Chemical and biological evaluations of an (111)in-labeled RGD-peptide targeting integrin alpha(v) beta(3) in a preclinical tumor model.

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1 Chemical and biological evaluations of an (111)in-labeled RGD-peptide targeting integrin alpha(v) beta(3) in a preclinical tumor model. Mitra Ahmadi, Lucie Sancey, Arnaud Briat, Laurent Riou, Didier Boturyn, Pascal Dumy, Daniel Fagret, Catherine Ghezzi, Jean-Philippe Vuillez To cite this version: Mitra Ahmadi, Lucie Sancey, Arnaud Briat, Laurent Riou, Didier Boturyn, et al.. Chemical and biological evaluations of an (111)in-labeled RGD-peptide targeting integrin alpha(v) beta(3) in a preclinical tumor model.. Cancer Biotherapy & Radiopharmaceuticals, 2008, 23 (6), pp < /cbr >. <inserm > HAL Id: inserm Submitted on 22 May 2014 HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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3 P rq s t s1 2 s q ❶ 9 ❷ ❹❸ t ❺ ❻ ❼ ❽r ❹❾ ❾8 ❿ ➀ 6 s9 s➁ ➁ ➂ ❾ ❺ ❹➀ ➃ ➄ ➅ ➆ ➇4➈ ➈ 3 ➉1 ➁ ➊ ➋ s➌ 7rq ➉110 9❼ ➌ 7 ❷ 8 109➍ ➎ ➏ P➎ s ➐ 1 8 ❷ ➑ ➀ ➆➒ ➉➓ 7 ➎ ❽ 1 9 ❽ ❹ 1 9 ➋ ❷ 8 ➀ 2❶➎ ➁ ❻ 3 1 9s➎ 109 s ❻ ➄ ➒ ➆ ➀ 8➑10 4 ❽ 1 9s ➋ ❷ ➀ ❻ r➆ ❽ 1 9s ❽ 1 9 ❷ ❻ 1 7 ➁ 1 s 4❸➊ 1 ❹ 2➒ rq ➃ ➄ ➅ ➆ ➇4➈ ➈r ➋ s1 ➁ ❹ ❶ 8 s➌ 7 q ➉1 9 s ➌ 7 ❷ 109 ➎ ➎ s ➆ ➓ 7 ➎ ❽ 1 9 ➇4➈ r ➐ 1 ❷ ➅ ➀ 9 10 q ➋ ➀ ❸ 1 9 ➍

4 ❸ s1 ❸ 7 7 ➁ s s 1 ❸ 1 ➊ s 8 s1 1 ➓ 9 s1 1 ❸ s1 ❸ ➉➀ ❸ 1 ❸ s r ➁ 7 ❸ s 7 ❼ s 8 ❸ 1 ➓ ❹ ➀ ➁ 7 7 s1 ➁ ➁ t7 7 ➁ 1 ❸ s1 ❸ ❸ 10 ➋ ➊ ➒ ❸ 1 1 s 1 ➓ ➁ 7 ➋ 9 9 3❽ 2 ➀ 7t 1 ➁ ➁ 1 7 s ❸ ❸ 7P 1 1 ➀ ❼ ➓ 7 ➉➓ 1 ➓ 7 9 s❾8 s1 ❸ 4❸ ➓ 9 9 s1 9s1 ❸ ➋ 9 ➁ 1 ➁ s 87 1 s 3❽ 2 ➀ 7 r ❹ r ❷ ➐ ➀ ❽ 2 ❷ ➐ ➀ 3❽ 2 ❶ 7 s1 9s 9 s ➀ 7 s ❸ 9 s ❸ ❸ ❹❹ ➉ s➈ ❹ ➀ ❾8 ➋ ➋ 9s1 1 ➋ ➋➀ ➄➊ ➄ ➄ ➄ ➀ ➋ s P 2 r➐ 9 s ❸ s1 ➁ ❹ ➊ s ➁ ➓ s1 ❶ s ➓ 7 ❸10 ➋ s ➁8 ❼ s❾4 s 9 ➁ 1 ➁ 731 ➊ ❽ 2 ➁ ➁ s ➈10 ➍➈ 10 ➍➈ s s ❸ 7 ➋ ➓ ➋ 10 ➃ ➀ 2 ➐ ➀ ❷ ➐ ➀ 3❽32 87 ❼ ❹ t s 8 ➓ ± s ➀ ➁ 1107 ➓ 1 7 ➀ ➋ ❼ ❸ 8 ➊ ➓ 7 9s s❾ ➋ ➊ 1 ➀ s ➓ 7 ➓ 9s 7 4 s1 1 ➋ 7 s ❸ 7 9❼9 9 ❸ ➊ 7 s1 ❹ 7 s9 ❹ ❸ ➓ 9 ➉1 9 ➋ 9 ➋ ➁ ➁ s 7 1 ➁ s 9➉1 1 9s ❹ 1 ➁8 1 9s 1 1 ➀ s ➓ 7 ➓ ➁ 9 s ❸ s ❸ 9s9s1 1 ➓ 7 9 s❾8 s1 1 1 ➏➁ 1107 ➀ s t s1 10 ❶1 ➓ 9 ➁ ❶ s ➋ 7 ❹ ➁ s ➁ 1 s 9 1 ❷ ➐ ➀ 3❽ 2 ➒ ❶ s 109 s ➊ ❹❸ s ❸ s1 ➁ s ➑

