttctggatt cagatcaggt 4560
gtttattggc tttgtattga aacagtttga atacattgaa gtgggccagt tcagggaatc 4620
agaggcaatc attccaaaca tctttttctt cttggtatta ctatcttatg aacgctatca 4680
ttcaaaacag atcattggaa ttcctaaaat cattcagctc tgtgatggca tcatggccag 4740
tggaaggaag gctgtgacac atgccatacc ggctctgcag cccatagtcc acgacctctt 4800
tgtattaaga ggaacaaata aagctgatgc aggaaaagag cttgaaaccc aaaaagaggt 4860
ggtggtgtca atgttactga gactcatcca gtaccatcag gtgttggaga tgttcattct 4920
tgtcctgcag cagtgccaca aggagaatga agacaagtgg aagcgactgt ctcgacagat 4980
agctgacatc atcctcccaa tgttagccaa acagcagatg cacattgact ctcatgaagc 5040
ccttggagtg ttaaatacat tatttgagat tttggcccct tcctccctcc gtccggtaga 5100
catgctttta cggagtatgt tcgtcactcc aaacacaatg gcgtccgtga gcactgttca 5160
actgtggata tcgggaattc tggccatttt gagggttctg atttcccagt caactgaaga 5220
tattgttctt tctcgtattc aggagctctc cttctctccg tatttaatct cctgtacagt 5280
aattaatagg ttaagagatg gggacagtac ttcaacgcta gaagaacaca gtgaagggaa 5340
acaaataaag aatttgccag aagaaacatt ttcaaggttt ctattacaac tggttggtat 5400
tcttttagaa gacattgtta caaaacagct gaaggtggaa atgagtgagc agcaacatac 5460
tttctattgc caggaactag gcacactgct aatgtgtctg atccacatct tcaagtctgg 5520
aatgttccgg agaatcacag cagctgccac taggctgttc cgcagtgatg gctgtggcgg 5580
cagtttctac accctggaca gcttgaactt gcgggctcgt tccatgatca ccacccaccc 5640
ggccctggtg ctgctctggt gtcagatact gctgcttgtc aaccacaccg actaccgctg 5700
gtgggcagaa gtgcagcaga ccccgaaaag acacagtctg tccagcacaa agttacttag 5760
tccccagatg tctggagaag aggaggattc tgacttggca gccaaacttg gaatgtgcaa 5820
tagagaaata gtacgaagag gggctctcat tctcttctgt gattatgtct gtcagaacct 5880
ccatgactcc gagcacttaa cgtggctcat tgtaaatcac attcaagatc tgatcagcct 5940
ttcccacgag cctccagtac aggacttcat cagtgccgtt catcggaact ctgctgccag 6000
cggcctgttc atccaggcaa ttcagtctcg ttgtgaaaac ctttcaactc caaccatgct 6060
gaagaaaact cttcagtgct tggaggggat ccatctcagc cagtcgggag ctgtgctcac 6120
gctgtatgtg gacaggcttc tgtgcacccc tttccgtgtg ctggctcgca tggtcgacat 6180
ccttgcttgt cgccgggtag aaatgcttct ggctgcaaat ttacagagca gcatggccca 6240
gttgccaatg gaagaactca acagaatcca ggaatacctt cagagcagcg ggctcgctca 6300
gagacaccaa aggctctatt ccctgctgga caggtttcgt ctctccacca tgcaagactc 6360
acttagtccc tctcctccag tctcttccca cccgctggac ggggatgggc acgtgtcact 6420
ggaaacagtg agtccggaca aagactggta cgttcatctt gtcaaatccc agtgttggac 6480
caggtcagat tctgcactgc tggaaggtgc agagctggtg aatcggattc ctgctgaaga 6540
tatgaatgcc ttcatgatga actcggagtt caacctaagc ctgctagctc catgcttaag 6600
cctagggatg agtgaaattt ctggtggcca gaagagtgcc ctttttgaag cagcccgtga 6660
ggtgactctg gcccgtgtga gcggcaccgt gcagcagctc cctgctgtcc atcatgtctt 6720
ccagcccgag ctgcctgcag agccggcggc ctactggagc aagttgaatg atctgtttgg 6780
ggatgctgca ctgtatcagt ccctgcccac tctggcccgg gccctggcac agtacctggt 6840
ggtggtctcc aaactgccca gtcatttgca ccttcctcct gagaaagaga aggacattgt 6900
gaaattcgtg gtggcaaccc ttgaggccct gtcctggcat ttgatccatg agcagatccc 6960
gctgagtctg gatctccagg cagggctgga ctgctgctgc ctggccctgc agctgcctgg 7020
cctctggagc gtggtctcct ccacagagtt tgtgacccac gcctgctccc tcatctactg 7080
tgtgcacttc atcctggagg ccgttgcagt gcagcctgga gagcagcttc ttagtccaga 7140
aagaaggaca aataccccaa aagccatcag cgaggaggag gaggaagtag atccaaacac 7200
acagaatcct aagtatatca ctgcagcctg tgagatggtg gcagaaatgg tggagtctct 7260
gcagtcggtg ttggccttgg gtcataaaag gaatagcggc gtgccggcgt ttctcacgcc 7320
attgctaagg aacatcatca tcagcctggc ccgcctgccc cttgtcaaca gctacacacg 7380
tgtgccccca ctggtgtgga agcttggatg gtcacccaaa ccgggagggg attttggcac 7440
agcattccct gagatccccg tggagttcct ccaggaaaag gaagtcttta aggagttcat 7500
ctaccgcatc aacacactag gctggaccag tcgtactcag tttgaagaaa cttgggccac 7560
cctccttggt gtcctggtga cgcagcccct cgtgatggag caggaggaga gcccaccaga 7620
agaagacaca gagaggaccc agatcaacgt cctggccgtg caggccatca cctcactggt 7680
gctcagtgca atgactgtgc ctgtggccgg caacccagct gtaagctgct tggagcagca 7740
gccccggaac aagcctctga aagctctcga caccaggttt gggaggaagc tgagcattat 7800
cagagggatt gtggagcaag agattcaagc aatggtttca aagagagaga atattgccac 7860
ccatcattta tatcaggcat gggatcctgt cccttctctg tctccggcta ctacaggtgc 7920
cctcatcagc cacgagaagc tgctgctaca gatcaacccc gagcgggagc tggggagcat 7980
gagctacaaa ctcggccagg tgtccataca ctccgtgtgg ctggggaaca gcatcacacc 8040
cctgagggag gaggaatggg acgaggaaga ggaggaggag gccgacgccc ctgcaccttc 8100
gtcaccaccc acgtctccag tcaactccag gaaacaccgg gctggagttg acatccactc 8160
ctgttcgcag tttttgcttg agttgtacag ccgctggatc ctgccgtcca gctcagccag 8220
gaggaccccg gccatcctga tcagtgaggt ggtcagatcc cttctagtgg tctcagactt 8280
gttcaccgag cgcaaccagt ttgagctgat gtatgtgacg ctgacagaac tgcgaagggt 8340
gcacccttca gaagacgaga tcctcgctca gtacctggtg cctgccacct gcaaggcagc 8400
tgccgtcctt gggatggaca aggccgtggc ggagcctgtc agccgcctgc tggagagcac 8460
gctcaggagc agccacctgc ccagcagggt tggagccctg cacggcgtcc tctatgtgct 8520
ggagtgcgac ctgctggacg acactgccaa gcagctcatc ccggtcatca gcgactatct 8580
cctctccaac ctgaaaggga tcgcccactg cgtgaacatt cacagccagc agcacgtact 8640
ggtcatgtgt gccactgcgt tttacctcat tgagaactat cctctggacg tagggccgga 8700
attttcagca tcaataatac agatgtgtgg ggtgatgctg tctggaagtg aggagtccac 8760
cccctccatc atttaccact gtgccctcag aggcctggag cgcctcctgc tctctgagca 8820
gctctcccgc ctggatgcag aatcgctggt caagctgagt gtggacagag tgaacgtgca 8880
cagcccgcac cgggccatgg cggctctggg cctgatgctc acctgcatgt acacaggaaa 8940
ggagaaagtc agtccgggta gaacttcaga ccctaatcct gcagcccccg acagcgagtc 9000
agtgattgtt gctatggagc gggtatctgt tctttttgat aggatcagga aaggctttcc 9060
ttgtgaagcc agagtggtgg ccaggatcct gccccagttt ctagacgact tcttcccacc 9120
ccaggacatc atgaacaaag tcatcggaga gtttctgtcc aaccagcagc cataccccca 9180
gttcatggcc accgtggtgt ataaggtgtt tcagactctg cacagcaccg ggcagtcgtc 9240
