Na leucemia mielóide crônica (LMC) a proteína Bcr-Abl possui atividade tirosina-quinase constitutivamente ativada, induzindo a mieloproliferação e a resistência das células à apoptose. A maioria dos pacientes na fase crônica da LMC tratados com inibidores de tirosina-quinase (TKIs), como o mesilato de imatinibe, apresenta remissão citogenética completa da doença, mas uma parcela desses pacientes tem se mostrado resistente à terapia. A fisiopatologia da LMC e os mecanismos celulares e moleculares envolvidos na resistência à terapia com TKIs são diversos e precisam ser melhor estudados. Nesse contexto, o objetivo do presente estudo foi quantificar os níveis de expressão do gene DIDO, incluindo suas diferentes isoformas (DIDO 1, 2 e 3) e promotores (DIDO PP e PD) em controles e em pacientes com LMC nas diferentes fases da doença, tratados ou não com TKIs, bem como em linhagens celulares BCR-ABL1+ sensíveis (S) e resistentes (R) ao mesilato de imatinibe (MI). A literatura relata que DIDO 1 participa do processo de apoptose e que alterações na expressão de DIDO 2 e DIDO 3 podem estar associadas com o desenvolvimento de neoplasias mielóides. Dessa forma, foram estudados 60 pacientes com LMC e 57 controles, assim como as linhagens celulares HL-60, HL-60.Bcr-Abl+, LAMA 84 S, LAMA 84 R, KCL 22 S e KCL 22 R. Foram separadas as células mononucleares de sangue periférico dos pacientes e controles, com posterior extração de RNA e síntese de cDNA, que foi então empregado nas reações de PCR em tempo real (qPCR) para quantificação das expressões gênicas de DIDO 1, 2, 3, PP, PD e ORF. As linhagens celulares foram tratadas por 4h com TKIs e então a expressão das diferentes isoformas de DIDO foi também quantificada por qPCR. A avaliação da expressão proteica de Bcr-Abl, c-Abl e proteínas fosforiladas nas linhagens foi realizada por Western-blotting. A expressão de DIDO 1 e 2 foi maior nos pacientes nas fases avançadas da LMC e nos pacientes na fase crônica da doença tratados com TKIs (mesilato de imatinibe ou dasatinibe) do que nos controles. Os pacientes na fase crônica da LMC tratados com MI expressaram mais DIDO 1 e 3 do que os pacientes na fase crônica sem tratamento. Houve uma correlação positiva entre expressão de BCR-ABL1 e de DIDO 2 e entre índice de Sokal dos pacientes e expressão de DIDO 2. Na linhagem HL60.Bcr-Abl+, a expressão de proteínas fosforiladas reduziu após tratamento de 4h com TKIs, mas não houve alteração na expressão gênica de DIDO. Nas linhagens celulares S e R, houve aumento da expressão de DIDO 1 após o tratamento de 4h com MI. Conclui-se, portanto, que as diferentes isoformas de DIDO parecem exercer funções distintas na leucemia mielóide crônica; que o tratamento de pacientes e linhagens BCR-ABL1 positivas com inibidores de tirosina-quinase aumenta expressão de DIDO 1; e que a expressão de DIDO 2 correlaciona-se positivamente à expressão de BCR-ABL1 e ao índice de Sokal dos pacientes. / In chronic myeloid leukemia (CML) the Bcr-Abl protein has constitutively activated tyrosine kinase activity, that induces to myeloproliferation and apoptosis resistance of the cells. Most patients in chronic phase of CML treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate have a complete cytogenetic remission, but a portion of these patients have been shown to be resistant to therapy. The pathophysiology of CML and the cellular and molecular mechanisms involved in resistance to TKIs therapy are diverse and require further study. In this sense, the aim of this study was to quantify the expression levels of the DIDO gene, including its isoforms (DIDO 1, 2 and 3) and promoters (DIDO PP and PD) in controls and in patients with CML in different phases of the disease treated or not treated with TKIs, as well as in cell lines BCR-ABL1+ sensitive (S) and resistant (R) to imatinib mesylate (IM). The literature reports that DIDO 1 is involved in apoptosis process and that alterations of DIDO 2 and DIDO 3 expression may be associated with the development of myeloid neoplasms. Thus, 60 CML patients, 57 control individuals and the cell lines HL-60, HL-60.Bcr-Abl+, LAMA 84 S, LAMA 84 R, KCL 22 S and KCL 22 R were studied. Peripheral blood mononuclear cells of patients and controls were isolated and RNA extraction and cDNA synthesis were performed. The cDNA samples were used in Real-Time PCR reactions (qPCR) to quantify the DIDO 1, 2, 3, PP, PD and ORF gene expression. The cell lines were treated during 4h with TKIs and then the expression of DIDO different isoforms was also quantified by qPCR. The assessment of protein expression of Bcr-Abl, c-Abl and phosphorylated proteins in this cell