5 ❸ s1 ❸ ➊➁ 1 7t7 1 ❸10 s ❸ 8 ➁ s ➁ ➀ 7 ❼ 4❸ 9s1 1 ➏➓ ❹ ➐ ➁ 7 s1 9s1 ❸ ➁ 1 9s1 ❸ s ➁ ➁ 1 ❸ 7t7 s s1 10 ❸ s1 ❸ 7 7 ➀ 7 ➁ ➁ ➋ ➓ ➓ 9s1 ➁ 1 ❸ 7 ❹1 9 s 4❸ ➉1 ❸ ❸ ➉1 1 ➋ s 4❸ ➁ ➀ 7 s ❸➊ 9s1 1 ➓ 87 7t 9 7 q ➁ ❹ s ➊ ➋ ➁ 7 7 s1 ➁ 7 ❹➁ s1 9 9❼ ❼ ➁ s s 4❸ ➉1 ❸ 7 7 r s ❸ s 7➒ ➁ 1 7t ❼ ❸ ❸ s ❹ 9➉ s ➓ 7 ❸ ❹ s ❹ 7 ❹❸ s 7 ❺ ➃ 4 7 ➋1 8 ➓ 9s1 ➁ 1 1 ➀ ❼ ➓ 7 ➓ 1 r 1 ➌ s 7 9 ➋ s1 ➋ 7 ❸ ❼ ❸ 7 7 s ❽ 2 ➀ 87t ➁ ❹➁ s 87 ➓ ❹❸ 8 7➊ 1 9 ➊ ➋ s 10 ❸ s ❸ ➁ ➃ ➏ ➊➁ 87 3 ➋ 7t ➓ 9 s1 9 9 ➓ 9➉1 ➁ s r 7 1 ❹ t ➓ 4 9❼ s❸ 107 ➓ ➊ ➋ ➐ s ❸ s s 9P ➋ ❶ ➁ 1 s 7t 7 ➁ 9 9❼ 1 ➓ 1 s 1 ➁ ➁ s9 9 7 s ❸ s ➊ ❶ 9 ➁ 7t7 1 ➌ s ➊7 s❸ s ➓ ➀ ➁ ➉➓ 1 9s 9 8 9s9 7 ❷ ❶ s 1 9s9 7 ➁ 7 7 ➓ s1 7 9 ➋➓ ➍ 7 s ❸ s ➁ 7 7 s1 7 ➊ 1 s 1 4❸ s1 ❸ ➁ 1 1 ❶ 7 7 ➁ r 1 ❶1 ❸ ❸ 7t7 ➓ 7 7 ➍ ❺ 1 9s 109 ❸ s ❸ 1 ❸ s1 ❸ ❸ ❼ 8 ❸ s s1 7 1 ❸ 9 s 9 ➁ 1 ➐ ➁ 1 ❹ 1 s 1 ❸ s1 ❸ ❸ s 9 s ❸P ➋ 9 ➏ ❽ 2❶➀ ➁ ➁ s 7 ❹ 7 ➋ ❼ 7 ➋ 1 s 10 ➍ r 9s1 1 ➓ 7 7t 9 ➓ 9➉1 ➁ 8 1 ❸ 1 s s ➍ ➃ 7 1 ❶1 8 ❸ ➓ ➓ 9 9s 1 ➁ ➀ 7 s ❸➊ 9s1 1 ❶➓ s s ❸ 7 9s ❹ ❸ s ❸ ❹➁ ➍ 9 s ➊ ➓ ❹ 7 r7 s 7

6 ➓ 9➉1 ➁ 9❼ s❸ ➊ ❷ ➐ ➀ 3❽ 2 P ❷ ➐ 3 ❸ s ➓ 9❼ 7t7 9 ❷10 s1 9 s❾8 ➋ ➐ ➁ 9 7 9s1 ➀ ➁ ❹➁ s ➍ ➑ 8 7❹ P 9s1 ➀ ➀ 3❽ 2 ➒➀ ❶ ❸ ➋ 1 r 7t7 9 8 ❼ ❶1 ❹ 1➊7 ➁ ❼ ➋ 9 9❼ ❹ ❸ 7 s ❸ ➁ ➒ ❹❸ 7 1 9s ❸ 10 ❷ ➐ ➀ 3❽ 2 r s1 9s ❼❾4 7 ➁ ➓ s1 7 9❼ P ➋ 7 ➉ ➋ ➒ 1r ❼ ➊7 ➁ 8 ❼ ➋ 9 9❼ 1 ➐ ❼ ❶ 1 ➓ 9➉1 ➁ ❼ 10 ❶➀ ➃ ➀ 9 9 ➉➓ ➉➓ 1 ❷ ➐ ➀ 3❽ 2 1 ➓ 9➍ 7 ➁ 1 ❹ 9 7 ❸ s1 ❸ 7 7 ➀ ➁ 7 7 s ❸ ❶1 ❸ s ❸ ❸ ➑ 1 ❹ ❼ 3 ➉1 7 s1 ❶ ➋ s ➒ 3 ❷ ➐ ➀ 3❽ s 3 7 ➊ 1 ➁ ➁ ➁ s9s1 s ❸ ➁ 9s 8 1 ➃ ➍➀ ➊ P ➁ ➀ P1 ➀ ❹➈ ➈ ➐ 1 s1 9➉ ➋ 9 ❷ ➐ ➀ ❽ 2 ➍ ➃ ❹ ➉ s➈ ❹ ➀ ➋ ❾8 9s1 1 ❹ ➀ ➄ ➉ 2 r➐ ❸ 1 ➁ 87 ➋ 1 ➁ ➁ ➉ 1 9s9s1 ➏ 1 s1 1 3 ➃ ➀ 2 ➐ ➀ 3 ❷ ➐ ➀ 3❽32 1 ➁ 9 1 ➀ ❹ s 4❸ ➉1 7 s1 1 r ➋ 1 1 ➀ s ➓ 7 ➓ 8 9 s ➊ ❹❸ s ❸ ❸ s1 ❸ 7 7