catggtccgg gactgggtca tgctgtccct ctccaacttc acgcagaggg ccccggtcgc 9300
catggccacg tggagcctct cctgcttctt tgtcagcgcg tccaccagcc cgtgggtcgc 9360
ggcgatcctc ccacatgtca tcagcaggat gggcaagctg gagcaggtgg acgtgaacct 9420
tttctgcctg gtcgccacag acttctacag acaccagata gaggaggagc tcgaccgcag 9480
ggccttccag tctgtgcttg aggtggttgc agccccagga agcccatatc accggctgct 9540
gacttgttta cgaaatgtcc acaaggtcac cacctgctga gcgccatggt gggagagact 9600
gtgaggcggc agctggggcc ggagcctttg gaagtctgcg cccttgtgcc ctgcctccac 9660
cgagccagct tggtccctat gggcttccgc acatgccgcg ggcggccagg caacgtgcgt 9720
gtctctgcca tgtggcagaa gtgctctttg tggcagtggc caggcaggga gtgtctgcag 9780
tcctggtggg gctgagcctg aggccttcca gaaagcagga gcagctgtgc tgcaccccat 9840
gtgggtgacc aggtcctttc tcctgatagt cacctgctgg ttgttgccag gttgcagctg 9900
ctcttgcatc tgggccagaa gtcctccctc ctgcaggctg gctgttggcc cctctgctgt 9960
cctgcagtag aaggtgccgt gagcaggctt tgggaacact ggcctgggtc tccctggtgg 10020
ggtgtgcatg ccacgccccg tgtctggatg cacagatgcc atggcctgtg ctgggccagt 10080
ggctgggggt gctagacacc cggcaccatt ctcccttctc tcttttcttc tcaggattta 10140
aaatttaatt atatcagtaa agagattaat tttaacgtaa ctctttctat gcccgtgtaa 10200
agtatgtgaa tcgcaaggcc tgtgctgcat gcgacagcgt ccggggtggt ggacagggcc 10260
cccggccacg ctccctctcc tgtagccact ggcatagccc tcctgagcac ccgctgacat 10320
ttccgttgta catgttcctg tttatgcatt cacaaggtga ctgggatgta gagaggcgtt 10380
agtgggcagg tggccacagc aggactgagg acaggccccc attatcctag gggtgcgctc 10440
acctgcagcc cctcctcctc gggcacagac gactgtcgtt ctccacccac cagtcaggga 10500
cagcagcctc cctgtcactc agctgagaag gccagccctc cctggctgtg agcagcctcc 10560
actgtgtcca gagacatggg cctcccactc ctgttccttg ctagccctgg ggtggcgtct 10620
gcctaggagc tggctggcag gtgttgggac ctgctgctcc atggatgcat gccctaagag 10680
tgtcactgag ctgtgttttg tctgagcctc tctcggtcaa cagcaaagct tggtgtcttg 10740
gcactgttag tgacagagcc cagcatccct tctgcccccg ttccagctga catcttgcac 10800
ggtgacccct tttagtcagg agagtgcaga tctgtgctca tcggagactg ccccacggcc 10860
ctgtcagagc cgccactcct atccccaggc caggtccctg gaccagcctc ctgtttgcag 10920
gcccagagga gccaagtcat taaaatggaa gtggattctg gatggccggg ctgctgctga 10980
tgtaggagct ggatttggga gctctgcttg ccgactggct gtgagacgag gcaggggctc 11040
tgcttcctca gccctagagg cgagccaggc aaggttggcg actgtcatgt ggcttggttt 11100
ggtcatgccc gtcgatgttt tgggtattga atgtggtaag tggaggaaat gttggaactc 11160
tgtgcaggtg ctgccttgag acccccaagc ttccacctgt ccctctccta tgtggcagct 11220
ggggagcagc tgagatgtgg acttgtatgc tgcccacata cgtgaggggg agctgaaagg 11280
gagcccctcc tctgagcagc ctctgccagg cctgtatgag gcttttccca ccagctccca 11340
acagaggcct cccccagcca ggaccacctc gtcctcgtgg cggggcagca ggagcggtag 11400
aaaggggtcc gatgtttgag gaggccctta agggaagcta ctgaattata acacgtaaga 11460
aaatcaccat tccgtattgg ttgggggctc ctgtttctca tcctagcttt ttcctggaaa 11520
gcccgctaga aggtttggga acgaggggaa agttctcaga actgttggct gctccccacc 11580
cgcctcccgc ctcccccgca ggttatgtca gcagctctga gacagcagta tcacaggcca 11640
gatgttgttc ctggctagat gtttacattt gtaagaaata acactgtgaa tgtaaaacag 11700
agccattccc ttggaatgca tatcgctggg ctcaacatag agtttgtctt cctcttgttt 11760
acgacgtgat ctaaaccagt ccttagcaag gggctcagaa caccccgctc tggcagtagg 11820
tgtcccccac ccccaaagac ctgcctgtgt gctccggaga tgaatatgag ctcattagta 11880
aaaatgactt cacccacgca tatacataaa gtatccatgc atgtgcatat agacacatct 11940
ataattttac acacacacct ctcaagacgg agatgcatgg cctctaagag tgcccgtgtc 12000
ggttcttcct ggaagttgac tttccttaga cccgccaggt caagttagcc gcgtgacgga 12060
catccaggcg tgggacgtgg tcagggcagg gctcattcat tgcccactag gatcccactg 12120
gcgaagatgg tctccatatc agctctctgc agaagggagg aagactttat catgttccta 12180
aaaatctgtg gcaagcaccc atcgtattat ccaaattttg ttgcaaatgt gattaatttg 12240
gttgtcaagt tttgggggtg ggctgtgggg agattgcttt tgttttcctg ctggtaatat 12300
cgggaaagat tttaatgaaa ccagggtaga attgtttggc aatgcactga agcgtgtttc 12360
tttcccaaaa tgtgcctccc ttccgctgcg ggcccagctg agtctatgta ggtgatgttt 12420
ccagctgcca agtgctcttt gttactgtcc accctcattt ctgccagcgc atgtgtcctt 12480
tcaaggggaa aatgtgaagc tgaaccccct ccagacaccc agaatgtagc atctgagaag 12540
gccctgtgcc ctaaaggaca cccctcgccc ccatcttcat ggagggggtc atttcagagc 12600
cctcggagcc aatgaacagc tcctcctctt ggagctgaga tgagccccac gtggagctcg 12660
ggacggatag tagacagcaa taactcggtg tgtggccgcc tggcaggtgg aacttcctcc 12720
cgttgcgggg tggagtgagg ttagttctgt gtgtctggtg ggtggagtca ggcttctctt 12780
gctacctgtg agcatccttc ccagcagaca tcctcatcgg gctttgtccc tcccccgctt 12840
cctccctctg cggggaggac ccgggaccac agctgctggc cagggtagac ttggagctgt 12900
cctccagagg ggtcacgtgt aggagtgaga agaaggaaga tcttgagagc tgctgaggga 12960
ccttggagag ctcaggatgg ctcagacgag gacactcgct tgccgggcct gggcctcctg 13020
ggaaggaggg agctgctcag aatgccgcat gacaactgaa ggcaacctgg aaggttcagg 13080
ggccgctctt cccccatgtg cctgtcacgc tctggtgcag tcaaaggaac gccttcccct 13140
cagttgtttc taagagcaga gtctcccgct gcaatctggg tggtaactgc cagccttgga 13200
ggatcgtggc caacgtggac ctgcctacgg agggtgggct ctgacccaag tggggcctcc 13260
ttgtccaggt ctcactgctt tgcaccgtgg tcagagggac tgtcagctga gcttgagctc 13320
ccctggagcc agcagggctg tgatgggcga gtcccggagc cccacccaga cctgaatgct 13380
tctgagagca aagggaagga ctgacgagag atgtatattt aattttttaa ctgctgcaaa 13440
cattgtacat ccaaattaaa ggaaaaaaat ggaaaccatc a 13481
<210> 3
<211> 3144
<212> PRT
<213> Homo sapiens
<400> 3
Met Ala Thr Leu Glu Lys Leu Met Lys Ala Phe Glu Ser Leu Lys Ser
1 5 10 15
Phe Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln
20 25 30
Gln Gln Gln Gln Gln Gln Gln Gln Pro Pro Pro Pro Pro Pro Pro Pro
35 40 45
Pro Pro Pro Gln Leu Pro Gln Pro Pro Pro Gln Ala Gln Pro Leu Leu
50 55 60
Pro Gln Pro Gln Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Gly Pro
65 70 75 80
