c544b4b088c65c2aaffd10050660cdd4 pmc_31533235.pdf 97855ec9e1780a05a2137919752955fd03fc1158 pmc_31533235.pdf 3cadd4c427451520dd4196906b81170a467f1d8bdf84b2214710014021315d6f pmc_31533235.pdf Title: BRAF Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale Subject: BRAF V600 mutations have been found in 1–2% of non-small-cell lung cancer (NSCLC) patients, with Food and Drug Administration (FDA) approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50–80% of BRAF mutations in lung cancer are non-V600, and can be class II, with intermediate to high kinase activity and RAS independence, or class III, with impaired kinase activity, upstream signaling dependence, and consequently, sensitivity to receptor tyrosine kinase (RTK) inhibitors. Plasma cell-free DNA (cfDNA) of 185 newly diagnosed advanced lung adenocarcinoma patients (Spanish Lung Liquid versus Invasive Biopsy Program, SLLIP, NCT03248089) was examined for BRAF and other alterations with a targeted cfDNA next-generation sequencing (NGS) assay (Guardant360®, Guardant Health Inc., CA, USA), and results were correlated with patient outcome. Cell viability with single or combined RAF, MEK, and SHP2 inhibitors was assessed in cell lines with BRAF class I, II, and III mutations. Out of 185 patients, 22 had BRAF alterations (12%) of which seven patients harbored amplifications (32%) and 17 had BRAF mutations (77%). Of the BRAF mutations, four out of 22 (18%) were V600E and 18/22 (82%) were non-V600. In vitro results confirmed sensitivity of class III and resistance of class I and II BRAF mutations, and BRAF wild type cells to SHP2 inhibition. Concomitant MEK or RAF and SHP2 inhibition showed synergistic effects, especially in the class III BRAF-mutant cell line. Our study indicates that the class of the BRAF mutation may have clinical implications and therefore should be defined in the clinical practice and used to guide therapeutic decisions. Keywords: BRAF; NSCLC; SHP2; PTPN11; MEK; MAPK Author: Jillian Wilhelmina Paulina Bracht, Niki Karachaliou, Trever Bivona, Richard B. Lanman, Iris Faull, Rebecca J. Nagy, Ana Drozdowskyj, Jordi Berenguer, Manuel Fernandez-Bruno, Miguel Angel Molina and Rafael Rosell Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Tue Sep 17 08:37:16 2019 CEST ModDate: Tue Sep 17 08:37:16 2019 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 13 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3083653 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- NEQLFV+URWPalladioL-Ital Type 1 Custom yes yes no 80 0 UHJCUO+URWPalladioL-BoldItal Type 1 Custom yes yes no 81 0 IDGWHW+URWPalladioL-Bold Type 1 Custom yes yes no 82 0 KTZIHQ+URWPalladioL-Roma Type 1 Custom yes yes no 83 0 XHDYZV+VnURWPalladioL Type 1 Custom yes yes no 84 0 TGMEOR+Rpcxr Type 1 Builtin yes yes no 85 0 OFLXAT+Rpxr Type 1 Builtin yes yes no 86 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 92 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 109 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 110 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 111 0 GBLQZB+Rpxi Type 1 Builtin yes yes no 168 0 IEMOOP+Calibri,Bold CID TrueType Identity-H yes yes yes 174 0 IEMPAA+Calibri CID TrueType Identity-H yes yes yes 175 0 IEMMME+PalatinoLinotype TrueType WinAnsi yes yes no 176 0 IEMNAF+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 177 