lines was performed by Western blotting. The DIDO 1 and 2 expression was higher in advanced phases patients and in chronic phase patients CML treated with TKIs (imatinib mesylate and dasatinib) than in controls. Chronic phase CML Patients treated with IM expressed more DIDO 1 and 3 than chronic phase untreated patients. There was a positive correlation between BCR-ABL1 expression and DIDO 2 expression and between Sokal score prognostic and DIDO 2 expression. In HL60.Bcr-Abl+ cells the expression of phosphorylated proteins was lower after treatment during 4h with TKIs, but there was no change in DIDO gene expression. There were an increase of DIDO 1 expression in all S and R cell lines after treatment during 4h with IM. Therefore we conclude that the DIDO different isoforms may have different functions in chronic myeloid leukemia; the treatment of patients and BCR-ABL1+ cell lines with TKIs increases DIDO 1 expression; and that the DIDO 2 expression is positively correlated to the BCR-ABL1 expression and Sokal score prognostic of CML patients.

Durante a divisão celular as Aurora-quinases (AURKA e AURKB) participam da formação e controle das fibras do fuso mitótico enquanto as isoformas proteicas (DIDO1, DIDO2 e DIDO3), originadas do splicing alternativo do gene DIDO, auxiliam na junção dos microtúbulos aos cinetócoros. Portanto, ambas são relevantes na regulação do ciclo celular. Interessantemente, a superexpressão (ou o ganho de função) das AURKs ou a baixa expressão (ou perda de função) das isoformas de DIDO estão ambos associados com amplificação dos centrossomos e à instabilidade cromossômica (CIN), com consequente aneuploidia. Dentre as doenças hematológicas com registros de CIN, a leucemia linfoide crônica (LLC) pode apresentar amplificação dos centrossomos e alteração nos níveis de expressão das AURKs acarretando aneuplodias. Apesar disso, não existem estudos avaliando a potencial associação destes genes com CIN na LLC. Avaliando seus níveis de expressão gênica em amostras de LLC de pacientes com ou sem aberrações cromossômicas, mostramos que o aumento dos níveis de AURKA e AURKB e, inversamente, a redução dos níveis das variantes de DIDO, são significativamente associados com ganhos cromossômicos e com aumento da contagem de glóbulos brancos (WBC). Claramente, amostras de LLC sem qualquer anormalidade citogenética apresentam níveis de expressão semelhantes às amostras que contêm aberrações não-numéricas. O achado de que níveis de expressão de AURKs e variantes de DIDO são completamente opostos, mostrando um padrão discreto de inter-relação, levou-nos a investigar o potencial mecanismo regulatório por trás disso. Tendo em vista que outros, anteriormente, mostraram que o cluster oncogênico miR-17~92 é significativamente hiper-regulado em células de pacientes com LLC purificadas expressando genes IGHV não mutados (em comparação com células mutadas de pacientes) e, que o miR-17 é expresso em níveis significativamente mais elevados em células IGHV não mutadas ou ZAP-70 positivas (mau prognóstico geralmente associada à CIN), resolvemos investigar o potencial de regulação negativa dos microRNAs deste cluster sobre as variantes de DIDO. Além disso, com base no mecanismo regulatório já descrito pelo qual a superexpressão de AURKA induz a transcrição do cluster miR-17~92, mediada por E2F1 (com uma correlação entre as expressões de ambas as proteínas em diferentes tipos de câncer), decidimos investigar este eixo regulatório em LLC. Notavelmente, todas as variantes de DIDO apresentam-se preditas como fortes alvos de vários microRNAs deste cluster oncogênico. Mostramos, então, que amostras de LLC com baixa expressão de DIDO, além dos já mencionados níveis elevados de AURK, exibiram níveis significativamente mais elevados do fator de transcrição E2F1 e de seu alvo transcricional, o transcrito primário do miR-17~92 (MIR17HG). Além disso, por meio do uso da linhagem de celular NTERA-2, como modelo experimental, mostramos que o siRNA nocaute para AURKA (nos níveis transcricional e proteico, como confirmado por qPCR e western blot) é acompanhada por uma significativa redução de E2F1 e também de MIR17HG. Ainda, a transfecção de células NTERA-2 com sintéticos microRNAs miméticos do cluster miR-17~92 (ou seja, 19a-miR, miR-20a e miR-92a) resultou em uma clara e significativa redução dos níveis de transcrição de todas as variantes de DIDO. Por fim, a inibição do siRNA especifico para a variante DIDO3 (mas não às outras variantes) levou a uma redução significativa dos níveis de transcrição de todas as variantes de DIDO, indicando um mecanismo adicional contribuindo para a downregulação