7 ❺ 2 r➐ ➀ ❷ ➐ 9➉1 ➀ ❽ 2 ➒➀ 2 ➐ ➀ ❷ ➐ ➀ ❽ ➒9 s❸ 1 s ❸ s β ❶ 7 1 s 7 s ❸ ➏➁ ➓ s1 7 9❼ P 7 ➉ ➋ ➁ 1 ➊7 7 7 ➁ ❹➁ s 7 t 9s ❾4 P 3 ➓ ➀❶ ❸ 6 ❹ 1 s➌ ❻ ❸ ➁ 6 ➀ r6 ❻ ➁ s 1 ➁ ➁ ➉➓ r ➋1 9 7t7t 10 ➐ 32 r➐ ➀ 3 ❷ ➐ ➀ 3❽ ➋ 109 ❶ ❸ 8 1 ➐ ❷ 7 ➈ 10 ❸ ❶1 9 ➊ 9 ➌ 1 1 ➃ ➃ ❻ s 1 P s 8 9s 6 ❹ ➄ ❹ 9 ❶ 7 1 ❶7 1 9➍ s1 1 r2 ➐ ➀ 3 ❷ ➐ ➀ 3❽ 2 s ➊ ❶1 ➋ 4 ➐ ➁ 1 s1 ➊ ❶ 7 7 ➏ 1 ➇ 7 s ❸ ❶❻ 9 ➋➓ s ❸ ➁ t7 ❹ s ➓ 7 ❸ 10 ➐ ➊ s1 7 ➁ 1 P s ❼ 4❸ 2 ➐ ➀ 3 ❷ ➐ ➀ 3❽ 2 1 s1 ❸ ❹ 1 ❹ ❺ ❼➃ ➃ ❻ 9 s ➊ ❶ ➒ 3➁ ➉➇ 1 ❹ 1 4 s 7 2 s 8 ➁ ❹➁ s s ➉ s1107 ❹ ❶ ➐ ➁ ➒➓ ➏ 1 ➈ ➊ 1 ❻ ❷ 1 1 ➁ s s❾ ➋ ❶ s1 10 q3➌ ➃ ➃ ❻ 9 ➋ r 1 ❹ ❸ ➐ ➀ ❷ ➐ ➀ 3❽ 2 s ➊ 1 ➉ 8 4 ➁ ➇ 10 ➋ ➈ t❻ 1 s 7 ➐ 7 1 ➃ ➀ 2 ➐ ➀ ❷ ➐ ➀ 3❽32 7❶ 7 s s❸ 8 3 ➉1 9 9 s ❸P ➁ 1 ❶ 6 ❻P ➐ s ➀ ➋ ❻ 1 1 ❸ ➁ ➐ ❻ ➃ ➀ 2 ➐ ➀ ❷ ➐ ➀ 3❽ ❼ ❸ ❶ 7 s 7 s ❸ 6 ❻ ➐ ❻ ❷ 1 6 ❻ 9❼ 7 7 ❶ ➏ ➀ ➑ ➁ ➁ ❶ ➀ 10➇ ❻ ➀ 7 ➁ 1 ➁ 1 1 ➆➒➂ ➀ ➂ ➊7 ❶ 7t ➋ 10 9s 9 6 ➀ 6 ❻ 9❼ 107t 7 ❶ 7 ➁ 1

8 ➃ ❻ 3 q3 6 ➀ ❻ ➇ 10 ➑ ➊ 7 s ❸ r❸ ➋ s 9 1 s 10 1 s9 r s 9 1 s s 10 q ➀ P s 7 ➑ q3 r 4➀ ➑10 ➊ s 7 1 ➑ 1 ➇4 q3 ➑10 4➀ s 7 ➇4 q➒ ➅ 9➍ s1 ❶ 7 ➁ ➍➈ 9 s ➐ 9 s1 ➉➓ ➍ ❼ 4❸ ➄ ➃➊➁ ➀ ❸ 1 s ❸ 7 7 ❻ 3q 3 ➃ ➃ ❻ 1 9s9 8 s r ❸ ➊ 1 ❷ 1 ➐ ❻P 9❼ 7 7t ➃ ➐ ❻ ➀ ❽ 6 9❼9 ❼ 7 P ❼❸ ➆ 7 9 ❸ 9 ➁ ❸ ❸ 9s 7t7r ❶ 7 7 ➋ ➒ 1 ➁ 1 87 ➋➓ 9➉ 7t ❹ 10 ➐ ➀ 7 ➓ ➈ q3➌ 1 ➃ ➀ 2 ➐ ➀ ❷ ➐ ➀ 3❽32 ❶ ➊ s ➁ 1 ➑ ➏ 1 7 ❶ 10 ➇ 9 q3➌ 1 7 ❹ 10 ➈ ❻ ❹ 7 ❼ ❸ 1 ➍ s1 107 s s ➊ ➁ 1 s 8 7 ➏ s 7 ❹ ➑ ➑ 1 7 ➏❹ 9s ➌ 1 1 ❶ s s1 ❶ 7 8 ❼ ❸ ➋ ➏ 9 ➊ 1 ❸ ❹ ➒1 ❶ ❸ t ➄➊ 1 7 ➁ 6 9s9 ➏ s 8 10➄ 1 10➄ s ❸ 1 ➑ ➊ s 7 ➐ s s1 7 ❶ 9❼ 7t 6 ❻ 1 s ➁ 8 ❸ 1 1 s 7 ➁ 1 ❹ s 9 1 9s 7 ➅ 9 ➋ 1 ➁ 1 s 9s ➁ 1 ❶ 1 7 s ❼ ❸ 1 10 ➋ 1 7 ➁ 1 s 7❹ s ➊ ➋ s ➐ ➀ ➁ α ➁ 1 7 ➉➓ 1 q 9➉ 8 ❶ β ❸ 1 7 9➉ ➁ 1 ➓ ❿ ❻ 1 9s9 ➃ ➄➏ ➅ ➆ ➇8➑ ➆ ➓ 7 ➍ 1 ❽ 1 9 ❷ t 9 s 6 ➃ 7 ➁ ➁ 9 ❹ ❷ ❻ ➀ ❽ 9➉ s ➑ 1 9 ➁ 9 9 s ❹ s ➒➆➒➃ 9 7 ➁ 1 s ❹ s ❸ 9 ❻ ❹ s s ➊ ➈ t❻ ❻ 1107 ➁ 9 ➋ ➋ ➁ ➁ 1 ❼ 9 ➋1 9 ➉ ❶ 7 1 ➓ ➁ 9s ❷ ❻ ➀ ➊ ➋ 10❻ ➒ 7 ❹ ➁ ➁ 1 8