0 IEMNBG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 178 0 IEMNOF+TimesNewRoman CID TrueType Identity-H yes yes yes 179 0 VUPETJ+Rpxb Type 1 Builtin yes yes no 215 0 CAMXTK+EURM10 Type 1 Builtin yes yes no 230 0 IEMMMD+PalatinoLinotype CID TrueType Identity-H yes yes yes 235 0 IEMMME+PalatinoLinotype TrueType WinAnsi yes yes no 236 0 IEMNAF+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 237 0 IEMNBG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 238 0 IEMNOF+TimesNewRoman CID TrueType Identity-H yes yes yes 239 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 273 0 Symbol CID TrueType Identity-H yes no yes 274 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 275 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 276 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 277 0 Times New Roman TrueType WinAnsi no no no 278 0 ABCDEE+Arial Bold,Bold TrueType WinAnsi yes yes no 293 0 Arial TrueType WinAnsi no no no 294 0 Symbol CID TrueType Identity-H yes no yes 295 0 ABCDEE+Calibri Bold,Bold TrueType WinAnsi yes yes no 296 0 ABCDEE+Calibri TrueType WinAnsi yes yes no 297 0 IEMOOP+Calibri,Bold CID TrueType Identity-H yes yes yes 343 0 IENCGM+Arial,Bold CID TrueType Identity-H yes yes yes 344 0 IENCNK+Arial CID TrueType Identity-H yes yes yes 345 0 IEMMME+PalatinoLinotype TrueType WinAnsi yes yes no 346 0 IEMNAF+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 347 0 IEMNBG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 348 0 IEMNOF+TimesNewRoman CID TrueType Identity-H yes yes yes 349 0 IEMMME+PalatinoLinotype TrueType WinAnsi yes yes no 387 0 IEMNAF+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 388 0 IEMNBG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 389 0 IEMNOF+TimesNewRoman CID TrueType Identity-H yes yes yes 390 0 WKQIZL+Pxsy Type 1 Builtin yes yes no 425 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2020-08-10 12:28:09 CEST RepresentationInformation: pmc_31533235.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2020-03-02 03:57:49 CET Size: 3083653 Format: PDF Version: 1.5 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 0 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: ぉのぴひはつふっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸲ Item: Title: げづびふぬぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮ㄩ‾㸊⡜㌷㙜㌷㝜〰いどててづひづのぴぜ〴ぜ〰ぃぬちびびづびぜ〴ぜ〰はてぜ〴ぜ〰あげぁうぜ〴ぜ〰きふぴちぴどはのびぜ〴ぜ〰ちのつぜ〴ぜ〰ぃは〭ぁぬぴづひちぴどはのびぜ〴ぜ〰どのぜ〴ぜ〰ぃづぬぬ〭うひづづぜ〴ぜ〰いぎぁぜ〴ぜ〰はてぜ〴ぜ〰がふのでぜ〴ぜ〰ぃちのっづひぜ〴ぜ〰ぐちぴどづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰あげぁうぜ〴ぜ〰ぃぬちびびぜ〴ぜ〰ぃはひひづぬちぴづつぜ〴ぜ〰ぴはぜ〴ぜ〰ぐひはでひづびびどはの〭うひづづぜ〴ぜ〰こふひぶどぶちぬぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰いどびぴどのっぴぜ〴ぜ〰あげぁうぜ〴ぜ〰ぃぬちびびづびぜ〴ぜ〰げづぱふどひづぜ〴ぜ〰こばづっどてどっぜ〴ぜ〰いひふでぜ〴ぜ〰ぃはねぢどのちぴどはのびぜ〴ぜ〰ぉのぜ〴ぜ〰ざどぴひはぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Children: Item: Title: いどててづひづのぴぜ〴ぜ〰ぃぬちびびづびぜ〴ぜ〰はてぜ〴ぜ〰あげぁうぜ〴ぜ〰きふぴちぴどはのびぜ〴ぜ〰ちのつぜ〴ぜ〰ぃは〭ぁぬぴづひちぴどはのびぜ〴ぜ〰どのぜ〴ぜ〰ぃづぬぬ〭うひづづぜ〴ぜ〰いぎぁぜ〴ぜ〰はてぜ〴ぜ〰がふのでぜ〴ぜ〰ぃちのっづひぜ〴ぜ〰ぐちぴどづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰あげぁうぜ〴ぜ〰ぃぬちびびぜ〴ぜ〰ぃはひひづぬちぴづつぜ〴ぜ〰ぴはぜ〴ぜ〰ぐひはでひづびびどはの〭うひづづぜ〴ぜ〰こふひぶどぶちぬぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰いどびぴどのっぴぜ〴ぜ〰あげぁうぜ〴ぜ〰ぃぬちびびづびぜ〴ぜ〰げづぱふどひづぜ〴ぜ〰こばづっどてどっぜ〴ぜ〰いひふでぜ〴ぜ〰ぃはねぢどのちぴどはのびぜ〴ぜ〰ぉのぜ〴ぜ〰ざどぴひはぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: