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1.
Nano Lett ; 19(9): 5844-5852, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31424944

RESUMO

The majority of developed and approved anticancer nanomedicines have been designed to exploit the dogma of the enhanced permeability and retention (EPR) effect, which is based on the leakiness of the tumor's blood vessels accompanied by impeded lymphatic drainage. However, the EPR effect has been under scrutiny recently because of its variable manifestation across tumor types and animal species and its poor translation to human cancer therapy. To facilitate the EPR effect, systemically injected NPs should overcome the obstacle of rapid recognition and elimination by the mononuclear phagocyte system (MPS). We hypothesized that circulating monocytes, major cells of the MPS that infiltrate the tumor, may serve as an alternative method for achieving increased tumor accumulation of NPs, independent of the EPR effect. We describe here the accumulation of liposomal quantum dots (LipQDs) designed for active delivery via monocytes, in comparison to LipQDs designed for passive delivery (via the EPR effect), following IV administration in a mammary carcinoma model. Hydrophilic QDs were synthesized and entrapped in functionalized liposomes, conferring passive ("stealth" NPs; PEGylated, neutral charge) and active (monocyte-mediated delivery; positively charged) properties by differing in their lipid composition, membrane PEGylation, and charge (positively, negatively, and neutrally charged). The various physicochemical parameters affecting the entrapment yield and optical stability were examined in vitro and in vivo. Biodistribution in the blood, various organs, and in the tumor was determined by the fluorescence intensity and Cd analyses. Following the treatment of animals (intact and mammary-carcinoma-bearing mice) with disparate formulations of LipQDs (differing by their lipid composition, neutrally and positively charged surfaces, and hydrophilic membrane), we demonstrate comparable tumor uptake of QDs delivered by the passive and the active routes (mainly by Ly-6Chi monocytes). Our findings suggest that entrapping QDs in nanosized liposomal formulations, prepared by a new facile method, imparts superior structural and optical stability and a suitable biodistribution profile leading to increased tumor uptake of fluorescently stable QDs.


Assuntos
Lipossomos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Sistema Fagocitário Mononuclear/química , Pontos Quânticos/química , Animais , Vasos Sanguíneos/efeitos dos fármacos , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Lipídeos/química , Lipídeos/farmacologia , Lipossomos/química , Neoplasias Mamárias Animais/patologia , Camundongos , Nanomedicina , Células Neoplásicas Circulantes , Permeabilidade/efeitos dos fármacos
2.
Plant Signal Behav ; 12(6): e1338224, 2017 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-28621569

RESUMO

The tomato dgt mutant, containing a single mutation in the Cyclophilin1 (SlCyp1) gene, is auxin insensitive and exhibits a pleotropic phenotype that includes lack of lateral roots, malformed xylem structure and reduced root-to-shoot ratio. Recently, we found that the SlCyp1 protein is phloem-mobile and traffic from shoot to root to induce lateral root formation. These processes are achieved through activation of auxin-mediated developmental programs. Inhibition of the trafficked SlCyp1 activity at the target site resulted in inhibition of the auxin response, supporting the hypothesis that this protein is indeed a mobile signal. Here, we show that partial silencing of SlCyp1 in the phloem only resulted in perturbed auxin response in the roots and reduced photosynthetic and transpiration rates. The presented data suggests that expression of SlCyp1 in the phloem is essential for proper auxin response at the whole plant level. We, therefore, propose that this protein acts as a long-distance signaling molecule acting as coordinator between roots and shoot activities.


Assuntos
Regulação para Baixo/genética , Regulação da Expressão Gênica de Plantas , Ácidos Indolacéticos/farmacologia , Lycopersicon esculentum/genética , Lycopersicon esculentum/fisiologia , Floema/metabolismo , Fotossíntese , Proteínas de Plantas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Lycopersicon esculentum/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Proteínas de Plantas/genética , Estômatos de Plantas/efeitos dos fármacos , Estômatos de Plantas/fisiologia , Regiões Promotoras Genéticas/genética
3.
Oncotarget ; 5(19): 9396-409, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25238049

RESUMO

Genomic instability, a hallmark of cancer, is commonly caused by failures in the DNA damage response. Here we conducted a bioinformatical screen to reveal DNA damage response genes that are upregulated by estrogen and highly mutated in breast and ovarian cancers. This screen identified 53 estrogen-dependent cancer genes, some of which are novel. Notably, the screen retrieved 9 DNA helicases as well as 5 nucleases. DNA2, which functions as both a helicase and a nuclease and plays a role in DNA repair and replication, was retrieved in the screen. Mutations in DNA2, found in estrogen-dependent cancers, are clustered in the helicase and nuclease domains, suggesting activity impairment. Indeed, we show that mutations found in ovarian cancers impair DNA2 activity. Depletion of DNA2 in cells reduces their tumorogenicity in mice. In human, high expression of DNA2 correlates with poor survival of estrogen receptor-positive patients but not of estrogen receptor-negative patients. We also demonstrate that depletion of DNA2 in cells reduces proliferation, while addition of estrogen restores proliferation. These findings suggest that cells responding to estrogen will proliferate despite impaired in DNA2 activity, potentially promoting genomic instability and triggering cancer development.


