e519dd751ebe8533050bc6f29047e4d8 284406.pdf 8de0959eb06a1cf002edb4b9f2369003c0131857 284406.pdf b74a111450ea555261ff74a3db673b7db67d53144dee7f43322e5548c17c1e0f 284406.pdf Title: Altered Brain Metabolome Is Associated with Memory Impairment in the rTg4510 Mouse Model of Tauopathy Subject: Alzheimer’s disease (AD) is characterized, amongst other features, by the pathologic accumulation of abnormally phosphorylated tau filaments in neurons that lead to neurofibrillary tangles. However, the molecular mechanisms by which the abnormal processing of tau leads to neurodegeneration and cognitive impairment remain unknown. Metabolomic techniques can comprehensively assess disturbances in metabolic pathways that reflect changes downstream from genomic, transcriptomic and proteomic systems. In the present study, we undertook a targeted metabolomic approach to determine a total of 187 prenominated metabolites in brain cortex tissue from wild type and rTg4510 animals (a mice model of tauopathy), in order to establish the association of metabolic pathways with cognitive impairment. This targeted metabolomic approach revealed significant differences in metabolite concentrations of transgenic mice. Brain glutamine, serotonin and sphingomyelin C18:0 were found to be predictors of memory impairment. These findings provide informative data for future research on AD, since some of them agree with pathological alterations observed in diseased humans. Keywords: metabolomics; Alzheimer’s disease; tauopathy; rTg4510 mice; cognitive impairment Author: Mireia Tondo, Brandi Wasek, Joan Carles Escola-Gil, David de Gonzalo-Calvo, Clinton Harmon, Erland Arning and Teodoro Bottiglieri Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.17 CreationDate: Fri Feb 14 12:07:49 2020 CET ModDate: Fri Feb 14 12:07:49 2020 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3860063 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- TFQHVT+URWPalladioL-Ital Type 1 Custom yes yes no 88 0 CQZMWX+URWPalladioL-Bold Type 1 Custom yes yes no 89 0 WXZKKH+URWPalladioL-Roma Type 1 Custom yes yes no 90 0 BAMNYG+VnURWPalladioL Type 1 Custom yes yes no 91 0 FATHTC+Rpxr Type 1 Builtin yes yes no 92 0 BVROXL+EURM10 Type 1 Builtin yes yes no 93 0 TWGUDY+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 99 0 ZZPUEX+ArialMT Type 1C WinAnsi yes yes no 100 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 119 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 120 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 121 0 WBHGRA+Pxsy Type 1 Builtin yes yes no 161 0 YICMPF+Rpcxr Type 1 Builtin yes yes no 176 0 FHNPON+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 193 0 FHNPPO+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 194 0 FHOABA+PalatinoLinotype TrueType WinAnsi yes yes no 195 0 FHNPON+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 216 0 FHNPPO+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 217 0 FHOABA+PalatinoLinotype TrueType WinAnsi yes yes no 218 0 FHNPON+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 245 0 FHNPPO+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 246 0 FHOABA+PalatinoLinotype TrueType WinAnsi yes yes no 247 0 FHNPON+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 262 0 FHNPPO+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 263 0 FHOABA+PalatinoLinotype