Ala Val Ala Glu Glu Pro Leu His Arg Pro Lys Lys Glu Leu Ser Ala
85 90 95
Thr Lys Lys Asp Arg Val Asn His Cys Leu Thr Ile Cys Glu Asn Ile
100 105 110
Val Ala Gln Ser Val Arg Asn Ser Pro Glu Phe Gln Lys Leu Leu Gly
115 120 125
Ile Ala Met Glu Leu Phe Leu Leu Cys Ser Asp Asp Ala Glu Ser Asp
130 135 140
Val Arg Met Val Ala Asp Glu Cys Leu Asn Lys Val Ile Lys Ala Leu
145 150 155 160
Met Asp Ser Asn Leu Pro Arg Leu Gln Leu Glu Leu Tyr Lys Glu Ile
165 170 175
Lys Lys Asn Gly Ala Pro Arg Ser Leu Arg Ala Ala Leu Trp Arg Phe
180 185 190
Ala Glu Leu Ala His Leu Val Arg Pro Gln Lys Cys Arg Pro Tyr Leu
195 200 205
Val Asn Leu Leu Pro Cys Leu Thr Arg Thr Ser Lys Arg Pro Glu Glu
210 215 220
Ser Val Gln Glu Thr Leu Ala Ala Ala Val Pro Lys Ile Met Ala Ser
225 230 235 240
Phe Gly Asn Phe Ala Asn Asp Asn Glu Ile Lys Val Leu Leu Lys Ala
245 250 255
Phe Ile Ala Asn Leu Lys Ser Ser Ser Pro Thr Ile Arg Arg Thr Ala
260 265 270
Ala Gly Ser Ala Val Ser Ile Cys Gln His Ser Arg Arg Thr Gln Tyr
275 280 285
Phe Tyr Ser Trp Leu Leu Asn Val Leu Leu Gly Leu Leu Val Pro Val
290 295 300
Glu Asp Glu His Ser Thr Leu Leu Ile Leu Gly Val Leu Leu Thr Leu
305 310 315 320
Arg Tyr Leu Val Pro Leu Leu Gln Gln Gln Val Lys Asp Thr Ser Leu
325 330 335
Lys Gly Ser Phe Gly Val Thr Arg Lys Glu Met Glu Val Ser Pro Ser
340 345 350
Ala Glu Gln Leu Val Gln Val Tyr Glu Leu Thr Leu His His Thr Gln
355 360 365
His Gln Asp His Asn Val Val Thr Gly Ala Leu Glu Leu Leu Gln Gln
370 375 380
Leu Phe Arg Thr Pro Pro Pro Glu Leu Leu Gln Thr Leu Thr Ala Val
385 390 395 400
Gly Gly Ile Gly Gln Leu Thr Ala Ala Lys Glu Glu Ser Gly Gly Arg
405 410 415
Ser Arg Ser Gly Ser Ile Val Glu Leu Ile Ala Gly Gly Gly Ser Ser
420 425 430
Cys Ser Pro Val Leu Ser Arg Lys Gln Lys Gly Lys Val Leu Leu Gly
435 440 445
Glu Glu Glu Ala Leu Glu Asp Asp Ser Glu Ser Arg Ser Asp Val Ser
450 455 460
Ser Ser Ala Leu Thr Ala Ser Val Lys Asp Glu Ile Ser Gly Glu Leu
465 470 475 480
Ala Ala Ser Ser Gly Val Ser Thr Pro Gly Ser Ala Gly His Asp Ile
485 490 495
Ile Thr Glu Gln Pro Arg Ser Gln His Thr Leu Gln Ala Asp Ser Val
500 505 510
Asp Leu Ala Ser Cys Asp Leu Thr Ser Ser Ala Thr Asp Gly Asp Glu
515 520 525
Glu Asp Ile Leu Ser His Ser Ser Ser Gln Val Ser Ala Val Pro Ser
530 535 540
Asp Pro Ala Met Asp Leu Asn Asp Gly Thr Gln Ala Ser Ser Pro Ile
545 550 555 560
Ser Asp Ser Ser Gln Thr Thr Thr Glu Gly Pro Asp Ser Ala Val Thr
565 570 575
Pro Ser Asp Ser Ser Glu Ile Val Leu Asp Gly Thr Asp Asn Gln Tyr
580 585 590
Leu Gly Leu Gln Ile Gly Gln Pro Gln Asp Glu Asp Glu Glu Ala Thr
595 600 605
Gly Ile Leu Pro Asp Glu Ala Ser Glu Ala Phe Arg Asn Ser Ser Met
610 615 620
Ala Leu Gln Gln Ala His Leu Leu Lys Asn Met Ser His Cys Arg Gln
625 630 635 640
Pro Ser Asp Ser Ser Val Asp Lys Phe Val Leu Arg Asp Glu Ala Thr
645 650 655
Glu Pro Gly Asp Gln Glu Asn Lys Pro Cys Arg Ile Lys Gly Asp Ile
660 665 670
Gly Gln Ser Thr Asp Asp Asp Ser Ala Pro Leu Val His Cys Val Arg
675 680 685
Leu Leu Ser Ala Ser Phe Leu Leu Thr Gly Gly Lys Asn Val Leu Val
690 695 700
Pro Asp Arg Asp Val Arg Val Ser Val Lys Ala Leu Ala Leu Ser Cys
705 710 715 720
Val Gly Ala Ala Val Ala Leu His Pro Glu Ser Phe Phe Ser Lys Leu
725 730 735
Tyr Lys Val Pro Leu Asp Thr Thr Glu Tyr Pro Glu Glu Gln Tyr Val
740 745 750
Ser Asp Ile Leu Asn Tyr Ile Asp His Gly Asp Pro Gln Val Arg Gly
755 760 765
Ala Thr Ala Ile Leu Cys Gly Thr Leu Ile Cys Ser Ile Leu Ser Arg
770 775 780
Ser Arg Phe His Val Gly Asp Trp Met Gly Thr Ile Arg Thr Leu Thr
785 790 795 800
Gly Asn Thr Phe Ser Leu Ala Asp Cys Ile Pro Leu Leu Arg Lys Thr
805 810 815
Leu Lys Asp Glu Ser Ser Val Thr Cys Lys Leu Ala Cys Thr Ala Val
820 825 830
Arg Asn Cys Val Met Ser Leu Cys Ser Ser Ser Tyr Ser Glu Leu Gly
835 840 845
Leu Gln Leu Ile Ile Asp Val Leu Thr Leu Arg Asn Ser Ser Tyr Trp
850 855 860
Leu Val Arg Thr Glu Leu Leu Glu Thr Leu Ala Glu Ile Asp Phe Arg
865 870 875 880
Leu Val Ser Phe Leu Glu Ala Lys Ala Glu Asn Leu His Arg Gly Ala
885 890 895
His His Tyr Thr Gly Leu Leu Lys Leu Gln Glu Arg Val Leu Asn Asn
900 905 910
Val Val Ile His Leu Leu Gly Asp Glu Asp Pro Arg Val Arg His Val
915 920 925
Ala Ala Ala Ser Leu Ile Arg Leu Val Pro Lys Leu Phe Tyr Lys Cys
930 935 940
Asp Gln Gly Gln Ala Asp Pro Val Val Ala Val Ala Arg Asp Gln Ser
945 950 955 960
Ser Val Tyr Leu Lys Leu Leu Met His Glu Thr Gln Pro Pro Ser His
965 970 975
Phe Ser Val Ser Thr Ile Thr Arg Ile Tyr Arg Gly Tyr Asn Leu Leu
980 985 990
Pro Ser Ile Thr Asp Val Thr Met Glu Asn Asn Leu Ser Arg Val Ile
995 1000 1005
Ala Ala Val Ser His Glu Leu Ile Thr Ser Thr Thr Arg Ala Leu
1010 1015 1020
Thr Phe Gly Cys Cys Glu Ala Leu Cys Leu Leu Ser Thr Ala Phe
1025 1030 1035
Pro Val Cys Ile Trp Ser Leu Gly Trp His Cys Gly Val Pro Pro
1040 1045 1050
Leu Ser Ala Ser Asp Glu Ser Arg Lys Ser Cys Thr Val Gly Met
1055 1060 1065
Ala Thr Met Ile Leu Thr Leu Leu Ser Ser Ala Trp Phe Pro Leu
1070 1075 1080
Asp Leu Ser Ala His Gln Asp Ala Leu Ile Leu Ala Gly Asn Leu
1085 1090 1095
Leu Ala Ala Ser Ala Pro Lys Ser Leu Arg Ser Ser Trp Ala Ser
1100 1105 1110
Glu Glu Glu Ala Asn Pro Ala Ala Thr Lys Gln Glu Glu Val Trp
1115 1120 1125
Pro Ala Leu Gly Asp Arg Ala Leu Val Pro Met Val Glu Gln Leu
1130 1135 1140
Phe Ser His Leu Leu Lys Val Ile Asn Ile Cys Ala His Val Leu
1145 1150 1155
Asp Asp Val Ala Pro Gly Pro Ala Ile Lys Ala Ala Leu Pro Ser
1160 1165 1170
Leu Thr Asn Pro Pro Ser Leu Ser Pro Ile Arg Arg Lys Gly Lys
1175 1180 1185
Glu Lys Glu Pro Gly Glu Gln Ala Ser Val Pro Leu Ser Pro Lys
1190 1195 1200
Lys Gly Ser Glu Ala Ser Ala Ala Ser Arg Gln Ser Asp Thr Ser
1205 1210 1215
Gly Pro Val Thr Thr Ser Lys Ser Ser Ser Leu Gly Ser Phe Tyr