Assuntos
Neoplasias da Mama/genética , DNA Helicases/genética , Reparo do DNA/genética , Estrogênios/farmacologia , Neoplasias Ovarianas/genética , Animais , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Dano ao DNA/genética , DNA Helicases/biossíntese , Feminino , Instabilidade Genômica/genética , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Transplante de Neoplasias , Neoplasias Ovarianas/mortalidade , Interferência de RNA , RNA Interferente Pequeno , Receptores Estrogênicos/metabolismo , Transplante Heterólogo
4.
Appl Ergon ; 45(3): 734-40, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24140244

RESUMO

This study aimed at identifying the roll motion parameters of a motorcycle simulator prototype. Experienced motorcyclists tuned the angular physical movement of the mock-up and that of the visual scene to achieve an optimal riding experience during curves. The participants exceeded the rolling angles that would be required in real-world riding, while avoiding leaning the mock-up beyond 10°. In addition, they were more influenced by the speed of the virtual motorcycle than by road curvature, especially in a wide field of view. Heterogeneity was found in the roll applied to the visual scene. The overall patterns suggest that at least when washout is not applied to remove the side forces that in real-world riding are compensated by a centrifugal force, greater roll of the visual at the expense of the mock-up is mandatory to avoid performance biases that might be enhanced due to fear of falling off the simulator. Future roll motion models must take into consideration factors such as riding postures, which might not only influence the forces operating on the rider-motorcycle system, but also how motorcyclists perceive the visual world.


Assuntos
Movimento (Física) , Motocicletas , Interface Usuário-Computador , Adulto , Feminino , Humanos , Masculino , Percepção de Movimento
5.
Cancer Res ; 72(21): 5613-24, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23090119

RESUMO

Regulatory factors controlling stem cell identity and self-renewal are often active in aggressive cancers and are thought to promote their growth and progression. TCF3 (also known as TCF7L1) is a member of the TCF/LEF transcription factor family that is central in regulating epidermal and embryonic stem cell identity. We found that TCF3 is highly expressed in poorly differentiated human breast cancers, preferentially of the basal-like subtype. This suggested that TCF3 is involved in the regulation of breast cancer cell differentiation state and tumorigenicity. Silencing of TCF3 dramatically decreased the ability of breast cancer cells to initiate tumor formation, and led to decreased tumor growth rates. In culture, TCF3 promotes the sphere formation capacity of breast cancer cells and their self-renewal. We found that in contrast to ES cells, where it represses Wnt-pathway target genes, TCF3 promotes the expression of a subset of Wnt-responsive genes in breast cancer cells while repressing another distinct target subset. In the normal mouse mammary gland, Tcf3 is highly expressed in terminal end buds, structures that lead duct development. Primary mammary cells are dependent on Tcf3 for mammosphere formation, and its overexpression in the developing gland disrupts ductal growth. Our results identify TCF3 as a central regulator of tumor growth and initiation, and a novel link between stem cells and cancer.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Neoplasias da Mama/genética , Transformação Celular Neoplásica/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Imunofluorescência , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma
6.
Accid Anal Prev ; 44(1): 88-96, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22062341

RESUMO

Studies of accident statistics suggest that motorcyclists are particularly vulnerable to collisions with other vehicles which pull out of side roads onto a main carriageway, failing to give way to the approaching motorcycle. Why might this happen? The typical response of the car driver is that they looked in the appropriate direction but simply failed to see the motorcycle. To assess the visual skills of drivers in such scenarios we compared the behaviour of novice and experienced drivers to a group of dual drivers (with both car and motorcycle experience). Participants watched a series of video clips, displayed across three screens, depicting the approach to various t-junctions. On reaching the junction, participants had to decide when it was safe to pull out. Responses and eye movements were measured. The results confirmed that dual drivers had the safest responses at junctions, especially in the presence of conflicting motorcycles. On a range of visual measures both novice and experienced drivers appeared inferior to dual drivers, though for potentially different reasons. There were however no differences in the time it took all drivers to first fixate approaching motorcycles. Instead the differences appeared to be due to the amount of time spent looking at the approaching motorcycle. The experienced drivers had shorter gazes on motorcycles than cars, suggesting that they either process less salient motorcycles faster than cars, or that they terminated the gaze prematurely perhaps because they did not realise they were fixating a motorcycle. We argue that this is potential evidence for an oculomotor basis for Look But Fail To See errors.