dos transcritos de DIDO. Ao todo, nossos resultados demonstram a existência de um potencial mecanismo regulatório interconectado entre AURK e DIDO, associado à CIN e maior contagem de WBC na LLC. Mais importante, os níveis de expressão elevada de AURKs e os baixos níveis associados das variantes de DIDO são especificamente relacionados com anormalidades citogenéticas apresentando ganhos cromossomais, com destaque para o mecanismo celular específico, subjacente à CIN, observado neste grupo distinto LLC. Dado o papel central da CIN na gênese e progressão do câncer, esses achados provavelmente terão um impacto importante no prognóstico ou tratamento da LLC. / During cell cycle division Aurora kinases (AURKA and AURKB) participate in the formation and control of mitotic spindle fibers, while, protein isoforms (DIDO1, DIDO2 and DIDO3), derived by alternative splicing of the DIDO gene, assist at the junction of microtubules to kinetochores. Thus, both are relevant to cell cycle maintenance. Interestingly, overexpression (or gain of function) of AURKs or low expression (or loss of function of DIDO) are both associated with centrosomal amplification and chromosomal instability (CIN), leading to aneuploidy. Among hematological diseases with CIN records, chronic lymphocytic leukemia (CLL) can display centrosome amplification and changes in AURKs expression levels leading to aneuploidy. Despite this, there are no studies evaluating the potential association of these genes with CIN in CLL. By evaluating their gene expression levels in CLL samples from patients with or without chromosomal aberrations, we show that increased levels of AURKA and AURKB and, conversely, reduced levels of DIDO variants, are both significantly associated with chromosomal gains and with increased white blood cell (WBC) counts. Clearly, CLL samples without any cytogenetic abnormality had expression levels similar to samples mostly harboring non-numerical aberrations. The finding that the expression levels of AURKs and DIDO variants are completely opposed, showing a discrete inter-related pattern, led us to investigate the potential regulatory mechanism behind this. Given that other have previously shown that the oncogenic miR-17~92 cluster is significantly upregulated in purified CLL patient cells expressing unmutated IGHV genes (as compared to mutated patient cells), and that miR-17 is expressed at significantly higher levels in unmutated or ZAP-70 high cases (bad prognostic cases generally associated with chromosomal instability), we investigated the potential negative regulation of DIDO variants by microRNAs from this cluster. In addition, based on the already described regulatory mechanism by which AURKA overexpression induces the E2F1-mediated transcription upregulation of the miR-17~92 cluster (with an observed expression correlation of both proteins in cancer specimens); we decided to investigate this regulatory axis in CLL. Notably, we found that all DIDO variants are predicted to be heavily targeted by several miRs of this oncogenic cluster. We show that CLL samples with low DIDO expression, in addition to the already mentioned AURK high levels, displayed significant higher levels of the transcription factor E2F1 and of its transcriptional target, the miR-17~92 primary transcript (MIR17HG). Moreover, by using the NTERA-2 cell line as a model, we show that siRNA knockdown of AURKA (at the transcript and protein level, as confirmed by qPCR and western blot) is accompanied by a striking significant reduction of E2F1 and also of MIR17HG. Furthermore, transfection of NTERA-2 cells with synthetic mimics of the miR-17~92 cluster (namely, miR-19a, miR-20a and miR-92a) results in a clear and significant reduction in the transcript levels of all DIDO variants. Finally, specific siRNA inhibition of the DIDO3 variant (but not the others) led to a significant reduction in the transcript levels of all DIDO variants, indicating an additional mechanism contributing to the downregulation of DIDO transcripts. Altogether, our results demonstrate the existence of a potential interconnected regulatory mechanism between AURK and DIDO, associated with CIN and higher WBC counts in CLL. More importantly, the high expression levels of AURKs and the associated low levels of DIDO variants are specifically associated with cytogenetic abnormalities presenting chromosomal gains, highlighting the specific cellular mechanism underlying the CIN observed in this distinct CLL group. Given the central role of CIN in cancer genesis and progression, these findings will likely have an important impact on prognosis or treatment of CLL.