9 7 s ❸ 9 7 7t ❾❶ 9 9 s ❸ ➊ s 7 ➑ ➊❸ ❻ 9s9 7 ❹ r 7 7 ➁ s 7 s9 ➄ ❻ ➁ s 7 s t ➋➓ s 9 7 7t 1 ➊➁ 7 7 ❶ ➀ 1 9s 9 ➊q3 9 ➊ 1 s 1 ❻ 9 7 ➓ ➋ ❽ ❶ s ❷ 8 ➐ ➊ 9 7 ❶ ➒1 ➋ ➁ s s9 ➊ s 7 s1 ➍ ➋ 87 7r 1 ❶ 7 ❹ s9 ➁ ❹ ➉ ➋ s ➁ 7 7 ❶ ➁ ➁ 1 ➓ ➋ ➊ 9 ❻ ➊ ❹ ➆ 7 ➊❻ 1 1 ➊❻ 8 ➊ ➋ ➊ ❹ ➓ s ➎ 7 ➊➎8 7 ❻ ➒ ➐ 1 ➋ ❷ 1 ❾ ➉1 ➑ ➑10 ➁ 7 ❹ ➁ ❹ 1 ➋ 1 ❾8 s ➓ 9 1 ❾8 s1 ➇ ➑ ❹ ➐ ➀ ➁ 9s9 7 s 4 r 1 ❹ 6 q➒ ❶ s t ➊ ❼ s s❸ 8 ❼ 9 ❸ 1 ➇rq3 9 r r 1 7 ➋ ➊ ❹➁ ➁ 1 9➉ ➊ 9 7 ❹ r 87 ❾ s ❹➁ 1 9 s ❹ ➋ ➉1 1 s ❹❹ r ➓ 1 9 ➀ ➈ ❸ ❸ 9 ❾8 s ➑ ❸ ➓ 1 9 ➀r ❸ ❸ ❸ 7➒1 ➃ ➀ 2 r➐ ➀ ❷ ➐ ➀ 3❽32 ❶ ❼ ❹ t 10 ➍➈ q ➌ s t 9s s 10 s ➋➓ 1 7 9➉ s 9 ❹ 9 s9 ➓ ❼ 1 10 ➋ ❹ ➑ ➊ ❶ 10➇➒ s9s1 s ❸❶ s t s1 s 9 7 ❶ ➁ ➏ ➋1 9s s 9 ❸ ➊ 1 ❻ ❶ ➋ ❸ 9 4➀ ❼ s ➀ 1 ➁ 9 ➊ ❹❸ ➌ 7 ➍ s1 87 ➁ 1 ➋ r s❾8 ➋ ➏ 7 ➁ ❹ 9 ❸ 9s ➓ 7 ➁ 9 s 1 7 ❶ ❼ 8 7 s 7 1 9s1 1 1 ❹ 1 9s9 ❶ ❼❸ ➋ 10 3 s1 ➋ ➓ 7 1 r 7 s ❸ ❸ 1 8 ➈

10 ➐ 1➊ s ❹ ➃ ➀ 2 ➐ ➀ ❷ ➐ ➀ 3❽ s s❾4 s 109 ➓ 9s1 1 ➒ s 1 9s9 ➑ ➊ ❹ ➑ ➊ 1 9 9s1 ❶ ❼ ❸ s 8 ➉1 1 ➑ q3➌➊1 10 ❹ ➁ s ➁ 1 ❼ 8 ➋ ➁ ➑ 10 ➑ q 9s1 1 ❶ 7 ❼ 9 s ❸ ➇4 ❸ 1 ➊ s 7 6 9➉ 7 ❶ 7 ➊ 9➍ r 1 ❸ ➒1 ❸ 9 ➄ 1107 ➁ 6 9s9 ➋ ➆ ➒ 9 ❾4 6 ➀ 6 ❻ ➆➒ s ❹ 9 7➒ 8 9 P 9s ➀ 6 ❻ ❷ 1 9 ➓ r ❶ ➊ ➏ s ➁ 1107 ➁ r ❹ ➁ ➈ ❸ 87 t 8 ❼ ❸ 1 s 7❶ 4 s ❸10 ➁ 7 ❹ s9 4 1 ❸ ➊➄ 1107 ❹➁ ❶ 9 ❾4 r 6 ➀ r6 ❻ ➇

11 ❺ ❺ ❺ 6 ➀ r6 ❻ 9❼ ➃ ➀ 2 ➐ ➀ ❷ ➐ ➀ ❽ 2 ❼ ➁ s ❸ 9 1 s1 ➓ 1 ➁ 1 ❷ s❸ q ➐ ➁ ❹ ❼ ➋ ➑10 ❼ 87 s1 ➋ 9 ➁ 1 ❶1 ➈ ➄ 1 ➀ 1 s s ➊ s s t ➋ s1 ➋ ➓ ❶ ➋ 1 ➓ 1 ➋1 9 ➊ s 9❼ s1 9s 9s ❼ ❸ ➋ 1 ➃ ➀ 2 r➐ ➀ ❷ ➐ ➀ 3❽32 ❶ s ➐ ❻ 7 ❼ ❸ 7 s9 8 ❸ 9 ➁ ❸ ❸ 9s 7 7 ➏ s ➁ 87t 4 1 ❶ 1 ➄❶ ❹ P ❶ 1 9 ➇4 ➑ 7 1 ❼9 ➁ 7 7t ➋ ➐ 9 ➊➃ 7t 1 s1 7 r 1 ➀ 1 s 10 ➊ s❸ 7 1 9➉➓ ➍➈ ➀ 8 ➍ ➒ ➋ 7 ➃ ➀ 2 r➐ ➀ ❷ ➐ ➀ 3❽32 s 10 1 ❸ s 3 s1 ➊ 9 ➁ 7 ❼❸ ➈ 3 s1 9s 9s ❼ ❸ s ➓ s1 7 1 s ➒ ❼ s❸ ➑ ➐ ❶ s ❸ ❶ s ➊ s 7 ➈ ❻ ➋ ➊➑ s 7 ❻ ➈ ❷ s❸ ➑ ❸ ❼ s1 ➏ s ➏9s ➋ 7 1 ➊ r 9s1 9 9 s ❸ ❹ 1 t q3 7 ❸ ➁ 1 9➉ ❸ ➁ ➁ s s1 9 9 s ❸ 7 ➁ 1 ➈ ❻ 3 s1 9s 9s ❼ ❸ ➋ ❶ s 9 ➊ ❶1 10 ➋ ➄ ➄ 4 10 ❹ 1 9s ❹ ➍ 1 s1 4❸ ➏1 10 ➍ s9 2 ➐ ➀ 3 ❷ ➐ ➀ 3❽ 2 ➐ 7 ❹ 7 1 s ❶ 1 s ❷ ❸ 8➑ q ➃ s ➊ s❸ 7 ❼ s ❸ ➋ 1 ➁ s 9 7 ❼9 ❶ ➋ ➏ s 2 r➐ ➀ ❷ ➐ ➀ 3❽32 ❼ ➀ 1 9➉ 109 ➉1 7 ❷ ❸ P➑ ❻ ➐ 87 s1 9s 9 ❼ ❸