1220 1225 1230
His Leu Pro Ser Tyr Leu Lys Leu His Asp Val Leu Lys Ala Thr
1235 1240 1245
His Ala Asn Tyr Lys Val Thr Leu Asp Leu Gln Asn Ser Thr Glu
1250 1255 1260
Lys Phe Gly Gly Phe Leu Arg Ser Ala Leu Asp Val Leu Ser Gln
1265 1270 1275
Ile Leu Glu Leu Ala Thr Leu Gln Asp Ile Gly Lys Cys Val Glu
1280 1285 1290
Glu Ile Leu Gly Tyr Leu Lys Ser Cys Phe Ser Arg Glu Pro Met
1295 1300 1305
Met Ala Thr Val Cys Val Gln Gln Leu Leu Lys Thr Leu Phe Gly
1310 1315 1320
Thr Asn Leu Ala Ser Gln Phe Asp Gly Leu Ser Ser Asn Pro Ser
1325 1330 1335
Lys Ser Gln Gly Arg Ala Gln Arg Leu Gly Ser Ser Ser Val Arg
1340 1345 1350
Pro Gly Leu Tyr His Tyr Cys Phe Met Ala Pro Tyr Thr His Phe
1355 1360 1365
Thr Gln Ala Leu Ala Asp Ala Ser Leu Arg Asn Met Val Gln Ala
1370 1375 1380
Glu Gln Glu Asn Asp Thr Ser Gly Trp Phe Asp Val Leu Gln Lys
1385 1390 1395
Val Ser Thr Gln Leu Lys Thr Asn Leu Thr Ser Val Thr Lys Asn
1400 1405 1410
Arg Ala Asp Lys Asn Ala Ile His Asn His Ile Arg Leu Phe Glu
1415 1420 1425
Pro Leu Val Ile Lys Ala Leu Lys Gln Tyr Thr Thr Thr Thr Cys
1430 1435 1440
Val Gln Leu Gln Lys Gln Val Leu Asp Leu Leu Ala Gln Leu Val
1445 1450 1455
Gln Leu Arg Val Asn Tyr Cys Leu Leu Asp Ser Asp Gln Val Phe
1460 1465 1470
Ile Gly Phe Val Leu Lys Gln Phe Glu Tyr Ile Glu Val Gly Gln
1475 1480 1485
Phe Arg Glu Ser Glu Ala Ile Ile Pro Asn Ile Phe Phe Phe Leu
1490 1495 1500
Val Leu Leu Ser Tyr Glu Arg Tyr His Ser Lys Gln Ile Ile Gly
1505 1510 1515
Ile Pro Lys Ile Ile Gln Leu Cys Asp Gly Ile Met Ala Ser Gly
1520 1525 1530
Arg Lys Ala Val Thr His Ala Ile Pro Ala Leu Gln Pro Ile Val
1535 1540 1545
His Asp Leu Phe Val Leu Arg Gly Thr Asn Lys Ala Asp Ala Gly
1550 1555 1560
Lys Glu Leu Glu Thr Gln Lys Glu Val Val Val Ser Met Leu Leu
1565 1570 1575
Arg Leu Ile Gln Tyr His Gln Val Leu Glu Met Phe Ile Leu Val
1580 1585 1590
Leu Gln Gln Cys His Lys Glu Asn Glu Asp Lys Trp Lys Arg Leu
1595 1600 1605
Ser Arg Gln Ile Ala Asp Ile Ile Leu Pro Met Leu Ala Lys Gln
1610 1615 1620
Gln Met His Ile Asp Ser His Glu Ala Leu Gly Val Leu Asn Thr
1625 1630 1635
Leu Phe Glu Ile Leu Ala Pro Ser Ser Leu Arg Pro Val Asp Met
1640 1645 1650
Leu Leu Arg Ser Met Phe Val Thr Pro Asn Thr Met Ala Ser Val
1655 1660 1665
Ser Thr Val Gln Leu Trp Ile Ser Gly Ile Leu Ala Ile Leu Arg
1670 1675 1680
Val Leu Ile Ser Gln Ser Thr Glu Asp Ile Val Leu Ser Arg Ile
1685 1690 1695
Gln Glu Leu Ser Phe Ser Pro Tyr Leu Ile Ser Cys Thr Val Ile
1700 1705 1710
Asn Arg Leu Arg Asp Gly Asp Ser Thr Ser Thr Leu Glu Glu His
1715 1720 1725
Ser Glu Gly Lys Gln Ile Lys Asn Leu Pro Glu Glu Thr Phe Ser
1730 1735 1740
Arg Phe Leu Leu Gln Leu Val Gly Ile Leu Leu Glu Asp Ile Val
1745 1750 1755
Thr Lys Gln Leu Lys Val Glu Met Ser Glu Gln Gln His Thr Phe
1760 1765 1770
Tyr Cys Gln Glu Leu Gly Thr Leu Leu Met Cys Leu Ile His Ile
1775 1780 1785
Phe Lys Ser Gly Met Phe Arg Arg Ile Thr Ala Ala Ala Thr Arg
1790 1795 1800
Leu Phe Arg Ser Asp Gly Cys Gly Gly Ser Phe Tyr Thr Leu Asp
1805 1810 1815
Ser Leu Asn Leu Arg Ala Arg Ser Met Ile Thr Thr His Pro Ala
1820 1825 1830
Leu Val Leu Leu Trp Cys Gln Ile Leu Leu Leu Val Asn His Thr
1835 1840 1845
Asp Tyr Arg Trp Trp Ala Glu Val Gln Gln Thr Pro Lys Arg His
1850 1855 1860
Ser Leu Ser Ser Thr Lys Leu Leu Ser Pro Gln Met Ser Gly Glu
1865 1870 1875
Glu Glu Asp Ser Asp Leu Ala Ala Lys Leu Gly Met Cys Asn Arg
1880 1885 1890
Glu Ile Val Arg Arg Gly Ala Leu Ile Leu Phe Cys Asp Tyr Val
1895 1900 1905
Cys Gln Asn Leu His Asp Ser Glu His Leu Thr Trp Leu Ile Val
1910 1915 1920
Asn His Ile Gln Asp Leu Ile Ser Leu Ser His Glu Pro Pro Val
1925 1930 1935
Gln Asp Phe Ile Ser Ala Val His Arg Asn Ser Ala Ala Ser Gly
1940 1945 1950
Leu Phe Ile Gln Ala Ile Gln Ser Arg Cys Glu Asn Leu Ser Thr
1955 1960 1965
Pro Thr Met Leu Lys Lys Thr Leu Gln Cys Leu Glu Gly Ile His
1970 1975 1980
Leu Ser Gln Ser Gly Ala Val Leu Thr Leu Tyr Val Asp Arg Leu
1985 1990 1995
Leu Cys Thr Pro Phe Arg Val Leu Ala Arg Met Val Asp Ile Leu
2000 2005 2010
Ala Cys Arg Arg Val Glu Met Leu Leu Ala Ala Asn Leu Gln Ser
2015 2020 2025
Ser Met Ala Gln Leu Pro Met Glu Glu Leu Asn Arg Ile Gln Glu
2030 2035 2040
Tyr Leu Gln Ser Ser Gly Leu Ala Gln Arg His Gln Arg Leu Tyr
2045 2050 2055
Ser Leu Leu Asp Arg Phe Arg Leu Ser Thr Met Gln Asp Ser Leu
2060 2065 2070
Ser Pro Ser Pro Pro Val Ser Ser His Pro Leu Asp Gly Asp Gly
2075 2080 2085
His Val Ser Leu Glu Thr Val Ser Pro Asp Lys Asp Trp Tyr Val
2090 2095 2100
His Leu Val Lys Ser Gln Cys Trp Thr Arg Ser Asp Ser Ala Leu
2105 2110 2115
Leu Glu Gly Ala Glu Leu Val Asn Arg Ile Pro Ala Glu Asp Met
2120 2125 2130
Asn Ala Phe Met Met Asn Ser Glu Phe Asn Leu Ser Leu Leu Ala
2135 2140 2145
Pro Cys Leu Ser Leu Gly Met Ser Glu Ile Ser Gly Gly Gln Lys
2150 2155 2160
Ser Ala Leu Phe Glu Ala Ala Arg Glu Val Thr Leu Ala Arg Val
2165 2170 2175
Ser Gly Thr Val Gln Gln Leu Pro Ala Val His His Val Phe Gln
2180 2185 2190
Pro Glu Leu Pro Ala Glu Pro Ala Ala Tyr Trp Ser Lys Leu Asn
2195 2200 2205
Asp Leu Phe Gly Asp Ala Ala Leu Tyr Gln Ser Leu Pro Thr Leu
2210 2215 2220
Ala Arg Ala Leu Ala Gln Tyr Leu Val Val Val Ser Lys Leu Pro
2225 2230 2235
Ser His Leu His Leu Pro Pro Glu Lys Glu Lys Asp Ile Val Lys
2240 2245 2250
Phe Val Val Ala Thr Leu Glu Ala Leu Ser Trp His Leu Ile His
2255 2260 2265
Glu Gln Ile Pro Leu Ser Leu Asp Leu Gln Ala Gly Leu Asp Cys
2270 2275 2280
Cys Cys Leu Ala Leu Gln Leu Pro Gly Leu Trp Ser Val Val Ser
2285 2290 2295
Ser Thr Glu Phe Val Thr His Ala Cys Ser Leu Ile Tyr Cys Val
2300 2305 2310
His Phe Ile Leu Glu Ala Val Ala Val Gln Pro Gly Glu Gln Leu
2315 2320 2325
Leu Ser Pro Glu Arg Arg Thr Asn Thr Pro Lys Ala Ile Ser Glu