あげぁうぜ〴ぜ〰ぃぬちびびぜ〴ぜ〰ぃはひひづぬちぴづつぜ〴ぜ〰ぴはぜ〴ぜ〰ぐひはでひづびびどはの〭うひづづぜ〴ぜ〰こふひぶどぶちぬぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰いどびぴどのっぴぜ〴ぜ〰あげぁうぜ〴ぜ〰ぃぬちびびづびぜ〴ぜ〰げづぱふどひづぜ〴ぜ〰こばづっどてどっぜ〴ぜ〰いひふでぜ〴ぜ〰ぃはねぢどのちぴどはのびぜ〴ぜ〰ぉのぜ〴ぜ〰ざどぴひはぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: いどびぴどのっぴぜ〴ぜ〰あげぁうぜ〴ぜ〰ぃぬちびびづびぜ〴ぜ〰げづぱふどひづぜ〴ぜ〰こばづっどてどっぜ〴ぜ〰いひふでぜ〴ぜ〰ぃはねぢどのちぴどはのびぜ〴ぜ〰ぉのぜ〴ぜ〰ざどぴひはぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: いどびっふびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: きちぴづひどちぬびぜ〴ぜ〰ちのつぜ〴ぜ〰きづぴとはつびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぐちぴどづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㈩‾㸊⡜㌷㙜㌷㝜〰ぐひはっづつふひづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰いちぴちぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぃとづねどっちぬびぜ〴ぜ〰ちのつぜ〴ぜ〰げづちでづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㔩‾㸊⡜㌷㙜㌷㝜〰ぃづぬぬぜ〴ぜ〰ざどちぢどぬどぴべぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㘩‾㸊⡜㌷㙜㌷㝜〰しづびぴづひのぜ〴ぜ〰あぬはぴぴどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Children: Item: Title: ぐちぴどづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㈩‾㸊⡜㌷㙜㌷㝜〰ぐひはっづつふひづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰いちぴちぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぃとづねどっちぬびぜ〴ぜ〰ちのつぜ〴ぜ〰げづちでづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㔩‾㸊⡜㌷㙜㌷㝜〰ぃづぬぬぜ〴ぜ〰ざどちぢどぬどぴべぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㘩‾㸊⡜㌷㙜㌷㝜〰しづびぴづひのぜ〴ぜ〰あぬはぴぴどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: ぐひはっづつふひづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰いちぴちぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぃとづねどっちぬびぜ〴ぜ〰ちのつぜ〴ぜ〰げづちでづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㔩‾㸊⡜㌷㙜㌷㝜〰ぃづぬぬぜ〴ぜ〰ざどちぢどぬどぴべぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㘩‾㸊⡜㌷㙜㌷㝜〰しづびぴづひのぜ〴ぜ〰あぬはぴぴどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: いちぴちぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぃとづねどっちぬびぜ〴ぜ〰ちのつぜ〴ぜ〰げづちでづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㔩‾㸊⡜㌷㙜㌷㝜〰ぃづぬぬぜ〴ぜ〰ざどちぢどぬどぴべぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㘩‾㸊⡜㌷㙜㌷㝜〰しづびぴづひのぜ〴ぜ〰あぬはぴぴどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: ぃとづねどっちぬびぜ〴ぜ〰ちのつぜ〴ぜ〰げづちでづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㔩‾㸊⡜㌷㙜㌷㝜〰ぃづぬぬぜ〴ぜ〰ざどちぢどぬどぴべぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㘩‾㸊⡜㌷㙜㌷㝜〰しづびぴづひのぜ〴ぜ〰あぬはぴぴどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: ぃづぬぬぜ〴ぜ〰ざどちぢどぬどぴべぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㘩‾㸊⡜㌷㙜㌷㝜〰しづびぴづひのぜ〴ぜ〰あぬはぴぴどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: しづびぴづひのぜ〴ぜ〰あぬはぴぴどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: ぃはのっぬふびどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: NEQLFV+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 121 FontDescriptor: FontName: NEQLFV+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: UHJCUO+URWPalladioL-BoldItal FontSubset: true FirstChar: 65 LastChar: 110 FontDescriptor: FontName: UHJCUO+URWPalladioL-BoldItal Flags: Symbolic FontBBox: -170, -300, 1073, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: IDGWHW+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: IDGWHW+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: KTZIHQ+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 241 FontDescriptor: FontName: KTZIHQ+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: XHDYZV+VnURWPalladioL FontSubset: true FirstChar: 225 LastChar: 226 FontDescriptor: FontName: XHDYZV+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: TGMEOR+Rpcxr FontSubset: true FirstChar: 