12 ❺ 7 ❹ 1 4 s 2 r➐ ➀ ❷ ➐ ➀ ❽ 2 s 10 ❶➀ s1➊1 9s ➋ ❷ 1 1 ➁ s 9 s1 s1 9s 9 ❼ ❸ ❶ 7 ➁ 1 r 7 s ❸ s1 1 ❹ 8 ❷ s 9 9❼ ➊9 9 s ❸ 8 7 ➋ 87 ➁10 ➁ ➉ 1 s1 ❶ 7 ➋ 10 2 ➐ ➀ ❷ ➐ ➀ 3❽ 2 1 9s r 9 9 ❸ 9 ➈ ➈10 ❹ 9 ➋ 7 7 ➐ 9s ➑ ➐ ❾4 7 s 4❸ 1 ➁ s s❾4 1 ➉1 107 ➄ 10 P s ❸ s ➊ s ➈ t❻ ❸ ➉ P r➐ ➀ ❷ ➐ ➀ 3❽ ➉ 9s 9 8 q3➌ 1 ➊ s 10 ➀❹ 8 ➆➒ ➊7 ➋1 s1 107 ❹ ❸ ➊➑ ❸ 1 ➁ ➁ s 1 109➉ ❶9 9 ➊ 87 ➁ 8 ➓ 9❼ q3➌ ❹ q3➌ 1 s ➉ ➀ ➍ s❸ ➁ 1 ➈ ➃ ➀ 2 ➐ ➀ ❷ ➐ ➀ 3❽32 7P s s 7 r6 ❻ ❶ 7 ➁ 1 ❶ ➓ ❹ ➉1 7 s ➁ 1 s 8 7 s ❶ 1➊➑ ➒ ➒➁ 1 ➐ 9 ➐ ❶ 6 ❻ s ❸ 7 1 ❶ 7 s ❸ 9 ➋ ➊ 1 ➋ ➓ ➁ s 8 s ➋ 9 7 ❹➁10 ❹ s1 s ➏ 87 ➏ ➋ ➁ 1 s1 9 9 ➁ ➁ s ➏ s ➋ 7 1 r7 ➃ ➀ 2 ➐ ➀ ❷ ➐ ➀ 3❽32 s 7 9 ➊ ❼ 7 10 ➑ ➏ 1 t7 9❼ ➑ 1 1 ➀ 1 s ➉ ➀ ❶ 7 ➋ ➑ 1 7 ❶ s s ❸ ❶ 4❸ ➉1 ❶ ➒➁ 9s 7 ➁ 1 s 7 s❸ 7 ❼ s 9 1 ➁ 9 ➃ ➀ 2 ➐ ➀ ❷ ➐ ➀ 3❽32 s1 7 4 s1 107 s ➐ ➀ ➁ 10 1 ➀ s ❸ ➊ ➁ 7t s ➐ 9 ➊ 3 ➁ 9 ❹ 1 ➋ s1 ➓ 1 9➉1 1 9 s ➓ 10 ➐ s 107 ➁ 7 ➋ s 1 1 9s ➊ s s1 ❷10 1 9s1 ➋ ➓ ❶ t ➓ ➏ s ➊ t 9 ➐ ❶1 ➀ 1 ➀ 9s1 1 ➐ q 1 ➀ 1 ➀ r 7t 9 ➐ ➉1 7 ➁ s 9s ➓ ➓ 8 10q31 s1 73 ❼ 8 s ❸ s ❸ s ➑ 1 10➇ 1 7 ❹ 7 7 s t 8 s ❹ s t s1 ➃ ➀ 2 r➐ ➀ ❹