2330 2335 2340
Glu Glu Glu Glu Val Asp Pro Asn Thr Gln Asn Pro Lys Tyr Ile
2345 2350 2355
Thr Ala Ala Cys Glu Met Val Ala Glu Met Val Glu Ser Leu Gln
2360 2365 2370
Ser Val Leu Ala Leu Gly His Lys Arg Asn Ser Gly Val Pro Ala
2375 2380 2385
Phe Leu Thr Pro Leu Leu Arg Asn Ile Ile Ile Ser Leu Ala Arg
2390 2395 2400
Leu Pro Leu Val Asn Ser Tyr Thr Arg Val Pro Pro Leu Val Trp
2405 2410 2415
Lys Leu Gly Trp Ser Pro Lys Pro Gly Gly Asp Phe Gly Thr Ala
2420 2425 2430
Phe Pro Glu Ile Pro Val Glu Phe Leu Gln Glu Lys Glu Val Phe
2435 2440 2445
Lys Glu Phe Ile Tyr Arg Ile Asn Thr Leu Gly Trp Thr Ser Arg
2450 2455 2460
Thr Gln Phe Glu Glu Thr Trp Ala Thr Leu Leu Gly Val Leu Val
2465 2470 2475
Thr Gln Pro Leu Val Met Glu Gln Glu Glu Ser Pro Pro Glu Glu
2480 2485 2490
Asp Thr Glu Arg Thr Gln Ile Asn Val Leu Ala Val Gln Ala Ile
2495 2500 2505
Thr Ser Leu Val Leu Ser Ala Met Thr Val Pro Val Ala Gly Asn
2510 2515 2520
Pro Ala Val Ser Cys Leu Glu Gln Gln Pro Arg Asn Lys Pro Leu
2525 2530 2535
Lys Ala Leu Asp Thr Arg Phe Gly Arg Lys Leu Ser Ile Ile Arg
2540 2545 2550
Gly Ile Val Glu Gln Glu Ile Gln Ala Met Val Ser Lys Arg Glu
2555 2560 2565
Asn Ile Ala Thr His His Leu Tyr Gln Ala Trp Asp Pro Val Pro
2570 2575 2580
Ser Leu Ser Pro Ala Thr Thr Gly Ala Leu Ile Ser His Glu Lys
2585 2590 2595
Leu Leu Leu Gln Ile Asn Pro Glu Arg Glu Leu Gly Ser Met Ser
2600 2605 2610
Tyr Lys Leu Gly Gln Val Ser Ile His Ser Val Trp Leu Gly Asn
2615 2620 2625
Ser Ile Thr Pro Leu Arg Glu Glu Glu Trp Asp Glu Glu Glu Glu
2630 2635 2640
Glu Glu Ala Asp Ala Pro Ala Pro Ser Ser Pro Pro Thr Ser Pro
2645 2650 2655
Val Asn Ser Arg Lys His Arg Ala Gly Val Asp Ile His Ser Cys
2660 2665 2670
Ser Gln Phe Leu Leu Glu Leu Tyr Ser Arg Trp Ile Leu Pro Ser
2675 2680 2685
Ser Ser Ala Arg Arg Thr Pro Ala Ile Leu Ile Ser Glu Val Val
2690 2695 2700
Arg Ser Leu Leu Val Val Ser Asp Leu Phe Thr Glu Arg Asn Gln
2705 2710 2715
Phe Glu Leu Met Tyr Val Thr Leu Thr Glu Leu Arg Arg Val His
2720 2725 2730
Pro Ser Glu Asp Glu Ile Leu Ala Gln Tyr Leu Val Pro Ala Thr
2735 2740 2745
Cys Lys Ala Ala Ala Val Leu Gly Met Asp Lys Ala Val Ala Glu
2750 2755 2760
Pro Val Ser Arg Leu Leu Glu Ser Thr Leu Arg Ser Ser His Leu
2765 2770 2775
Pro Ser Arg Val Gly Ala Leu His Gly Val Leu Tyr Val Leu Glu
2780 2785 2790
Cys Asp Leu Leu Asp Asp Thr Ala Lys Gln Leu Ile Pro Val Ile
2795 2800 2805
Ser Asp Tyr Leu Leu Ser Asn Leu Lys Gly Ile Ala His Cys Val
2810 2815 2820
Asn Ile His Ser Gln Gln His Val Leu Val Met Cys Ala Thr Ala
2825 2830 2835
Phe Tyr Leu Ile Glu Asn Tyr Pro Leu Asp Val Gly Pro Glu Phe
2840 2845 2850
Ser Ala Ser Ile Ile Gln Met Cys Gly Val Met Leu Ser Gly Ser
2855 2860 2865
Glu Glu Ser Thr Pro Ser Ile Ile Tyr His Cys Ala Leu Arg Gly
2870 2875 2880
Leu Glu Arg Leu Leu Leu Ser Glu Gln Leu Ser Arg Leu Asp Ala
2885 2890 2895
Glu Ser Leu Val Lys Leu Ser Val Asp Arg Val Asn Val His Ser
2900 2905 2910
Pro His Arg Ala Met Ala Ala Leu Gly Leu Met Leu Thr Cys Met
2915 2920 2925
Tyr Thr Gly Lys Glu Lys Val Ser Pro Gly Arg Thr Ser Asp Pro
2930 2935 2940
Asn Pro Ala Ala Pro Asp Ser Glu Ser Val Ile Val Ala Met Glu
2945 2950 2955
Arg Val Ser Val Leu Phe Asp Arg Ile Arg Lys Gly Phe Pro Cys
2960 2965 2970
Glu Ala Arg Val Val Ala Arg Ile Leu Pro Gln Phe Leu Asp Asp
2975 2980 2985
Phe Phe Pro Pro Gln Asp Ile Met Asn Lys Val Ile Gly Glu Phe
2990 2995 3000
Leu Ser Asn Gln Gln Pro Tyr Pro Gln Phe Met Ala Thr Val Val
3005 3010 3015
Tyr Lys Val Phe Gln Thr Leu His Ser Thr Gly Gln Ser Ser Met
3020 3025 3030
Val Arg Asp Trp Val Met Leu Ser Leu Ser Asn Phe Thr Gln Arg
3035 3040 3045
Ala Pro Val Ala Met Ala Thr Trp Ser Leu Ser Cys Phe Phe Val
3050 3055 3060
Ser Ala Ser Thr Ser Pro Trp Val Ala Ala Ile Leu Pro His Val
3065 3070 3075
Ile Ser Arg Met Gly Lys Leu Glu Gln Val Asp Val Asn Leu Phe
3080 3085 3090
Cys Leu Val Ala Thr Asp Phe Tyr Arg His Gln Ile Glu Glu Glu
3095 3100 3105
Leu Asp Arg Arg Ala Phe Gln Ser Val Leu Glu Val Val Ala Ala
3110 3115 3120
Pro Gly Ser Pro Tyr His Arg Leu Leu Thr Cys Leu Arg Asn Val
3125 3130 3135
His Lys Val Thr Thr Cys
3140
<210> 4
<211> 20
<212> DNA
<213> Artificial sequence
<220>
<223> Synthetic oligonucleotide
<400> 4
ctcagtaaca ttgacaccac 20
Claims (94)
- 청구항 1에 있어서, 상기 변형된 올리고뉴클레오타이드가 나트륨 염 또는 칼륨 염인, 방법.
- HD 개선을 필요로 하는 인간 대상체에서 HD를 개선시키는 방법으로서, 상기 방법이 변형된 올리고뉴클레오타이드의 치료학적 유효량을 상기 인간 대상체에게 투여하는 단계를 포함하고, 상기 변형된 올리고뉴클레오타이드가 mCes Teo mCeo Aeo Ges Tds Ads Ads mCds Ads Tds Tds Gds Ads mCds Aeo mCeo mCeo Aes mCe (서열번호 4)의 화학적 표기법(5'에서 3')을 갖고; 여기서,
A = 아데닌 뉴클레오염기,
mC = 5-메틸 시토신 뉴클레오염기,
G = 구아닌 뉴클레오염기,
T = 티민 뉴클레오염기,
e = 2'-MOE 당 모이어티,
d = 2'-β-D-데옥시리보실 당 모이어티,
s = 포스포로티오에이트 뉴클레오시드간 연결, 및
o = 포스포디에스테르 뉴클레오시드간 연결
인, 방법. - 청구항 1 내지 4 중 어느 한 항에 있어서, HD의 적어도 하나의 증상이 개선되는, 방법.
- 청구항 5에 있어서, 상기 적어도 하나의 증상이 뇌 위축증, 뇌 활동 감소증, 뇌 연결성 감소증, 근육 위축증, 신경 변성, 심부전, 내당능 손상, 체중 감소증, 골다공증, 고환 위축증, 전반적인 기능 손상, 운동 기능 손상, 인지 기능 손상, 일상 기능 손상, 주의력 손상, 시각 지각 처리 손상, 작업 기억 손상, 정신 운동 속도 손상, 언어 운동 아웃풋 손상, 독립성 정도 손상, 무감각증 손상, 학습 능력 손상, 정신 집중력 손상, 언어 손상, 우울증, 과민성, 분노, 운동능 손상, 자기 관리 손상, 통증, 불편함, 불안증, 자살 생각, 자살 행동 또는 이들의 조합을 포함하는, 방법.
- 청구항 7에 있어서, 상기 변형된 올리고뉴클레오타이드가 나트륨 염 또는 칼륨 염인, 방법.
- HTT RNA 감소를 필요로 하는 인간 대상체에서 HTT RNA를 감소시키는 방법으로서, 상기 방법이 변형된 올리고뉴클레오타이드의 치료학적 유효량을 상기 인간 대상체에게 투여하는 단계를 포함하고, 상기 변형된 올리고뉴클레오타이드가 mCes Teo mCeo Aeo Ges Tds Ads Ads mCds Ads Tds Tds Gds Ads mCds Aeo mCeo mCeo Aes mCe (서열번호 4)의 화학적 표기법(5'에서 3')을 갖고; 여기서,
A = 아데닌 뉴클레오염기,
mC = 5-메틸 시토신 뉴클레오염기,
G = 구아닌 뉴클레오염기,
T = 티민 뉴클레오염기,
e = 2'-MOE 당 모이어티,
d = 2'-β-D-데옥시리보실 당 모이어티,
s = 포스포로티오에이트 뉴클레오시드간 연결, 및
o = 포스포디에스테르 뉴클레오시드간 연결
인, 방법. - 청구항 11에 있어서, 상기 변형된 올리고뉴클레오타이드가 나트륨 염 또는 칼륨 염인, 방법.