TrueType WinAnsi yes yes no 264 0 WBVKDJ+URWPalladioL-BoldItal Type 1 Custom yes yes no 280 0 QPJIPF+EURB10 Type 1 Builtin yes yes no 292 0 FHNPON+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 318 0 FHNPPN+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 319 0 FHNPPO+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 320 0 FHOAAP+PalatinoLinotype CID TrueType Identity-H yes yes yes 321 0 FHOABA+PalatinoLinotype TrueType WinAnsi yes yes no 322 0 FHOFGB+PalatinoLinotype,BoldItalic TrueType WinAnsi yes yes no 323 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-11-10 02:35:47 CET RepresentationInformation: 284406.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-11-09 10:48:09 CET Size: 3860063 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: 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㈮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぁのどねちぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰あづとちぶどはひちぬぜ〴ぜ〰ごづびぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰ぐひづばちひちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰あひちどのぜ〴ぜ〰ぅへぴひちっぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰きづぴちぢはぬはねどっびぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰いづぴづひねどのちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぐひはぴづどのぜ〴ぜ〰ぅへばひづびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Children: Item: Title: ぁのどねちぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰あづとちぶどはひちぬぜ〴ぜ〰ごづびぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰ぐひづばちひちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰あひちどのぜ〴ぜ〰ぅへぴひちっぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰きづぴちぢはぬはねどっびぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰いづぴづひねどのちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぐひはぴづどのぜ〴ぜ〰ぅへばひづびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: あづとちぶどはひちぬぜ〴ぜ〰ごづびぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰ぐひづばちひちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰あひちどのぜ〴ぜ〰ぅへぴひちっぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰きづぴちぢはぬはねどっびぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰いづぴづひねどのちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぐひはぴづどのぜ〴ぜ〰ぅへばひづびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: ぐひづばちひちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰あひちどのぜ〴ぜ〰ぅへぴひちっぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰きづぴちぢはぬはねどっびぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰いづぴづひねどのちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぐひはぴづどのぜ〴ぜ〰ぅへばひづびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: きづぴちぢはぬはねどっびぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰いづぴづひねどのちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぐひはぴづどのぜ〴ぜ〰ぅへばひづびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: いづぴづひねどのちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぐひはぴづどのぜ〴ぜ〰ぅへばひづびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ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⡳畢獥捴楯渮㌮ㄩ‾㸊⡜㌷㙜㌷㝜〰きづねはひべぜ〴ぜ〰ぉねばちどひねづのぴぜ〴ぜ〰どのぜ〴ぜ〰ぴとづぜ〴ぜ〰ごひちのびでづのどっぜ〴ぜ〰きどっづぜ〴ぜ〰きはつづぬぜ〴ぜ〰ひごで〴〵〱〰ぜ〴ぜ〰はてぜ〴ぜ〰ごちふはばちぴとべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ぁぬぴづひづつぜ〴ぜ〰あひちどのぜ〴ぜ〰きづぴちぢはぬはねづぜ〴ぜ〰ぐひはてどぬづぜ〴ぜ〰どのぜ〴ぜ〰ひごで〴〵〱〰ぜ〴ぜ〰きどっづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰あひちどのぜ〴ぜ〰きづぴちぢはぬどっぜ〴ぜ〰ぐひはてどぬづぜ〴ぜ〰ちのつぜ〴ぜ〰きづねはひべぜ〴ぜ〰ぉねばちどひねづのぴぜ〴ぜ〰ぁびびはっどちぴどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰あひちどのぜ〴ぜ〰ぇぬふぴちねどのづ〬ぜ〴ぜ〰こづひはぴはのどのぜ〴ぜ〰ちのつぜ〴ぜ〰こきぜ〴ぜ〰ぃ〱〸〺〰ぜ〴ぜ〰ぁひづぜ〴ぜ〰ぐひづつどっぴはひびぜ〴ぜ〰はてぜ〴ぜ〰きづねはひべぜ〴ぜ〰ぉねばちどひねづのぴぜ〴ぜ〰どのぜ〴ぜ〰ひごで〴〵〱〰ぜ〴ぜ〰きどっづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Children: Item: Title: きづねはひべぜ〴ぜ〰ぉねばちどひねづのぴぜ〴ぜ〰どのぜ〴ぜ〰ぴとづぜ〴ぜ〰ごひちのびでづのどっぜ〴ぜ〰きどっづぜ〴ぜ〰きはつづぬぜ〴ぜ〰ひごで〴〵〱〰ぜ〴ぜ〰はてぜ〴ぜ〰ごちふはばちぴとべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ぁぬぴづひづつぜ〴ぜ〰あひちどのぜ〴ぜ〰きづぴちぢはぬはねづぜ〴ぜ〰ぐひはてどぬづぜ〴ぜ〰どのぜ〴ぜ〰ひごで〴〵〱〰ぜ〴ぜ〰きどっづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰あひちどのぜ〴ぜ〰きづぴちぢはぬどっぜ〴ぜ〰ぐひはてどぬづぜ〴ぜ〰ちのつぜ〴ぜ〰きづねはひべぜ〴ぜ〰ぉねばちどひねづのぴぜ〴ぜ〰ぁびびはっどちぴどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰あひちどのぜ〴ぜ〰ぇぬふぴちねどのづ〬ぜ〴ぜ〰こづひはぴはのどのぜ〴ぜ〰ちのつぜ〴ぜ〰こきぜ〴ぜ〰ぃ〱〸〺〰ぜ〴ぜ〰ぁひづぜ〴ぜ〰ぐひづつどっぴはひびぜ〴ぜ〰はてぜ〴ぜ〰きづねはひべぜ〴ぜ〰ぉねばちどひねづのぴぜ〴ぜ〰どのぜ〴ぜ〰ひごで〴〵〱〰ぜ〴ぜ〰きどっづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ぁぬぴづひづつぜ〴ぜ〰あひちどのぜ〴ぜ〰きづぴちぢはぬはねづぜ〴ぜ〰ぐひはてどぬづぜ〴ぜ〰どのぜ〴ぜ〰ひごで〴〵〱〰ぜ〴ぜ〰きどっづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰あひちどのぜ〴ぜ〰きづぴちぢはぬどっぜ〴ぜ〰ぐひはてどぬづぜ〴ぜ〰ちのつぜ〴ぜ〰きづねはひべぜ〴ぜ〰ぉねばちどひねづのぴぜ〴ぜ〰ぁびびはっどちぴどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰あひちどのぜ〴ぜ〰ぇぬふぴちねどのづ〬ぜ〴ぜ〰こづひはぴはのどのぜ〴ぜ〰ちのつぜ〴ぜ〰こきぜ〴ぜ〰ぃ〱〸〺〰ぜ〴ぜ〰ぁひづぜ〴ぜ〰ぐひづつどっぴはひびぜ〴ぜ〰はてぜ〴ぜ〰きづねはひべぜ〴ぜ〰ぉねばちどひねづのぴぜ〴ぜ〰どのぜ〴ぜ〰ひごで〴〵〱〰ぜ〴ぜ〰きどっづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: あひちどのぜ〴ぜ〰きづぴちぢはぬどっぜ〴ぜ〰ぐひはてどぬづぜ〴ぜ〰ちのつぜ〴ぜ〰きづねはひべぜ〴ぜ〰ぉねばちどひねづのぴぜ〴ぜ〰ぁびびはっどちぴどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰あひちどのぜ〴ぜ〰ぇぬふぴちねどのづ〬ぜ〴ぜ〰こづひはぴはのどのぜ〴ぜ〰ちのつぜ〴ぜ〰こきぜ〴ぜ〰ぃ〱〸〺〰ぜ〴ぜ〰ぁひづぜ〴ぜ〰ぐひづつどっぴはひびぜ〴ぜ〰はてぜ〴ぜ〰きづねはひべぜ〴ぜ〰ぉねばちどひねづのぴぜ〴ぜ〰どのぜ〴ぜ〰ひごで〴〵〱〰ぜ〴ぜ〰きどっづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: あひちどのぜ〴ぜ〰ぇぬふぴちねどのづ〬ぜ〴ぜ〰こづひはぴはのどのぜ〴ぜ〰ちのつぜ〴ぜ〰こきぜ〴ぜ〰ぃ〱〸〺〰ぜ〴ぜ〰ぁひづぜ〴ぜ〰ぐひづつどっぴはひびぜ〴ぜ〰はてぜ〴ぜ〰きづねはひべぜ〴ぜ〰ぉねばちどひねづのぴぜ〴ぜ〰どのぜ〴ぜ〰ひごで〴〵〱〰ぜ〴ぜ〰きどっづぜ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: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: YICMPF+Rpcxr FontSubset: true FirstChar: 151 LastChar: 174 FontDescriptor: FontName: YICMPF+Rpcxr Flags: Symbolic FontBBox: -212, -286, 1344, 973 FontFile: true Font: BaseFont: WBHGRA+Pxsy FontSubset: true FirstChar: 0 LastChar: 14 FontDescriptor: FontName: WBHGRA+Pxsy Flags: Symbolic FontBBox: -21, -994, 1292, 912 FontFile: true Font: BaseFont: QPJIPF+EURB10 FontSubset: true FirstChar: 12 LastChar: 26 FontDescriptor: FontName: QPJIPF+EURB10 Flags: Symbolic FontBBox: -30, -247, 1178, 723 FontFile: true Font: BaseFont: TFQHVT+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 122 FontDescriptor: FontName: TFQHVT+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: WBVKDJ+URWPalladioL-BoldItal FontSubset: true FirstChar: 112 LastChar: 112 FontDescriptor: FontName: WBVKDJ+URWPalladioL-BoldItal Flags: Symbolic FontBBox: -170, -300, 1073, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: CQZMWX+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: CQZMWX+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: WXZKKH+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 151 FontDescriptor: FontName: WXZKKH+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: BAMNYG+VnURWPalladioL FontSubset: true FirstChar: 178 LastChar: 226 FontDescriptor: FontName: BAMNYG+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: FATHTC+Rpxr FontSubset: true FirstChar: 11 LastChar: 61 FontDescriptor: FontName: FATHTC+Rpxr Flags: Symbolic FontBBox: -40, -283, 904, 728 FontFile: true Font: BaseFont: BVROXL+EURM10 FontSubset: true