13 ❷ ➐ ➀ 3❽ 2 ➁ ➏ s ➐ ➀ ➁ ➏8 10 ➈ ➃ 2 ❸ ➐ 1 9 ➁ ➏ ❹ 7 s 7 s9 s❾8 ❹ ➑ t7 ❼ ➋ ➁ ➁ 1 ❼ 9 10 ➍➈ ➃ 2 ❸ ➑ 10➇r 1 t7 ➄ 1 ➀ s ➓ 7 ➓ ➁ 9 1 9➉ ➀ 1 s ❸ s ❸ s ❸ ➁ ❸ 7 9s9s1 ❶ ➓ 7 9s 7t s1 1 9s9r 1 7 ❶ 10➇ 1 7 ➁ 87 ➍➓ s ➊ ❸ 1 s ➋ ➏ ➑ 1 t ➒ ❼ ❷ s❸ 10 7 ➁10 1 r s1 7 ➉ 4 s s❸10 10 r 9 s1 1 ❹ ❶ ❹ ➓ s ➏ 107 q3 s1 7 4 s1 7 s ➋ s 109 s1 ❶ 7 ➁ ➃ 2 ❸➊ 10➇ 1 t7 s t 8 s1 10 ➐ ➏7 9 ➍ 1 ➃ ➀ 2 r➐ ➀ 3 ❷ ➐ ➀ 3❽ 2 ❶ 7 ❼ ➋ s 1 7 ➊ 9s1 1 9s ➓ ➑ ➊ 1 7 ❷ 1 9s ❹ s1 ➋ ❶ 7 ❹ ➊➈ ➈ ➐ 9s ➏ 10 P1 ❶ ❹ 1 s ➋ s1 ➓ 87 1 ➓ ❹ 1 ➊➁ s s1 1 9 r 9 107t 7 1 s 9 ➓ ➒ ➋ ➒1 ➁ 107➒ ➒ ➑10 s ➁ 1 87 ➁ ➓ 9❼ ➒ 1 1 ➀ 1 s 10 ➀❹ ➃ ➀ 2 ➐ ➀ 3 ❷ ➐ ➀ 3❽ 2 ➆➒ s 9 ➓ 7 1 ➋ ➏ s1 ➊ 9 ➁ 1 ➃ ➀ 2 r➐ ➀ ❷ ➐ ➀ 3❽ ➁ ➓ 9❼ ➇ ➃ s 1 9➉ 8 1 ➋ s1 ➓ 1 87 ➁ 1 1 ➊ ➋1 ➁ 9 ➊9s 9 ➋ ➋ 1 ➑ ➀ 1 s 10 ➀❹ 87 ➋1 ➓ 10 ➊➁ ➁ 7 ❼ 4❸ 1 r s1 ➓ ❶ 7 1 ➈➊ s 7 6 ❻ 1 7 r 9 s1 ➊➁ 1 s s 1 ➁ 1 ❶ 7➏ 7 ➊ 7 ➃ ➀ 2 r➐ ❶ ❶ ❶ ❷ s 9s9❼ 9s1 1 s1 ➋ ➓ ❶ 7 ➋ 9s ➋ s t s1 10

14 ➀ ❷ 1 ➁ 7 ➋ ➏ 3❽32❶➀ 7 ➋ 7 ❸ s ❸ 1 9 ❸ s1 ❸ 7 7 ➁ 87 s 7 ➓ 9 1 ➁ ❹ s t ❹ 7 ❹ 9 ➊ 7 s ➄ 9 P s ➁ ❹ ❶ 8 7 ❶ ➁ 1 ➓ s s ➓ 9 9 s 1 s1 ➋ ❹ ❾8 s1 ➋ t7 8 1 ➋ ➋ 9 ➓ 9❼ s➀ ❸ s1 ❸ 1 ➁ ❹ ➓ 9s1 ➁ ➊ 8 t ❷ 1 s 7 ➋ ❻ s9 ❸ ➋ 10 r s❸ s 9 3 3❽ 2 ➀ 7 ➊ s s 1 1 s ❸ s ❼ s ➁ 7 ➃ ➃➊ 9 ❼ 9 s 9 ➐ 8 ➉➀ ➂ ➅ ❽ ❷ ➀ 1 ➁ 1 ➓ 7 s 7 8 P ➁ ➁ 1 ➓ ➋ 1 1 ➓ ➋1 9s1 9 ❹ 1 ➀ ❼9 9 ❸ ❹ 7 87 ➋ ➏ ➓ 9➉1 ➁ 8 1 ➏ 109➍ ➓ 9 8 3❽ 2 ➀ ❷ ➐ ➀ 3❽ s ➁10 ❹➁ s ➁ ➉ 109 9s 8 1 r 9s ❼➓ 1 ❸ ❼ ❸ ❸ 10 ❸ ➊➁ ➓ s1 7 9❼ ➏ ❷ ➐ ➀ 3❽ 2 7 ❼❸ 9❼ 7 ➁ ❼ 1 s ❸ s 10 ❶ ❶ ❶ s ➊➀❹ r9 9 s ❸➊ 7 s ❸ 2 r➐ ❸ 1 ➁ ❶ ➒1 1 ❹ 8 ➓ 7❹ 1➏ ➓ 9s1 ➁ ➓ 9 ➃ ➀ 2 ➐ ➀ ❷ ➐ ➀ 3❽ 2 87 ➊ ➁ 87 7 s1 ➑ 1 s 7 s1 7 ➉ 4 ➉1 ➍ ➏ ➊➁ t7 ➁ ➉➓ ➏1 ➊9 9 s ❸ ❶ 1 1 s1 ➁ ➒➁ ➁ s ➓ 7 ❸ 1 t7 ➁ ➓ s1 7 9❼ 1 7 3❽32❶➀ ➋ 7 ➋1 9s ➋ ❶ 9 s α β ➁ 1107 ➓ ➊ 10 1 ➀ s ❸ 9 7 ❶ 9 ➋ 9 ➋ ➋ 9s1 ➀ ❽ 2 ➀ 3❽ 2 ❶➀ ➁ ➁ ➉ ➉1 s ➀ ➑10 1 ❶1 ❸ s 4❸ ❺ ➐ 7 7 s 9s 9 8 ❹➁ 1 s9 ❹ ❶ 1 8 s ➒ ❽ 2 ➀ 87 ➋ ❹ 7 1➊ r 9 ❼ 7 ❶ ➓ 9➉1 ➁ 1 ❶1 s ❸ s ❸➊ ➒ ➁ ➍ ❺ 1 ❸ ➁ 87 s ➀ ❹ ➊ 7t7 1 ➋ ➍ 9 ❼ 4❸ ❹❸ ➋ s ➓ 7 ❸ ➋ 1 1 ❹ ❸ s1 ❸ 7 7 s ❸ s ❸ 1 s1 9s ❹ ➁ 7 s 7 ❼ ➍ ❺ ➐ 1 9 ➏ 9 s ❸ ❹❸10 2 ➐ ❹ ➋ 1 ➉ 7 ➁ s 8 7 ➋ 7 ➏ 1 7 9s ➒➁ 9 7 ➒➓ ➐ ➉ 9 1 ➑