- HTT 단백질 감소를 필요로 하는 인간 대상체에서 HTT 단백질을 감소시키는 방법으로서, 상기 방법이 변형된 올리고뉴클레오타이드의 치료학적 유효량을 상기 인간 대상체에게 투여하는 단계를 포함하고, 상기 변형된 올리고뉴클레오타이드가 mCes Teo mCeo Aeo Ges Tds Ads Ads mCds Ads Tds Tds Gds Ads mCds Aeo mCeo mCeo Aes mCe (서열번호 4)의 화학적 표기법(5'에서 3')을 갖고; 여기서,
A = 아데닌 뉴클레오염기,
mC = 5-메틸 시토신 뉴클레오염기,
G = 구아닌 뉴클레오염기,
T = 티민 뉴클레오염기,
e = 2'-MOE 당 모이어티,
d = 2'-β-D-데옥시리보실 당 모이어티,
s = 포스포로티오에이트 뉴클레오시드간 연결, 및
o = 포스포디에스테르 뉴클레오시드간 연결
인, 방법. - 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 10 mg인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 30 mg인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 60 mg인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 90 mg인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 120 mg인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 약 10 mg인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 약 30 mg인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 약 60 mg인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 약 90 mg인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 약 120 mg인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 및 300 mg 중 어느 하나인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 약 5 mg, 약 10 mg, 약 15 mg, 약 20 mg, 약 25 mg, 약 30 mg, 약 35 mg, 약 40 mg, 약 45 mg, 약 50 mg, 약 55 mg, 약 60 mg, 약 65 mg, 약 70 mg, 약 75 mg, 약 80 mg, 약 85 mg, 약 90 mg, 약 95 mg, 약 100 mg, 약 105 mg, 약 110 mg, 약 115 mg, 약 120 mg, 약 125 mg, 약 130 mg, 약 135 mg, 약 140 mg, 약 145 mg, 약 150 mg, 약 155 mg, 약 160 mg, 약 165 mg, 약 170 mg, 약 175 mg, 약 180 mg, 약 185 mg, 약 190 mg, 약 195 mg, 약 200 mg, 약 205 mg, 약 210 mg, 약 215 mg, 약 220 mg, 약 225 mg, 약 230 mg, 약 235 mg, 약 240 mg, 약 245 mg, 약 250 mg, 약 255 mg, 약 260 mg, 약 265 mg, 약 270 mg, 약 275 mg, 약 280 mg, 약 285 mg, 약 290 mg, 약 295 mg, 및 약 300 mg 중 어느 하나인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 115.0 mg, 115.1 mg, 115.2 mg, 115.3 mg, 115.4 mg, 115.5 mg, 115.6 mg, 115.7 mg, 115.8 mg, 115.9 mg, 116.0 mg, 116.1 mg, 116.2 mg, 116.3 mg, 116.4 mg, 116.5 mg, 116.6 mg, 116.7 mg, 116.8 mg, 116.9 mg, 117.0 mg, 117.1 mg, 117.2 mg, 117.3 mg, 117.4 mg, 117.5 mg, 117.6 mg, 117.7 mg, 117.8 mg, 117.9 mg, 118.0 mg, 118.1 mg, 118.2 mg, 118.3 mg. 118.4 mg, 118.5 mg, 118.6 mg, 118.7 mg, 118.8 mg, 118.9 mg, 119.0 mg, 119.1 mg, 119.2 mg, 119.3 mg, 119.4 mg, 119.5 mg, 119.6 mg, 119.7 mg, 119.8 mg, 119.9 mg, 120.0 mg, 120.1 mg, 120.2 mg, 120.3 mg, 120.4 mg, 120.5 mg, 120.6 mg, 120.7 mg, 120.8 mg, 120.9 mg, 121.0 mg, 121.1 mg, 121.2 mg, 121.3 mg, 121.4 mg, 121.5 mg, 121.6 mg, 121.7 mg, 121.8 mg, 121.9 mg, 122.0 mg, 122.1 mg, 122.2 mg, 122.3 mg, 122.4 mg, 122.5 mg, 122.6 mg, 122.7 mg, 122.8 mg, 122.9 mg, 123.0 mg, 123.1 mg, 123.2 mg, 123.3 mg, 123.4 mg, 123.5 mg, 123.6 mg, 123.7 mg, 123.8 mg, 123.9 mg, 124.0 mg, 124.1 mg, 124.2 mg, 124.3 mg, 124.4 mg, 124.5 mg, 124.6 mg, 124.7 mg, 124.8 mg, 124.9 mg, 및 125.0 mg 중 어느 하나인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 약 115.0 mg, 약 115.1 mg, 약 115.2 mg, 약 115.3 mg, 약 115.4 mg, 약 115.5 mg, 약 115.6 mg, 약 115.7 mg, 약 115.8 mg, 약 115.9 mg, 약 116.0 mg, 약 116.1 mg, 약 116.2 mg, 약 116.3 mg, 약 116.4 mg, 약 116.5 mg, 약 116.6 mg, 약 116.7 mg, 약 116.8 mg, 약 116.9 mg, 약 117.0 mg, 약 117.1 mg, 약 117.2 mg, 약 117.3 mg, 약 117.4 mg, 약 117.5 mg, 약 117.6 mg, 약 117.7 mg, 약 117.8 mg, 약 117.9 mg, 약 118.0 mg, 약 118.1 mg, 약 118.2 mg, 약 118.3 mg. 118.4 mg, 약 118.5 mg, 약 118.6 mg, 약 118.7 mg, 약 118.8 mg, 약 118.9 mg, 약 119.0 mg, 약 119.1 mg, 약 119.2 mg, 약 119.3 mg, 약 119.4 mg, 약 119.5 mg, 약 119.6 mg, 약 119.7 mg, 약 119.8 mg, 약 119.9 mg, 약 120.0 mg, 약 120.1 mg, 약 120.2 mg, 약 120.3 mg, 120.4 mg, 약 120.5 mg, 약 120.6 mg, 약 120.7 mg, 약 120.8 mg, 약 120.9 mg, 약 121.0 mg, 약 121.1 mg, 약 121.2 mg, 약 121.3 mg, 약 121.4 mg, 약 121.5 mg, 약 121.6 mg, 약 121.7 mg, 약 121.8 mg, 약 121.9 mg, 약 122.0 mg, 약 122.1 mg, 약 122.2 mg, 약 122.3 mg, 122.4 mg, 약 122.5 mg, 약 122.6 mg, 약 122.7 mg, 약 122.8 mg, 약 122.9 mg, 약 123.0 mg, 약 123.1 mg, 약 123.2 mg, 약 123.3 mg, 약 123.4 mg, 약 123.5 mg, 약 123.6 mg, 약 123.7 mg, 약 123.8 mg, 약 123.9 mg, 약 124.0 mg, 약 124.1 mg, 약 124.2 mg, 약 124.3 mg, 124.4 mg, 약 124.5 mg, 약 124.6 mg, 약 124.7 mg, 약 124.8 mg, 약 124.9 mg, 및 약 125.0 mg 중 어느 하나인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 40 mg 내지 200 mg, 40 mg 내지 190 mg, 40 mg 내지 180 mg, 40 mg 내지 170 mg, 40 mg 내지 160 mg, 40 mg 내지 150 mg, 40 mg 내지 140 mg, 40 mg 내지 120 mg, 40 mg 내지 110 mg, 40 mg 내지 100 mg, 40 mg 내지 80 mg, 40 mg 내지 70 mg, 40 mg 내지 60 mg, 40 mg 내지 50 mg, 50 mg 내지 200 mg, 50 mg 내지 190 mg, 50 mg 내지 180 mg, 50 mg 내지 170 mg, 50 mg 내지 160 mg, 50 mg 내지 150 mg, 50 mg 내지 140 mg, 50 mg 내지 120 mg, 50 mg 내지 110 mg, 50 mg 내지 100 mg, 50 mg 내지 80 mg, 50 mg 내지 70 mg, 50 mg 내지 60 mg, 60 mg 내지 200 mg, 60 mg 내지 190 mg, 60 mg 내지 180 mg, 60 mg 내지 170 mg, 60 mg 내지 160 mg, 60 mg 내지 150 mg, 60 mg 내지 140 mg, 60 mg 내지 120 mg, 60 mg 내지 110 mg, 60 mg 내지 100 mg, 60 mg 내지 80 mg, 60 mg 내지 70 mg, 70 mg 내지 200 mg, 70 mg 내지 190 mg, 70 mg 내지 180 mg, 70 mg 내지 170 mg, 70 mg 내지 160 mg, 70 mg 내지 150 mg, 70 mg 내지 140 mg, 70 mg 내지 120 mg, 70 mg 내지 110 mg, 70 mg 내지 100 mg, 70 mg 내지 80 mg, 80 mg 내지 200 mg, 80 mg 내지 190 mg, 80 mg 내지 180 mg, 80 mg 내지 170 mg, 80 mg 내지 160 mg, 80 mg 내지 150 mg, 80 mg 내지 140 mg, 80 mg 내지 120 mg, 80 mg 내지 110 mg, 80 mg 내지 100 mg, 80 mg 내지 90 mg, 90 mg 내지 200 mg, 90 mg 내지 190 mg, 90 mg 내지 180 mg, 90 mg 내지 170 mg, 90 mg 내지 160 mg, 90 mg 내지 150 mg, 90 mg 내지 140 mg, 90 mg 내지 120 mg, 90 mg 내지 110 mg, 90 mg 내지 100 mg, 100 mg 내지 200 mg, 100 mg 내지 190 mg, 100 mg 내지 180 mg, 100 mg 내지 170 mg, 100 mg 내지 160 mg, 100 mg 내지 150 mg, 100 mg 내지 140 mg, 100 mg 내지 120 mg, 100 mg 내지 110 mg, 110 mg 내지 200 mg, 110 mg 내지 190 mg, 110 mg 내지 180 mg, 110 mg 내지 170 mg, 110 mg 내지 160 mg, 110 mg 내지 150 mg, 110 mg 내지 140 mg, 110 mg 내지 130 mg, 110 mg 내지 120 mg, 120 mg 내지 200 mg, 120 mg 내지 190 mg, 120 mg 내지 180 mg, 120 mg 내지 170 mg, 120 mg 내지 160 mg, 120 mg 내지 150 mg, 120 mg 내지 140 mg, 120 mg 내지 130 mg, 130 mg 내지 200 mg, 130 mg 내지 190 mg, 130 mg 내지 180 mg, 130 mg 내지 170 mg, 130 mg 내지 160 mg, 130 mg 내지 150 mg, 130 mg 내지 140 mg, 140 mg 내지 200 mg, 140 mg 내지 190 mg, 140 mg 내지 180 mg, 140 mg 내지 170 mg, 140 mg 내지 160 mg, 140 mg 내지 150 mg, 150 mg 내지 200 mg, 150 mg 내지 190 mg, 150 mg 내지 180 mg, 150 mg 내지 170 mg, 150 mg 