FirstChar: 12 LastChar: 26 FontDescriptor: FontName: BVROXL+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 75, 757, 207, 793 Annotation: Subtype: Link Rect: 474, 757, 519, 793 Annotation: Subtype: Link Rect: 150, 640, 161, 654 Annotation: Subtype: Link Rect: 347, 640, 358, 654 Annotation: Subtype: Link Rect: 481, 640, 492, 654 Annotation: Subtype: Link Rect: 356, 626, 367, 640 Annotation: Subtype: Link Rect: 466, 475, 518, 494 Annotation: Subtype: Link Rect: 411, 194, 418, 203 ActionDest: 441 Annotation: Subtype: Link Rect: 271, 167, 278, 176 ActionDest: 441 Annotation: Subtype: Link Rect: 416, 113, 423, 122 ActionDest: 441 Annotation: Subtype: Link Rect: 426, 113, 433, 122 ActionDest: 441 Annotation: Subtype: Link Rect: 398, 72, 405, 81 ActionDest: 441 Annotation: Subtype: Link Rect: 172, 38, 260, 50 Annotation: Subtype: Link Rect: 390, 38, 519, 50 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 152, 621, 159, 630 ActionDest: 441 Annotation: Subtype: Link Rect: 162, 621, 174, 630 ActionDest: 474 Annotation: Subtype: Link Rect: 442, 526, 453, 535 ActionDest: 474 Annotation: Subtype: Link Rect: 456, 526, 468, 535 ActionDest: 474 Annotation: Subtype: Link Rect: 491, 499, 503, 508 ActionDest: 474 Annotation: Subtype: Link Rect: 503, 499, 515, 508 ActionDest: 474 Annotation: Subtype: Link Rect: 122, 432, 134, 441 ActionDest: 474 Annotation: Subtype: Link Rect: 124, 285, 136, 294 ActionDest: 474 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 303, 223, 315, 232 ActionDest: 474 Annotation: Subtype: Link Rect: 316, 222, 328, 232 ActionDest: 474 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 148, 360, 160, 369 ActionDest: 474 Annotation: Subtype: Link Rect: 354, 330, 438, 342 Annotation: Subtype: Link Rect: 285, 197, 292, 209 ActionDest: 183 Annotation: Subtype: Link Rect: 380, 170, 387, 182 ActionDest: 183 Annotation: Subtype: Link Rect: 445, 156, 451, 168 ActionDest: 183 Annotation: Subtype: Link Rect: 209, 102, 216, 114 ActionDest: 237 Page: Sequence: 5 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 203, 478, 210, 490 ActionDest: 237 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 104, 713, 111, 725 ActionDest: 276 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 164, 508, 171, 520 ActionDest: 289 Page: Sequence: 9 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 213, 639, 220, 651 ActionDest: 309 Annotation: Subtype: Link Rect: 190, 444, 197, 456 ActionDest: 309 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 322, 715, 329, 725 ActionDest: 441 Annotation: Subtype: Link Rect: 330, 715, 337, 725 ActionDest: 441 Annotation: Subtype: Link Rect: 337, 715, 349, 725 ActionDest: 474 Annotation: Subtype: Link Rect: 350, 715, 362, 725 ActionDest: 474 Annotation: Subtype: Link Rect: 445, 715, 452, 725 ActionDest: 441 Annotation: Subtype: Link Rect: 369, 648, 381, 657 ActionDest: 474 Annotation: Subtype: Link Rect: 381, 648, 393, 657 ActionDest: 474 Annotation: Subtype: Link Rect: 214, 553, 226, 562 ActionDest: 474 Annotation: Subtype: Link Rect: 226, 553, 238, 562 ActionDest: 474 Annotation: Subtype: Link Rect: 239, 553, 251, 562 ActionDest: 474 Annotation: Subtype: Link Rect: 253, 553, 265, 562 ActionDest: 474 Annotation: Subtype: Link Rect: 489, 540, 501, 549 ActionDest: 474 Annotation: Subtype: Link Rect: 503, 472, 515, 481 ActionDest: 474 