15 1 1 9s s 9 ➁ ➁ 9 s1 7 ➓ 1 ❹1 ❸ s1 ❶1 s1 ❶ ➃ 10 ➐ ➊ ➉1 9 ➋ 9 s ❸ ➋ ➉1 ➁10 ❹ ➊ 73 ❼ 9➉ ➋ ➊ ➋ s1 ➌ 9 ➉ ❹ 1 1 s ➁ 9 ➃ ➋➓ ❹ 9 s ➓ 7 ❸ 1 7➊ ➁ ❹➁ s 1 ➋ s ➁ s1 1 P 9 9❼ 1 1 9❼9 1 1 ➁8 ❼ 9 s s ❸ 7 9 ➃ ➒➁ 1 ❹ ➋ 1 t7 ❶ ➁ ❹ s ➉1 ❼ ➓ 2 r➐ ➀ ❷ ➐ ➀ 3❽32 s 10 s1 1 ➋ 8 s1 1 s ❹ P ➋1 ➁ ➐ ➋ s1 ❶ ➁ s ➊ s❾8 ➋ 1 1 ❹ ❼ s❸ 7 ➋ ➋ s 4❸➏ s ➊ 7 ➁ ➒➁ ➒ 7 9s1 7 ➁ 1 7t ➁ ➓ ➁ ➁ ➉ ❸ s1 10 ➃ 1 1 ➍ s1 7 ❼ ❸ s 7 ➈ t❻ ❶ s ➊ 9s9 s1 9s 9 s ❸➊ 8➃ ➁ ➊ ➊1 ❹ ❼ ❷ s 9s9s ➁ ➁ s ➋1 ➉1 ➁ ➁ s s 10 ➀ ➉1 ➓ 1 ➋ 109 9❼ 1 1 9s9 ➋ 10 ➃ P 9s1 ❶ r➐ ➀ ❷ ➐ ➀ 3❽ s ➍ ➁ 1 1 9➉ ➋ 9 s ❸ ❷10 1 ➏9s1 ❶ ➁ ➁8 s s ➀ s1 ❶1 9s 9➉ 1 7 7❶1 1 ➀ 1 s s ➁ ❹ ➉ 9 9❼ s s1 ➃ ➒ ➒ 1 ➀ 1 s s ➋ 1 ❸ ➓ ❼ 7 1 ➍ 1 ➏ ❶ 1 ➁ ➊9➉ ➋ s ❸ 1 9s ❸ 9s1 7t7 1 1 ➓ r 1 ❹ s❸ s1 ➊ s❸ ➒ ➁ 1 ➁ ❹ s s1 4❸ ➀ 7 ❼9 1 ➏ s ➒➁ s 7 ❶ ➓ 1 9➍ 10 ➊1 ➃ ➀ 2 r➐ ➀ 3 ❷ ➐ ➀ ❽ ➍ s1 1➏ s 8 ➁ s 9 10➃ 7 7 ➁ ➁ s ❼ 10 ❶➀ s1 ❹ ❸ ➊ 1 ❹ ➒ 1 ❹ 8 s1➊1 9s ➋ 7 4 ➒ 1 ❶ 7 ➌ ➋ ➒ 1 1 s 1 ➁8 ❼ 910 ➋ s1 9 9 s ❸ ❷ 1 s1 10 ➋ s1 9s 9s ❼ ❸ ❶ ❼9 6 ➀ r6 ❻P ➐ ❻ 9s 107t 7 ➐ ❼ 9 ➋ s1 ➊ 9 ➁ ❶ 7 1 ➓ ➈ q3 1 ❼ ❸ s 8 ➋ s 8 1 ➏7 9 ➍ 1 ➋ ❶ 7 7 ➉ s s9 r6 ❻ ➑ ➊ 1 7 s s1 s 7 1 s ➊ ➋ ➒ ❶7 s ➁ 1 ➁ 1 ➓ ➁ 1 7 s❾8 ➋ ➒1 9s s1 ➓ 9 9 ➁ ❹ s 73 1 s 7 ➁ 9s ❼ ❹ q39s1 1 ❹

16 ➑10 ➓ ❹ 7t ❹➁ s 9❼ ➉ 1 t7 s t s1 10 4➐ 9➉1 ❼ s ❸ 1 ❹ 1 ➁ 9s 7 ➊➁ 1 s ➏ 7 3 9s s ➉1 1 ➃ ➀ 2 ➐ ➀ ❷ ➐ ➀ 3❽ 2 ➋ s1 ➓ 1 9s s ❶ ➁ 7 ❶ ➍ ➍➈ ➃ 2 ❸ 1 ❹ s t s1 1 ❶ ➓ 1 9 ➁ 87➊7 s9 9 1 ➓ ➃ 2 ❸ 1 7 ➒ ❼ t s1 10 ➐ 7 ➁ ➓ 9 7 ❶ ❹ ➊ ❼ ➐ ➀ ❷ ➐ ➀ 3❽32 ➑ ➍➈ ➈ 10 ➇ ➃ 2 ❸ ➒r 4 q 9s 10 ➐ 9 9 ➋ ➃ 9s 9 ❷ ➐ ➀ ❽ ➋ ❹➁ s 9s1 1 P 9 ❹ 9s1 7t 9 ➁ 9s9s1 ❶ ❼ ❸ ➐ q ➐ s ➋ ❸ ❼ ❸ ➐ 7 7 ➋1 ❹ ➍ 9 ➍ ➒ ❹ ❶ 7t 9s ➁ 7 7 ❹ ➁ ❺ 2 ❸ ➋➓ 9s1 ➁ ➋ 7t ➓ 9 10 ❶➀ 9 ➋ 9 ❽ 2❶➀ ❹ 7 ❺ 10➐ 1 s ➋ ➏ 10 1 ➁ 1 ➒ ➁ ➁ 1 9 P 2 r➐ ➀ 3❽32❶➀ ➋ ➃ 2 ❸ ➑ 1 t7 ❹ ➊ s t s ❸ ❸ 1 ➃ ➀ µ ➃ ➀ 2 ➐ ➀ ➅ ➀ 3❽32➒ r➃ ➁ ❶ 1 7 ❶ 7 9 ➓ 7 9❼ 7t 7 s ❸P 1 ➀ s ➓ 7 ➓ 1 9s s ❸ s ❸ ➐ s ❸ 7 1 ➋ ❶ 7 ❹➁ s 9s 9 s ➋ 4 1 ❸ s 107 ➏ s 1 ➁ s 9s1 1 9s 8 1 ➓ ❹ 9 ➁ ❼ 8 7 s❸ ➒ ➒➑ 1 7 ➐ 9 ➁ 1 s1 9➉ ➋ 9 ➋ ➁ ➁ s 7 7 9s1 ❸ 8 7 ➊ ➋ ➍ ➓ 1 ➉1 1 ➉ ➋ 7 ❺ ❹ s ➁ s ➏ ➉1 s ➍ 9 1 ➁ ➀ 1 s ➉ ➏ 1 ➁ 1 ➐ ➁ 1 7 ❹➁ ➁ ➏ s ➊ ❼ ➊ s r6 ❻ 1 ➊ 7 1 9s 7 ➊7 ➁ 1 s9 7 ➃ ➀ 2 ➐ 9s1 s s ❸ ➁ s 89 ❸ ➋ s1 1 ➊ ❶9➉ ❼ ❸ 1 P ➁ 8 1 ➃ ➀ 2 r➐ s 107 ➐ ➋ s1 9 s ❸ 1 ➁ ➉ 93 9 ➋ ➋➓ ❸ 1 1 9s ➋ 109 ➊ s❸ 8 r ➏ ❸ ❸ ❹ P 7 s s 107 ➁ 1 ➁ s 7 ➍ 7 ➁ 1 ➋ s1 P 1 109➉ ➓ s1 9 s❾8 s ❸ ➏2 ➐ ➋ 9 4 ➃ ➀ 2 r➐ s 1 ❹ ➐ 7 s 7 ➁ 1 7t7 9 9 ➓ ❸ 1 7 ❼ s 7 9 ➐ 7 s 107 1➏ ➊ 9 10 ❶1 ➓ 10 7 ➁ ➉ 1