내지 160 mg, 160 mg 내지 200 mg, 160 mg 내지 190 mg, 160 mg 내지 180 mg, 160 mg 내지 170 mg, 180 mg 내지 200 mg, 180 mg 내지 190 mg, 190 mg 내지 200 mg, 105 mg 내지 135 mg, 105 mg 내지 130 mg, 105 mg 내지 125 mg 105 mg 내지 120 mg, 110 mg 내지 135 mg, 110 mg 내지 130 mg, 110 mg 내지 125 mg, 110 mg 내지 120 mg, 115 mg 내지 135 mg, 115 mg 내지 130 mg, 115 mg 내지 125 mg, 115 mg 내지 120 mg, 115 mg 내지 125 mg, 115 mg 내지 120 mg, 120 mg 내지 135 mg, 120 mg 내지 125 mg, 125 mg 내지 140 mg, 125 mg 내지 130 mg, 130 mg 내지 135 mg, 135 mg 내지 140 mg, 120 mg 내지 129 mg, 120 mg 내지 128 mg, 120 mg 내지 127 mg, 120 mg 내지 86 mg, 120 mg 내지 124 mg, 120 mg 내지 123 mg, 120 mg 내지 122 mg, 120 mg 내지 121 mg, 121 mg 내지 130 mg, 122 mg 내지 129 mg, 122 mg 내지 128 mg, 122 mg 내지 127 mg, 122 mg 내지 126 mg, 122 mg 내지 125 mg, 122 mg 내지 124 mg, 122 mg 내지 123 mg, 123 mg 내지 130 mg, 123 mg 내지 129 mg, 123 mg 내지 128 mg, 123 mg 내지 127 mg, 123 mg 내지 126 mg, 123 mg 내지 125 mg, 123 mg 내지 124 mg, 124 mg 내지 130 mg, 124 mg 내지 129 mg, 124 mg 내지 128 mg, 124 mg 내지 127 mg, 124 mg 내지 126 mg, 124 mg 내지 125 mg, 125 mg 내지 129 mg, 125 mg 내지 128 mg, 125 mg 내지 127 mg, 125 mg 내지 126 mg, 126 mg 내지 130 mg, 126 mg 내지 129 mg, 126 mg 내지 128 mg, 126 mg 내지 127 mg, 127 mg 내지 130 mg, 127 mg 내지 129 mg, 127 mg 내지 128 mg, 128 mg 내지 130 mg, 128 mg 내지 129 mg, 및 129 mg 내지 130 mg 중 임의의 범위 내에 있는, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 300 mg 미만, 295 mg 미만, 290 mg 미만, 285 mg 미만, 280 mg 미만, 275 mg 미만, 270 mg 미만, 265 mg 미만, 260 mg 미만, 255 mg 미만, 250 mg 미만, 245 mg 미만, 240 mg 미만, 235 mg 미만, 230 mg 미만, 225 mg 미만, 220 mg 미만, 215 mg 미만, 210 mg 미만, 205 mg 미만, 200 mg 미만, 195 mg 미만, 190 mg 미만, 185 mg 미만, 180 mg 미만, 175 mg 미만, 170 mg 미만, 165 mg 미만, 160 mg 미만, 150 mg 미만, 145 mg 미만, 140 mg 미만, 135 mg 미만, 130 mg 미만, 125 mg 미만, 120 mg 미만, 115 mg 미만, 110 mg 미만, 105 mg 미만, 100 mg 미만, 95 mg 미만, 90 mg 미만, 85 mg 미만, 80 mg 미만, 75 mg 미만, 70 mg 미만, 65 mg 미만, 60 mg 미만, 55 mg 미만, 50 mg 미만, 45 mg 미만, 40 mg 미만, 35 mg 미만, 30 mg 미만, 25 mg 미만, 20 mg 미만, 15 mg 미만, 10 mg 미만, 및 5 mg 미만 중 어느 하나인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 약 300 mg 미만, 약 295 mg 미만, 약 290 mg 미만, 약 285 mg 미만, 약 280 mg 미만, 약 275 mg 미만, 약 270 mg 미만, 약 265 mg 미만, 약 260 mg 미만, 약 255 mg 미만, 약 250 mg 미만, 약 245 mg 미만, 약 240 mg 미만, 약 235 mg 미만, 약 230 mg 미만, 약 225 mg 미만, 약 220 mg 미만, 약 215 mg 미만, 약 210 mg 미만, 약 205 mg 미만, 약 200 mg 미만, 약 195 mg 미만, 약 190 mg 미만, 약 185 mg 미만, 약 180 mg 미만, 약 175 mg 미만, 약 170 mg 미만, 약 165 mg 미만, 약 160 mg 미만, 약 150 mg 미만, 약 145 mg 미만, 약 140 mg 미만, 약 135 mg 미만, 약 130 mg 미만, 약 125 mg 미만, 약 120 mg 미만, 약 115 mg 미만, 약 110 mg 미만, 약 105 mg 미만, 약 100 mg 미만, 약 95 mg 미만, 약 90 mg 미만, 약 85 mg 미만, 약 80 mg 미만, 약 75 mg 미만, 약 70 mg 미만, 약 65 mg 미만, 약 60 mg 미만, 약 55 mg 미만, 약 50 mg 미만, 약 45 mg 미만, 약 40 mg 미만, 약 35 mg 미만, 약 30 mg 미만, 약 25 mg 미만, 약 20 mg 미만, 약 15 mg 미만, 약 10 mg 미만, 및 약 5 mg 미만 중 어느 하나인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 적어도 5 mg, 적어도 10 mg, 적어도 15 mg, 적어도 20 mg, 적어도 25 mg, 적어도 30 mg, 적어도 35 mg, 적어도 40 mg, 적어도 45 mg, 적어도 50 mg, 적어도 55 mg, 적어도 60 mg, 적어도 65 mg, 적어도 70 mg, 적어도 75 mg, 적어도 80 mg, 적어도 85 mg, 적어도 90 mg, 적어도 95 mg, 적어도 약 100 mg, 적어도 105 mg, 적어도 115 mg, 적어도 120 mg, 적어도 125 mg, 적어도 130 mg, 적어도 135 mg, 적어도 140 mg, 적어도 145 mg, 적어도 150 mg, 적어도 155 mg, 적어도 160 mg, 적어도 165 mg, 적어도 170 mg, 적어도 175 mg, 적어도 180 mg, 적어도 185, 적어도 190 mg, 적어도 195 mg, 및 적어도 200 mg 중 어느 하나인, 방법.
- 청구항 1 내지 14 중 어느 한 항에 있어서, 상기 치료학적 유효량이 적어도 약 5 mg, 적어도 약 10 mg, 적어도 약 15 mg, 적어도 약 20 mg, 적어도 약 25 mg, 적어도 약 30 mg, 적어도 약 35 mg, 적어도 약 40 mg, 적어도 약 45 mg, 적어도 약 50 mg, 적어도 약 55 mg, 적어도 약 60 mg, 적어도 약 65 mg, 적어도 약 70 mg, 적어도 약 75 mg, 적어도 약 80 mg, 적어도 약 85 mg, 적어도 약 90 mg, 적어도 약 95 mg, 적어도 약 100 mg, 적어도 약 105 mg, 적어도 약 115 mg, 적어도 약 120 mg, 적어도 약 125 mg, 적어도 약 130 mg, 적어도 약 135 mg, 적어도 약 140 mg, 적어도 약 145 mg, 적어도 약 150 mg, 적어도 약 155 mg, 적어도 약 160 mg, 적어도 약 165 mg, 적어도 약 170 mg, 적어도 약 175 mg, 적어도 약 180 mg, 적어도 약 185, 적어도 약 190 mg, 적어도 약 195 mg, 및 적어도 약 200 mg 중 어느 하나인, 방법.
- 청구항 1 내지 33 중 어느 한 항에 있어서, 4주 마다 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 1 내지 33 중 어느 한 항에 있어서, 8주 마다 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 1 내지 33 중 어느 한 항에 있어서, 12주 마다 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 1 내지 33 중 어느 한 항에 있어서, 16주 마다 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 1 내지 33 중 어느 한 항에 있어서, 20주 마다 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 1 내지 33 중 어느 한 항에 있어서, 4주 마다 약 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 1 내지 33 중 어느 한 항에 있어서, 8주 마다 약 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 1 내지 33 중 어느 한 항에 있어서, 12주 마다 약 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 1 내지 33 중 어느 한 항에 있어서, 16주 마다 약 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 1 내지 33 중 어느 한 항에 있어서, 20주 마다 약 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 1 내지 33 중 어느 한 항에 있어서, 1주 마다 1회, 2주 마다 1회, 3주 마다 1회, 4주 마다 1회, 5주 마다 1회, 6주 마다 1회, 7주 마다 1회, 8주 마다 1회, 9주 마다 1회, 10주 마다 1회, 11주 마다 1회, 12주 마다 1회, 13주 마다 1회, 14주 마다 1회, 15주 마다 1회, 16주 마다 1회, 17주 마다 1회, 18주 마다 1회, 19주 마다 1회, 및 20주 마다 1회 중 어느 하나로 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 1 내지 33 중 어느 한 항에 있어서, 약 1주 마다 1회, 약 2주 마다 1회, 약 3주 마다 1회, 약 4주 마다 1회, 약 5주 마다 1회, 약 6주 마다 1회, 약 7주 마다 1회, 약 8주 마다 1회, 약 9주 마다 1회, 약 10주 마다 1회, 약 11주 마다 1회, 약 12주 마다 1회, 약 13주 마다 1회, 약 14주 마다 1회, 약 15주 마다 1회, 약 16주 마다 1회, 약 17주 마다 1회, 약 18주 마다 1회, 약 19주 마다 1회, 및 약 20주 마다 1회 중 어느 하나로 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 1 내지 33 중 어느 한 항에 있어서, 상기 변형된 올리고뉴클레오타이드 120 mg의 초기 부하 용량을 상기 인간 대상체에게 투여하는 단계를 포함하는, 방법.
- 청구항 46에 있어서, 상기 초기 부하 용량 4주 후 상기 변형된 올리고뉴클레오타이드 120 mg의 제2 부하 용량을 상기 인간 대상체에게 투여하는 단계를 포함하는, 방법.
- 청구항 47에 있어서, 상기 제2 부하 용량 4주 후 상기 변형된 올리고뉴클레오타이드 120 mg의 유지 용량을 상기 인간 대상체에게 투여하는 단계를 포함하는, 방법.
- 청구항 47에 있어서, 상기 제2 부하 용량 8주 후 상기 변형된 올리고뉴클레오타이드 120 mg의 유지 용량을 상기 인간 대상체에게 투여하는 단계를 포함하는, 방법.
- 청구항 47에 있어서, 상기 제2 부하 용량 12주 후 상기 변형된 올리고뉴클레오타이드 120 mg의 유지 용량을 상기 인간 대상체에게 투여하는 단계를 포함하는, 방법.
- 청구항 47에 있어서, 상기 제2 부하 용량 16주 후 상기 변형된 올리고뉴클레오타이드 120 mg의 유지 용량을 상기 인간 대상체에게 투여하는 단계를 포함하는, 방법.
- 청구항 7 내지 10 및 15 내지 51 중 어느 한 항에 있어서, 상기 HTT RNA가 mHTT RNA인, 방법.
- 청구항 11 내지 51 중 어느 한 항에 있어서, 상기 HTT 단백질이 mHTT 단백질인, 방법.
- 청구항 54에 있어서, 상기 변형된 올리고뉴클레오타이드가 나트륨 염 또는 칼륨 염인, 방법.