Thesis (MA (Afrikaans and Dutch))--University of Stellenbosch, 2010. / AFRIKAANSE OPSOMMING: E.K.M. Dido publiseer in 1996 haar eerste roman, Die storie van Monica Peters, en word so een van die eerste bruin vrouens wat ‟n bydra tot die Afrikaanse letterkunde lewer. In Dido se romans word daar altyd ‟n vrou as hooffiguur gestel, en dit is van belang om na die konstruksie van die identiteite van die vroulike hooffigure ondersoek in te stel. Die romans lig invloede op, en aspekte van, identiteit uit en demonstreer hoe kwessies soos identiteitsmerkers ‟n rol in die konstruksie van identiteit speel. Die konstruksie van die vroulike figure se identiteite wys op die veranderende aard van identiteit, en die stemme van die gemarginaliseerdes van die verlede word in twee van hierdie romans deur hierdie figure gehoor. Dido self skryf vanuit die posisie van die voorheen gemarginaliseerde. Deur die konstruksie van die hooffigure vind die gemarginaliseerdes van die verlede ‟n geleentheid om hul eie verhale te vertel, en so verbreek Dido die stiltes wat in die verlede geskep is. Die postkoloniale aard van Dido se romans speel ‟n ondermynende rol binne ‟n letterkunde wat steeds verteenwoordigend is van die magstrukture van die verlede. Die konsep van hibriditeit word uitgelig as een wat positief eerder as negatief is. So word daar byvoorbeeld ‟n nuwe perspektief op wit mense gegee, soos gesien deur die oë van die historiese ‟Ander‟. Die posisie van swart skrywers in die huidige Afrikaanse letterkunde is een wat ondersoek moet word en uiteindelik moet hierdie posisionering van swart skrywers herevalueer word. Daar is ‟n vraag na ‟n literêre geskiedenis wat verteenwoordigend is van al die stemme wat in die Afrikaanse geskiedenis teenwoordig is. Uiteindelik is dit nodig om te bepaal waar presies Dido in hierdie literêre sisteem geposisioneer is, en of haar stem as swart vroueskrywer werklik gehoor word. / ENGLISH SUMMARY: E.K.M. Dido published her first novel, Die storie van Monica Peters (The story of Monica Peters) in 1996 and so doing became one of the first brown women to make a contribution to Afrikaans literature. The central character in Dido‟s novel is always a woman and this study will focus on the methods of construction of the identities of the female characters. The novels highlight the influences of external factors such as markers of identity on the construction of identity. The changeable nature of identity is demonstrated through the construction of the identities of these female characters. The voices of the marginalised figures from the past are heard through these characters in two of Dido‟s novels. Dido writes from the position of a previously marginalised woman. She breaks the silences of the past by the construction of the female characters‟ identities in such a way that they are able to tell their stories. The postcolonial nature of her work acts to undermine a literature which still reflects the power relations of the past. Dido‟s novels look at the concept of hybridity and see it as a positive, rather than negative, state of being. The white characters in the novels undergo a process of “Othering” which gives a new perspective on race relations from colonial times. There is a need to investigate and rethink the position of black writers within the Afrikaans literary system. Critics have expressed a desire for a literary history which is representative of all voices in Afrikaans. Dido‟s position in the literary system has to be investigated and it needs to be determined whether her voice as a black Afrikaans woman writer is being heard.