17 7 P P q r s t q ❶ 10 4 ❷ P ❶ ❸ ❹ 1 ❺ ❻ 7 ❼ ❽ ❾ q 3 ❿ 10 q ➀ 10 q ➁ ❷ ➂ P ➃ ➃ 4 4 P 4 t ❷ ❾ ➂ ➄ ➅ ➆ ➀ ➈➇ ➉ ➂ ➇ ➊ ➋ ➌ ➍ ➎ ➏ ➐ ➐

18 ❶ 3 ➊10 ➉ ➌ 1 3 P ❽ ❽ P

19 P P ❷ P ➍ ➐ P 4 4 ❽ 4 ➍ ➎ ➎ ➊❸ 6 8 ➊❸ ➁ 6 ➎ ➎ ➐ 4 10 ➍ ➎ ➎ ➉ ❽ ❾ ➏ ➊ ❾ 8 ➈ ➀ ➀ 4 P P P ➍ ➎ ➎ ➉ ➂ 4 ➂ 2 ➁ P ➎ ➎ ➎ ➐ ➐ ➊❹ 8 ➈ ➊10 ➉ P ➊ 4 q 4 ➎ ➍ ➍ ➍ ❽ ➋ 8 ❽ ➏➊10 3 ➂ ❶ ➎ ➎ ➎ ➍ ❽ ➉ 3 4 ➁ P ➎ ➎ ➐ ➎ ➊❸ ➉ ➉ ❷ ➂ ➃ ➁ 1 ➍ ➎ ➎ ➎ ➎ ➉ ❷ ❷ ➍ ➍ ➍ ➊❹ 8 ➍ ➐ ➍ ➍ ➐ ➊❸ ➏ 4 P ➊➂➊ ➈ ➍1 ➂ ❶ 10 ➎ ➎ ➍ ➎ ➎ ➊❸ ❷ 4 q ❷ ➂ 1 ❹ ➁ r ➎ ➎ ➐

20 4 ➐ ➎ ➎ ❽ ➊❹ P ❾ 6 ➊➀ ➍ ➐ ❷ ➎ ➎ ➐ ➉ ❶ 4 ❸ ❽ 4 ➇ q 1 ❹ ➐ ➐ ➎ ➎ 4 ➉ ❷ ➏ ➌ q 6 ➎ ➎ ➍ ➎ ❷ ➏ P ➀ ➁ ➁ P ➁ ➎ ➎ ➐ ➏ 4 4 ➊❸ P ❷ ➀ ➍ ➍ P ➈ ➎ ➐ ➎ ➎ ➐ ➉ ❷ ❷ 3 s ➐ ➎ ➎ ➎ P ❽ ❸ t ❾ 2 10 ➍ ➎ ➎ ❷ 4 ❾ ➃ ❹ ❷ P 4 4 P ➎ ➎ ➁ ❸ ❷ ❷ ➃ ➏ ➏ P ➎ ➎ ➍ ➍ ➍ q q ❾ ❽ ➌ ➂ 6 t ➐ ➎ ➎ ➐ ❸ 4 6 ➎ ➍ ➎ ➎ ➐ ❽ ➏ ➋ ❶➋ 4 ❸ ➍ ➍ q r ➎ ➎ ➐ 10 ➋ t ❹ ❶ ❸ ➀ P ➐ ➎ ➐ ➎ ➎

21 ➍ ❽ q ❷ ➉ P ❷ ➐ ➎ ➎ ➎ ➉ ➊10 4 ➍ ➍ 8 8 ➁ r P ❹ 10 q ➀ 10 ➍ ➎ ➂ P ➍ ➍ ➍ ❽ ➀➊❹ ➊10 ➂ 2 ➌ ❽ 10 ❹ ➍ ➎ ➌ 6 ➎ ➍ ➍ ➋ ➈ ➈ ➊ ➎ ➐ ➎ ➎ ➉ 6 ➊❹ ❶ 4 ➊❹ ❶ ➉4 1 q P ➎ ➍ ➍ q ❽ q ❾ 8 ➌ ❽ ❷ ➃ ➍ ➎ ➎ ➐ r 8 ❸ ❾ 8 4 P ➐ ➎ ➎ ➍