169 LastChar: 174 FontDescriptor: FontName: TGMEOR+Rpcxr Flags: Symbolic FontBBox: -212, -286, 1344, 973 FontFile: true Font: BaseFont: OFLXAT+Rpxr FontSubset: true FirstChar: 11 LastChar: 62 FontDescriptor: FontName: OFLXAT+Rpxr Flags: Symbolic FontBBox: -40, -283, 904, 728 FontFile: true Font: BaseFont: CAMXTK+EURM10 FontSubset: true FirstChar: 12 LastChar: 22 FontDescriptor: FontName: CAMXTK+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: VUPETJ+Rpxb FontSubset: true FirstChar: 61 LastChar: 61 FontDescriptor: FontName: VUPETJ+Rpxb Flags: Symbolic FontBBox: -57, -266, 932, 729 FontFile: true Font: BaseFont: GBLQZB+Rpxi FontSubset: true FirstChar: 11 LastChar: 11 FontDescriptor: FontName: GBLQZB+Rpxi Flags: Symbolic FontBBox: -162, -280, 856, 733 FontFile: true Font: BaseFont: WKQIZL+Pxsy FontSubset: true FirstChar: 0 LastChar: 14 FontDescriptor: FontName: WKQIZL+Pxsy Flags: Symbolic FontBBox: -21, -994, 1292, 912 FontFile: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 75, 757, 193, 793 Annotation: Subtype: Link Rect: 474, 757, 519, 793 Annotation: Subtype: Link Rect: 249, 641, 260, 655 Annotation: Subtype: Link Rect: 466, 427, 518, 446 Annotation: Subtype: Link Rect: 168, 38, 256, 50 Annotation: Subtype: Link Rect: 404, 38, 519, 50 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 189, 696, 196, 705 ActionDest: 451 Annotation: Subtype: Link Rect: 174, 588, 181, 597 ActionDest: 451 Annotation: Subtype: Link Rect: 181, 588, 188, 597 ActionDest: 451 Annotation: Subtype: Link Rect: 184, 534, 190, 543 ActionDest: 451 Annotation: Subtype: Link Rect: 320, 507, 327, 516 ActionDest: 451 Annotation: Subtype: Link Rect: 321, 493, 328, 502 ActionDest: 451 Annotation: Subtype: Link Rect: 274, 439, 281, 448 ActionDest: 451 Annotation: Subtype: Link Rect: 126, 399, 133, 408 ActionDest: 451 Annotation: Subtype: Link Rect: 133, 399, 140, 408 ActionDest: 451 Annotation: Subtype: Link Rect: 286, 372, 293, 381 ActionDest: 451 Annotation: Subtype: Link Rect: 293, 372, 300, 381 ActionDest: 451 Annotation: Subtype: Link Rect: 301, 372, 308, 381 ActionDest: 451 Annotation: Subtype: Link Rect: 308, 372, 315, 381 ActionDest: 476 Annotation: Subtype: Link Rect: 218, 345, 225, 354 ActionDest: 451 Annotation: Subtype: Link Rect: 294, 331, 306, 340 ActionDest: 476 Annotation: Subtype: Link Rect: 113, 277, 120, 286 ActionDest: 451 Annotation: Subtype: Link Rect: 340, 250, 352, 259 ActionDest: 476 Annotation: Subtype: Link Rect: 375, 169, 387, 178 ActionDest: 476 Annotation: Subtype: Link Rect: 288, 115, 295, 124 ActionDest: 451 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 308, 661, 320, 671 ActionDest: 476 Annotation: Subtype: Link Rect: 305, 498, 312, 510 ActionDest: 165 Annotation: Subtype: Link Rect: 366, 498, 373, 510 ActionDest: 212 Annotation: Subtype: Link Rect: 117, 417, 124, 429 ActionDest: 165 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 505, 740, 512, 752 ActionDest: 165 Annotation: Subtype: Link Rect: 372, 648, 379, 657 ActionDest: 451 Annotation: Subtype: Link Rect: 245, 248, 252, 260 ActionDest: 212 Annotation: Subtype: Link Rect: 414, 221, 421, 233 ActionDest: 226 Annotation: Subtype: Link Rect: 505, 181, 512, 193 ActionDest: 226 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 508, 402, 515, 411 ActionDest: 451 Annotation: Subtype: Link Rect: 413, 388, 420, 397 ActionDest: 