Approved for public release, distribution is unlimited / A Halo orbit about a libration point of a restricted three-body system provides additional opportunities for surveillance, communication, and exploratory missions in lieu of the classical spacecraft orbit. Historically libration point missions have focused on Halo orbits and trajectories about the Sun-Earth System. This thesis will focus on libration point orbit solutions in the Earth-Moon system using the restricted three body equations of motion with three low-thrust control functions. These classical dynamics are used to design and optimize orbital trajectories about stable and unstable libration points of the Earth-Moon system using DIDO, a dynamic optimization software. The solutions for the optimized performance are based on a quadratic cost function. Specific constraints and bounds were placed on the potential solution set in order to ensure correct target trajectories. This approach revealed locally optimal solutions for orbits about a stable and unstable libration point. / Lieutenant, United States Navy

Approved for public release, distribution is unlimited / problem, with engine thrust as the only possible perturbation. The optimal control problems are solved using the general purpose dynamic optimization software, DIDO. The dynamical model together with the fuel optimal control problem is validated by simulating several well known orbit transfers. By replicating the single satellite model, this thesis shows that a multi-satellite model which optimizes all vehicles concurrently can be easily built. The specific scenario under study involves the injection of multiple satellites from a common launch vehicle; however, the methods and model are applicable to spacecraft formation problems as well. / Major, United States Air Force

Cette thèse présente une étude historique des traductions et imitations britanniques du livre IV de l’Énéide de Virgile aux XVIe et XVIIe siècles, depuis l’Eneados de Gavin Douglas [1513] jusqu’au Dryden’s Virgil de 1697. À travers une étude comparative des traductions successives de l’épisode, on y dégage les transformations de la notion d’ imitation comme modèle de la traduction littéraire au cours de la période. À une conception de la traduction dominée au XVIe siècle par le modèle rhétorique antique de l’imitatio, et par le souci de développer l’épopée vernaculaire sur le modèle virgilien, succède dans la première moitié du XVIIe siècle une définition spécifique de l’imitation comme modalité de la traduction libre. Dans un contexte de crise politique et de compétition entre les différentes versions de l’épisode, les “imitations” deviennent le lieu de prises de position idéologiques et esthétiques, dans des interprétations contrastées du modèle épique virgilien. Les réécritures du livre IV de l’Énéide qui marquent le second XVIIe siècle témoignent d’un certain éclatement de la notion d’ imitation, qui désigne à la fois les réécritures satiriques et parodiques de l’épisode, et l’entreprise de fondation culturelle et esthétique de l’âge “augustéen”. Au modèle herméneutique hérité des traducteurs humanistes se substitue alors avec Dryden une conception esthétique de la traduction littéraire comme mimesis artistique. L’étude associe l’analyse des stratégies formelles et interprétatives propres à chaque traduction à une réflexion sur la réception britannique de l’Énéide et offre des éléments de méthode pour l’analyse historique des traductions sur la longue durée. / This thesis consists in a historical study of the translations and imitations of Virgil’s Aeneid IV in XVIth- and XVIIth century Britain. Through a comparative analysis of the many translations of the episode between Douglas’s Eneados [1513] and Dryden’s 1697 Virgil, this study highlights the main transformations of the notion of imitation as a central concept in Early Modern translation theory and practice. First dominated by the Classical model of rhetorical imitatio and by the Humanist fashioning of the vernacular epic after Virgil’s Aeneid, the concept of imitation is reinterpreted in the first half of the XVIIth century as an form of free translation. In a context of political crisis, of competing translations of the episode, and of clashing interpretations of the virgilian epic model, the practice of imitation reads as an assertion of the translators’ aesthetic and political agendas. In the second half of the XVIIth century, the rewritings of Aeneid IV reveal a paradoxical reappropriation of the notion of imitation, which is used at once to define the satirical parodies of Virgil’s epic, and to establish the political and cultural foundations of the “Augustan age”. With Dryden’s Virgil, the hermeneutic model of translation inherited from the Humanists is replaced by a specifically aesthetic theory of literary translation modelled on the neoclassical discourse on mimesis. The aim of this study is to combine a detailed analysis of the literary and interpretive strategies at work in each translation with a broader discussion of the reception of Virgil’s Aeneid, and to develop a method for the historical analysis of the translations of a given text over a long period of time.

Thesis (Ph. D.)--University of Chicago. / Includes bibliographical references.