- HD 개선, HTT RNA 감소, HTT 단백질 감소, HTT mRNA 감소 또는 mHTT 단백질 감소를 필요로 하는 인간 대상체에서 HD 개선, HTT RNA 감소, HTT 단백질 감소, HTT mRNA 감소 또는 mHTT 단백질을 감소시키는 방법으로서, 상기 방법이 변형된 올리고뉴클레오타이드의 120 mg 또는 약 120 mg의 치료학적 유효량을 상기 인간 대상체에게 척수강내 투여하는 단계를 포함하고, 상기 변형된 올리고뉴클레오타이드가 mCes Teo mCeo Aeo Ges Tds Ads Ads mCds Ads Tds Tds Gds Ads mCds Aeo mCeo mCeo Aes mCe (서열번호 4)의 화학적 표기법(5'에서 3')을 갖고; 여기서,
A = 아데닌 뉴클레오염기,
mC = 5-메틸 시토신 뉴클레오염기,
G = 구아닌 뉴클레오염기,
T = 티민 뉴클레오염기,
e = 2'-MOE 당 모이어티,
d = 2'-β-D-데옥시리보실 당 모이어티,
s = 포스포로티오에이트 뉴클레오시드간 연결, 및
o = 포스포디에스테르 뉴클레오시드간 연결
인, 방법. - 청구항 54 내지 57 중 어느 한 항에 있어서, 4주 마다 약 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 54 내지 57 중 어느 한 항에 있어서, 8주 마다 약 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 54 내지 57 중 어느 한 항에 있어서, 16주 마다 약 1회 상기 변형된 올리고뉴클레오타이드를 투여하는 단계를 포함하는, 방법.
- 청구항 54 내지 57 중 어느 한 항에 있어서, 상기 인간 대상체에게 하기를 투여하는 단계를 포함하는 방법:
a) 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 초기 부하 용량,
b) 상기 초기 부하 용량 투여 약 4주 후에 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 제2 부하 용량;
c) 상기 제2 부하 용량 투여 약 8주 후에 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 제1 유지 용량;
d) 상기 제1 유지 용량 투여 약 8주 후에 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 제2 유지 용량. - 청구항 54 내지 57 중 어느 한 항에 있어서, 상기 인간 대상체에게 하기를 투여하는 단계를 포함하는 방법:
a) 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 초기 부하 용량,
b) 상기 초기 부하 용량 투여 약 4주 후에 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 제2 부하 용량;
c) 상기 제2 부하 용량 투여 약 16주 후에 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 제1 유지 용량;
d) 상기 제1 유지 용량 투여 약 16주 후에 상기 변형된 올리고뉴클레오타이드의 약 120 mg의 제2 유지 용량. - 청구항 54 내지 62 중 어느 한 항에 있어서, HD의 적어도 하나의 증상이 개선되는, 방법.
- 청구항 63에 있어서, 상기 적어도 하나의 증상이 뇌 위축증, 뇌 활동 감소증, 뇌 연결성 감소증, 근육 위축증, 신경 변성, 심부전, 내당능 손상, 체중 감소증, 골다공증, 고환 위축증, 전반적인 기능 손상, 운동 기능 손상, 인지 기능 손상, 일상 기능 손상, 주의력 손상, 시각 지각 처리 손상, 작업 기억 손상, 정신 운동 속도 손상, 언어 운동 아웃풋 손상, 독립성 정도 손상, 무감각증 손상, 학습 능력 손상, 정신 집중력 손상, 언어 손상, 우울증, 과민성, 분노, 운동능 손상, 자기 관리 손상, 통증, 불편함, 불안증, 자살 생각, 자살 행동 또는 이들의 조합을 포함하는, 방법.
- 청구항 1 내지 64 중 어느 한 항에 있어서, 상기 인간 대상체가 적어도 하나의 IT15 유전자에 돌연변이를 갖는, 방법.
- 청구항 1 내지 65 중 어느 한 항에 있어서, 상기 인간 대상체의 적어도 하나의 IT15 유전자에서 돌연변이를 동정하는 단계를 포함하는, 방법.
- 청구항 65 또는 66에 있어서, 상기 적어도 하나의 IT15 유전자가 적어도 25, 적어도 26, 적어도 27, 적어도 28, 적어도 29, 적어도 30, 적어도 31, 적어도 32, 적어도 33, 적어도 34, 적어도 35, 적어도 36, 적어도 37, 적어도 38, 적어도 39, 적어도 40, 적어도 41, 적어도 42, 적어도 43, 적어도 44, 적어도 45, 적어도 46, 적어도 47, 적어도 48, 적어도 49, 적어도 50, 적어도 51, 적어도 52, 적어도 53, 적어도 54, 적어도 55, 적어도 56, 적어도 57, 적어도 58, 적어도 59, 또는 적어도 60개 연속 CAG 반복체 중 어느 하나를 갖는, 방법.
- 청구항 65 또는 66에 있어서, 상기 적어도 하나의 IT15 유전자가 27 내지 35개 연속 CAG 반복체를 갖는, 방법.
- 청구항 65 또는 66에 있어서, 상기 적어도 하나의 IT15 유전자가 35 내지 60개 연속 CAG 반복체를 갖는, 방법.
- 청구항 65 또는 66에 있어서, 상기 적어도 하나의 IT15 유전자가 60개 초과의 연속 CAG 반복체를 갖는, 방법.
- 청구항 1 내지 70 중 어느 한 항에 있어서, 상기 변형된 올리고뉴클레오타이드가 상기 인간 대상체의 CNS에 투여되는, 방법.
- 청구항 1 내지 71 중 어느 한 항에 있어서, 상기 변형된 올리고뉴클레오타이드가 척수강내 투여에 의해 투여되는, 방법.
- 청구항 1 내지 72 중 어느 한 항에 있어서, 상기 변형된 올리고뉴클레오타이드가 볼러스(bolus) 척수강내 투여에 의해 투여되는, 방법.
- 청구항 1 내지 73 중 어느 한 항에 있어서, HTT RNA가 감소되는, 방법.
- 청구항 1 내지 74 중 어느 한 항에 있어서, HTT 단백질이 감소되는, 방법.
- 청구항 1 내지 75 중 어느 한 항에 있어서, mHTT RNA가 감소되는, 방법.
- 청구항 1 내지 76 중 어느 한 항에 있어서, mHTT 단백질이 감소되는, 방법.
- 청구항 1 내지 77 중 어느 한 항에 있어서, 상기 인간 대상체 기원의 생물학적 샘플 중에 mHTT RNA의 양을 검출하는 단계를 포함하는, 방법.
- 청구항 1 내지 78 중 어느 한 항에 있어서, 상기 인간 대상체 기원의 생물학적 샘플 중에 mHTT 단백질의 양을 검출하는 단계를 포함하는, 방법.
- 청구항 1 내지 79 중 어느 한 항에 있어서, 상기 생물학적 샘플이 뇌척수액을 포함하는, 방법.
- 청구항 78 내지 80 중 어느 한 항에 있어서, 상기 검출이 투여 전에 수행되는, 방법.
- 청구항 78 내지 80 중 어느 한 항에 있어서, 상기 검출이 투여 후에 수행되는, 방법.
- 청구항 78 내지 80 중 어느 한 항에 있어서, 상기 검출이 투여 전 및 후에 수행되는, 방법.
- 청구항 78 내지 83 중 어느 한 항에 있어서, HTT RNA, HTT 단백질, mHTT RNA, mHTT 단백질 또는 이의 조합의 양을 검출한 후 투여되는 초기 부하 용량, 부하 용량, 유지 용량 또는 치료학적 유효량을 조정하는 단계를 포함하는, 방법.
- 청구항 1 내지 84 중 어느 한 항에 있어서, 상기 대상체에 대해 뇌파도(EEG) 또는 자기공명영상(MRI)을 수행함으로써 대상체의 뇌 활동, 뇌 크기, 또는 이들의 조합을 분석하는 단계를 포함하는, 방법.
- 청구항 85에 있어서, 상기 EEG 또는 MRI가 투여 전, 투여 후 또는 이의 조합으로 수행되는, 방법.
- 청구항 86에 있어서, 상기 EEG 또는 MRI를 수행한 후 치료학적 유효량을 결정하거나 조정하는 단계를 포함하는, 방법.
- 청구항 87에 있어서, 투여 후 상기 EEG 또는 MRI를 수행하는 단계 및 EEG 또는 MRI를 수행한 후 투여 빈도를 조정하는 단계를 포함하는, 방법.
- 청구항 85 내지 88 중 어느 한 항에 있어서, 상기 EEG 또는 MRI가 투여 1, 2, 4, 6, 8, 12 또는 24시간 이내에 수행되는, 방법.
- 청구항 85 내지 89 중 어느 한 항에 있어서, 투여 전 EEG를 수행하는 단계 및 투여 후 분석하는 단계, 제1 EEG로부터 제2 EEG까지의 EEG 신호 전력에서 4 Hz 미만의 증가를 검출하는 단계, 및 이어서 상기 변형된 올리고뉴클레오타이드의 치료학적 유효량을 투여하는 빈도를 증가시키는 단계를 포함하는, 방법.
- 청구항 90에 있어서, 약 4주 마다 1회 부하 용량을 투여하는 단계 및 제1 EEG를 기록하기 전 약 8주 또는 16주 마다 1회 유지 용량을 투여하는 단계 및 약 8주 미만 마다 또는 약 16주 미만 마다 유지 용량을 투여하는 단계를 포함하는, 방법.
- 청구항 85 내지 91 중 어느 한 항에 있어서, 투여 전 제1 EEG를 기록하는 단계, 및 투여 후 제2 EEG를 기록하는 단계, 제1 EEG에서 제2 EEG까지 EEG 신호 전력에서 4 Hz 미만의 증가를 검출하는 단계, 및 이어서 치료학적 유효량 초과인 변형된 올리고뉴클레오타이드의 용량을 투여하는 단계를 포함하는, 방법.
- 청구항 92에 있어서, 상기 용량이 치료학적 유효량의 적어도 약 10%, 적어도 약 20%, 적어도 약 30%, 적어도 약 40%, 적어도 약 50%, 적어도 약 60%, 적어도 약 70%, 적어도 약 90%, 또는 적어도 약 100% 초과인, 방법.
- 청구항 85 내지 93 중 어느 한 항에 있어서, 상기 치료학적 유효량이 약 120 mg 또는 120 mg인, 방법.
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