451 Annotation: Subtype: Link Rect: 187, 332, 194, 343 ActionDest: 226 Annotation: Subtype: Link Rect: 232, 332, 239, 343 ActionDest: 267 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 512, 740, 519, 752 ActionDest: 226 Annotation: Subtype: Link Rect: 125, 726, 132, 738 ActionDest: 267 Annotation: Subtype: Link Rect: 144, 659, 151, 671 ActionDest: 226 Annotation: Subtype: Link Rect: 106, 632, 113, 644 ActionDest: 267 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 320, 632, 327, 644 ActionDest: 334 Annotation: Subtype: Link Rect: 106, 591, 113, 603 ActionDest: 334 Annotation: Subtype: Link Rect: 371, 524, 378, 535 ActionDest: 334 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 511, 666, 518, 678 ActionDest: 379 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 356, 620, 368, 629 ActionDest: 476 Annotation: Subtype: Link Rect: 503, 444, 515, 454 ActionDest: 476 Annotation: Subtype: Link Rect: 340, 417, 352, 427 ActionDest: 476 Annotation: Subtype: Link Rect: 172, 336, 184, 345 ActionDest: 476 Annotation: Subtype: Link Rect: 412, 239, 419, 251 ActionDest: 379 Annotation: Subtype: Link Rect: 428, 161, 435, 170 ActionDest: 451 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 285, 633, 359, 645 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 272, 348, 284, 358 ActionDest: 476 Annotation: Subtype: Link Rect: 285, 348, 297, 358 ActionDest: 476 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 333, 608, 518, 619 Annotation: Subtype: Link Rect: 100, 360, 137, 370 Annotation: Subtype: Link Rect: 143, 360, 179, 370 Annotation: Subtype: Link Rect: 478, 334, 516, 344 Annotation: Subtype: Link Rect: 100, 322, 136, 332 Annotation: Subtype: Link Rect: 100, 296, 137, 306 Annotation: Subtype: Link Rect: 143, 296, 179, 306 Annotation: Subtype: Link Rect: 389, 257, 427, 267 Annotation: Subtype: Link Rect: 433, 257, 469, 267 Annotation: Subtype: Link Rect: 158, 205, 196, 215 Annotation: Subtype: Link Rect: 100, 154, 137, 164 Annotation: Subtype: Link Rect: 428, 114, 466, 125 Annotation: Subtype: Link Rect: 279, 75, 316, 86 Annotation: Subtype: Link Rect: 322, 75, 358, 86 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 154, 715, 192, 725 Annotation: Subtype: Link Rect: 198, 715, 234, 725 Annotation: Subtype: Link Rect: 213, 676, 251, 686 Annotation: Subtype: Link Rect: 257, 676, 293, 686 Annotation: Subtype: Link Rect: 309, 637, 346, 648 Annotation: Subtype: Link Rect: 168, 612, 205, 622 Annotation: Subtype: Link Rect: 246, 586, 284, 596 Annotation: Subtype: Link Rect: 100, 560, 137, 570 Annotation: Subtype: Link Rect: 143, 560, 179, 570 Annotation: Subtype: Link Rect: 279, 521, 316, 531 Annotation: Subtype: Link Rect: 323, 521, 359, 531 Annotation: Subtype: Link Rect: 406, 482, 443, 493 Annotation: Subtype: Link Rect: 449, 482, 485, 493 Annotation: Subtype: Link Rect: 213, 444, 251, 454 Annotation: Subtype: Link Rect: 257, 444, 293, 454 Annotation: Subtype: Link Rect: 218, 418, 256, 428 Annotation: Subtype: Link Rect: 262, 418, 298, 428 Annotation: Subtype: Link Rect: 414, 378, 451, 389 Annotation: Subtype: Link Rect: 457, 378, 493, 389 Annotation: Subtype: Link Rect: 76, 336, 166, 368 Annotation: Subtype: Link Rect: 234, 331, 407, 342 Checksum: dbd0820c Type: CRC32 Checksum: c544b4b088c65c2aaffd10050660cdd4 Type: MD5 Checksum: 97855ec9e1780a05a2137919752955fd03fc1158 Type: SHA-1