MARTINS, C. H. S. Desigualdade isoperimétrica: aspectos históricos e uma abordagem para o ensino médio. 2016. 30f. Dissertação (Mestrado Profissional em Matemática) - Departamento de Matemática, Universidade Federal do Ceará, Fortaleza, 2016. / Submitted by Jessyca Silva (jessyca@mat.ufc.br) on 2017-03-06T15:32:24Z No. of bitstreams: 1 2016_dis_chsmartins.pdf: 555526 bytes, checksum: 8868d747ffd7a013dc7e9a39950f6b99 (MD5) / Rejected by Rocilda Sales (rocilda@ufc.br), reason: Ficha catalográfica e o Sumário não estão de acordo com os padrões adotados na UFC. on 2017-03-06T15:39:46Z (GMT) / Submitted by Jessyca Silva (jessyca@mat.ufc.br) on 2017-03-08T13:51:28Z No. of bitstreams: 1 2016_dis_chsmartins.pdf: 14646883 bytes, checksum: ffc10a0c4a1110c572c44d1d66359c38 (MD5) / Approved for entry into archive by Rocilda Sales (rocilda@ufc.br) on 2017-03-08T15:16:29Z (GMT) No. of bitstreams: 1 2016_dis_chsmartins.pdf: 14646883 bytes, checksum: ffc10a0c4a1110c572c44d1d66359c38 (MD5) / Made available in DSpace on 2017-03-08T15:16:29Z (GMT). No. of bitstreams: 1 2016_dis_chsmartins.pdf: 14646883 bytes, checksum: ffc10a0c4a1110c572c44d1d66359c38 (MD5) Previous issue date: 2016-01-15 / This dissertation aims to know the historical process of the emergence of mathematics and isoperimetric inequalities, as well as to present approaches of isoperimetric problems that can be used in high school. On order to achieve the objective of this research, bibliographical research was adopted as methodology. Despite the long existence of the study of the isoperimetric problem over time this is still the focus of many mathematicians. Many generalizations of isoperimetric inequalities in the most varied mathematical contexts are much studied in different areas of mathematical investigation. Ot is pertinent to note that demonstrations can be made in various ways and the approach to these formulas is scarcely mentioned in the books. The organization of school knowledge allows us to introduce a new pedagogical practice of the teacher, in which the process of reflection and interpretation about different procedures allows us to establish a relation between theory and everyday life. With the proposals here reported it is desired to continue adding new elements capable of enriching and making more accessible the process of construction of mathematical knowledge in this area. Since all mathematical theoretical knowledge that has existed before by actual experience, our preoccupation with contextualizing isoperimetric inequalities in their initial event, as well as punctuating some questions of the development of mathematics, proving how much it has arisen, is and will be relevant to the development of man. / Essa dissertação tem como objetivo conhecer o processo histórico do surgimento da matemática e das desigualdades isoperimétricas, bem como apresentar abordagens de desigualdades isoperimétricas que podem ser utilizadas no ensino médio. Para concretização do objetivo dessa pesquisa adotou-se como metodologia a pesquisa bibliográfica. Apesar da longa existência do estudo do problema isoperimétrico ao longo dos tempos este ainda é alvo da atenção de muitos matemáticos. Muitas generalizações de desigualdades isoperimétricas nos mais variados contextos matemáticos são muito estudadas em diferentes áreas de investigação matemática. Sendo pertinente observar que as demonstrações podem ser feitas de várias maneiras e a abordagem dessas fórmulas é pouco citada nos livros. A organização dos conhecimentos escolares permitem introduzir um novo fazer pedagógico do professor, na qual o processo de reflexão e interpretação sobre diferentes procedimentos permitem estabelecer uma relação entre a teoria e o cotidiano. Com as propostas aqui relatadas deseja-se continuar agregando novos elementos capazes de enriquecer e tornar mais acessível o processo de construção do conhecimento matemático nessa área. Visto que todo conhecimento teórico matemático que existe passou antes pela experiência real, daí nossa preocupação de contextualizar as desigualdades isoperimétricas em seu evento inicial, bem como pontuar algumas questões do desenvolvimento da matemática, provando o quanto seu surgimento foi, é e será relevante para o desenvolvimento do homem.

Thesis--Columbia University, 1931. / Includes bibliographical references (p. 92-95).

Thesis--Columbia University, 1931. / Includes bibliographical references (p. 92-95).