Annotation: Subtype: Link Rect: 483, 310, 495, 319 ActionDest: 474 Annotation: Subtype: Link Rect: 213, 297, 225, 306 ActionDest: 474 Annotation: Subtype: Link Rect: 228, 297, 240, 306 ActionDest: 505 Annotation: Subtype: Link Rect: 238, 283, 250, 292 ActionDest: 505 Annotation: Subtype: Link Rect: 314, 283, 326, 292 ActionDest: 505 Annotation: Subtype: Link Rect: 508, 270, 515, 279 ActionDest: 441 Annotation: Subtype: Link Rect: 216, 229, 227, 238 ActionDest: 505 Annotation: Subtype: Link Rect: 450, 148, 457, 157 ActionDest: 441 Annotation: Subtype: Link Rect: 458, 148, 464, 157 ActionDest: 441 Annotation: Subtype: Link Rect: 465, 148, 472, 157 ActionDest: 441 Annotation: Subtype: Link Rect: 472, 148, 484, 157 ActionDest: 474 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 151, 648, 163, 657 ActionDest: 505 Annotation: Subtype: Link Rect: 287, 634, 299, 644 ActionDest: 505 Annotation: Subtype: Link Rect: 161, 580, 173, 590 ActionDest: 505 Annotation: Subtype: Link Rect: 173, 580, 185, 590 ActionDest: 505 Annotation: Subtype: Link Rect: 279, 567, 286, 576 ActionDest: 441 Annotation: Subtype: Link Rect: 128, 526, 140, 535 ActionDest: 505 Annotation: Subtype: Link Rect: 348, 486, 360, 495 ActionDest: 505 Annotation: Subtype: Link Rect: 363, 486, 375, 495 ActionDest: 505 Annotation: Subtype: Link Rect: 327, 459, 338, 468 ActionDest: 505 Annotation: Subtype: Link Rect: 339, 459, 351, 468 ActionDest: 505 Annotation: Subtype: Link Rect: 109, 445, 121, 454 ActionDest: 505 Annotation: Subtype: Link Rect: 121, 445, 133, 454 ActionDest: 505 Annotation: Subtype: Link Rect: 226, 445, 238, 454 ActionDest: 505 Annotation: Subtype: Link Rect: 241, 445, 253, 454 ActionDest: 505 Annotation: Subtype: Link Rect: 110, 405, 122, 414 ActionDest: 529 Annotation: Subtype: Link Rect: 163, 351, 175, 360 ActionDest: 529 Annotation: Subtype: Link Rect: 279, 283, 291, 292 ActionDest: 529 Annotation: Subtype: Link Rect: 104, 256, 116, 265 ActionDest: 474 Annotation: Subtype: Link Rect: 116, 256, 128, 265 ActionDest: 529 Annotation: Subtype: Link Rect: 131, 256, 143, 265 ActionDest: 529 Annotation: Subtype: Link Rect: 120, 242, 132, 252 ActionDest: 529 Annotation: Subtype: Link Rect: 132, 242, 144, 252 ActionDest: 529 Annotation: Subtype: Link Rect: 310, 229, 322, 238 ActionDest: 529 Annotation: Subtype: Link Rect: 323, 229, 335, 238 ActionDest: 529 Annotation: Subtype: Link Rect: 261, 202, 273, 211 ActionDest: 474 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 478, 354, 516, 364 Annotation: Subtype: Link Rect: 100, 341, 136, 351 Annotation: Subtype: Link Rect: 455, 327, 493, 338 Annotation: Subtype: Link Rect: 232, 302, 269, 312 Annotation: Subtype: Link Rect: 275, 302, 311, 312 Annotation: Subtype: Link Rect: 382, 275, 420, 286 Annotation: Subtype: Link Rect: 480, 237, 516, 248 Annotation: Subtype: Link Rect: 265, 199, 302, 209 Annotation: Subtype: Link Rect: 384, 173, 421, 183 Annotation: Subtype: Link Rect: 213, 134, 250, 144 Annotation: Subtype: Link Rect: 373, 95, 411, 106 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 150, 715, 187, 725 Annotation: Subtype: Link Rect: 428, 676, 466, 686 Annotation: Subtype: Link Rect: 472, 676, 508, 686 Annotation: Subtype: Link Rect: 478, 637, 516, 648 Annotation: Subtype: Link Rect: 100, 625, 136, 635 Annotation: Subtype: Link Rect: 244, 586, 282, 596 Annotation: Subtype: Link Rect: 288, 586, 324, 596 Annotation: Subtype: Link Rect: 186, 547, 223, 557 Annotation: Subtype: Link Rect: 229, 547, 265, 557 Annotation: Subtype: Link Rect: 286, 508, 323, 519 Annotation: Subtype: Link Rect: 100, 483, 137, 493 Annotation: Subtype: Link Rect: 479, 456, 516, 467 Annotation: Subtype: Link Rect: 329, 418, 367, 428 Annotation: Subtype: Link Rect: 479, 378, 516, 389 Annotation: Subtype: Link Rect: 127, 341, 165, 351 Annotation: Subtype: Link Rect: 405, 314, 442, 325 Annotation: Subtype: Link Rect: 465, 275, 501, 286 Annotation: Subtype: Link Rect: 235, 224, 273, 234 Annotation: Subtype: Link Rect: 279, 224, 315, 234 Annotation: Subtype: Link Rect: 271, 185, 309, 196 Annotation: Subtype: Link Rect: 315, 185, 351, 196 Annotation: Subtype: Link Rect: 274, 159, 311, 170 Annotation: Subtype: Link Rect: 317, 159, 353, 170 Annotation: Subtype: Link Rect: 385, 120, 422, 131 Annotation: Subtype: Link Rect: 384, 94, 421, 105 Annotation: Subtype: Link Rect: 408, 69, 446, 80 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 461, 727, 499, 738 Annotation: Subtype: Link Rect: 383, 688, 420, 699 Annotation: Subtype: Link Rect: 438, 663, 475, 673 Annotation: Subtype: Link Rect: 481, 663, 516, 673 Annotation: Subtype: Link Rect: 100, 625, 137, 635 Annotation: Subtype: Link Rect: 145, 586, 183, 596 Annotation: Subtype: Link Rect: 189, 586, 225, 596 Annotation: Subtype: Link Rect: 418, 546, 455, 557 Annotation: Subtype: Link Rect: 277, 508, 315, 519 Annotation: Subtype: Link Rect: 367, 469, 405, 480 Annotation: Subtype: Link Rect: 100, 444, 137, 454 Annotation: Subtype: Link Rect: 448, 418, 486, 428 Annotation: Subtype: Link Rect: 419, 391, 456, 402 Annotation: Subtype: Link Rect: 361, 378, 399, 389 Annotation: Subtype: Link Rect: 310, 340, 347, 351 Annotation: Subtype: Link Rect: 353, 340, 389, 351 Annotation: Subtype: Link Rect: 435, 301, 472, 312 Annotation: Subtype: Link Rect: 478, 301, 514, 312 Annotation: Subtype: Link Rect: 190, 276, 228, 286 Annotation: Subtype: Link Rect: 234, 276, 270, 286 Annotation: Subtype: Link Rect: 303, 237, 341, 247 Annotation: Subtype: Link Rect: 362, 211, 398, 222 Annotation: Subtype: Link Rect: 100, 173, 137, 183 Annotation: Subtype: Link Rect: 216, 134, 254, 144 Annotation: Subtype: Link Rect: 100, 95, 137, 105 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 446, 714, 483, 725 Annotation: Subtype: Link Rect: 213, 675, 251, 686 Annotation: Subtype: Link Rect: 400, 638, 438, 648 Annotation: Subtype: Link Rect: 444, 638, 480, 648 Annotation: Subtype: Link Rect: 284, 598, 322, 609 Annotation: Subtype: Link Rect: 328, 598, 364, 609 Annotation: Subtype: Link Rect: 136, 573, 174, 583 Annotation: Subtype: Link Rect: 180, 573, 216, 583 Annotation: Subtype: Link Rect: 392, 546, 429, 557 Annotation: Subtype: Link Rect: 213, 508, 250, 519 Annotation: Subtype: Link Rect: 257, 508, 293, 519 Annotation: Subtype: Link Rect: 231, 470, 269, 480 Annotation: Subtype: Link Rect: 382, 431, 419, 441 Annotation: Subtype: Link Rect: 167, 392, 205, 402 Annotation: Subtype: Link Rect: 367, 354, 404, 364 Annotation: Subtype: Link Rect: 76, 311, 166, 343 Annotation: Subtype: Link Rect: 234, 306, 407, 317 Checksum: d8437967 Type: CRC32 Checksum: e519dd751ebe8533050bc6f29047e4d8 Type: MD5 Checksum: 8de0959eb06a1cf002edb4b9f2369003c0131857 Type: SHA-1