Assuntos
Acidentes de Trânsito/prevenção & controle , Atenção , Condução de Veículo , Conscientização , Motocicletas , Percepção Visual , Adolescente , Adulto , Movimentos Oculares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Reação , Reino Unido
7.
Accid Anal Prev ; 44(1): 104-10, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22062343

RESUMO

Right of way violation crashes are the most common type of accidents that motorcyclists face. This study assessed right of way decisions in scenarios which require noticing whether there is traffic from behind that is about to overtake. A test was created which presents participants clips with a wide field of vision (from a driver's perspective in a moving vehicle), with mirror information inset that allows either cars or motorcycles that are about to overtake, to be attended. Novice and experienced car drivers, and dual drivers (with both car and motorcycle experience), watched these clips while their eye movements were monitored. The results indicated that in the rear-view and the right-side mirrors, and in the right hand lane, conflicting motorcycles garnered more attention than conflicting cars. This pattern however was particularly driven by the dual drivers group. Additionally, novice drivers and dual drivers made more use of the right side mirror than the experienced drivers. Dual drivers also made more use of the rear view mirror than experienced drivers. Finally, significant positive correlations that were found between percentages of safe manoeuvres and measures of visual search provide direct evidence demonstrating that the frequency of risky manoeuvres was indeed larger in those cases where less time was spent gazing at the mirrors, indicating that the additional attention devoted to process conflicting vehicles contributes to reduce risky manoeuvres. The general pattern of results also provides some indirect support that non-motorcyclists drivers are more likely to have Look But Fail To See errors with conflicting motorcycles than motorcyclist drivers.


Assuntos
Acidentes de Trânsito/prevenção & controle , Condução de Veículo , Conscientização , Motocicletas , Equipamentos de Proteção , Campos Visuais , Adulto , Atenção , Movimentos Oculares , Feminino , Humanos , Masculino , Assunção de Riscos , Reino Unido , Gravação em Vídeo , Percepção Visual
8.
Accid Anal Prev ; 43(5): 1743-50, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21658502

RESUMO

This study sought to provide a first crucial step in the direction of developing an intervention program aimed at improving safe attitudes and skills among car drivers towards motorcycles. We intended to improve drivers' attitudes towards motorcyclists by exposing them to demands that motorcyclists face on the road. Car drivers were exposed to hazard perception clips taken from a motorcyclist's perspective, and interactive hazards in a motorcycle simulator. Car hazard perception clips and a car simulator were used as control conditions. A questionnaire assessed participant knowledge and attitudes towards motorcyclists before and after the intervention. After the intervention participants had more empathic- and fewer negative-attitudes, as well as safer attitudes towards motorcyclists. Self-reported attitude-change suggested that the use of motorcycle hazard perception clips was more effective than the simulator, and the intervention was most effective for those car drivers who reported the most negative attitudes prior viewing the clips or riding the simulator. Providing car drivers with a perspective of the motorcyclist may prove to be a useful tool for promoting safer attitudes towards motorcyclists.


Assuntos
Atitude , Condução de Veículo/psicologia , Empatia , Motocicletas , Adulto , Condução de Veículo/educação , Simulação por Computador , Feminino , Humanos , Masculino , Segurança , Autorrelato
9.
Accid Anal Prev ; 42(6): 1577-84, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20728606

RESUMO

A typical hazard perception test presents participants with a single-screen view of the road ahead. This study assessed how increasing this field of view would affect hazard perception abilities. Drivers were shown video clips of driving situations containing at least one hazard either on a single screen, or with the addition of side views on two separate but adjacent screens that extended the perceived worldview to approximately 180 degrees. Mirror information was also included to allow information from behind the vehicle to be attended. Participants were instructed to press a button as soon as they saw a hazard. Faster response times were found for hazards that appeared in the centre of the central screen, than in the periphery of the central screen, with hazards that first appeared in the lateral screens responded to slowest. Additionally, responses to the hazards were faster and were more likely to occur in the three-, as compared to the single-screen condition. These results suggest that providing participants with a wider field of view, which includes more environmental cues that are related to the relevant hazardous situation increases their ability to detect hazards, and some limited support to that providing them with a wider view increases this ability even when all hazard-relevant information appear only in the central screen. A number of reasons for the three-screen advantage are discussed. This study suggests that even responses to central hazards may be under-estimated in a typical single-screen hazard perception test, and that improvements can be made for new hazard perception tests, by including visual information from the side and from behind the driver. This new methodology not only allows testing hazard perception skills in a potentially more immersive and realistic environment, but also enables to create hazard perception clips that cannot be realised in a typical single-screen test.


Assuntos
Acidentes de Trânsito/prevenção & controle , Atenção , Condução de Veículo/psicologia , Percepção de Movimento , Orientação , Reconhecimento Visual de Modelos , Desempenho Psicomotor , Campos Visuais , Acidentes de Trânsito/psicologia , Adulto , Conscientização , Sinais (Psicologia) , Feminino , Humanos , Masculino , Tempo de Reação , Risco , Gravação em Vídeo , Adulto Jovem
10.
Accid Anal Prev ; 41(4): 723-8, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19540960

RESUMO

The purpose of the study was to compare the reported approaches of truck drivers to those of non-truck drivers toward reckless on-road behaviors. One hundred and sixty-seven adult males, including 70 non-truck drivers, completed the questionnaires voluntarily. The truck drivers were employees of a concrete manufacturing company working at various company plants throughout Israel. Seventy were professional mixer truckers and 27 were tip-truckers. The participants completed the Reckless Driving Self-Report Scale based on Taubman Ben-Ari et al. [Taubman Ben-Ari, O., Florian, V., Mikulincer, M., 1999. The impact of mortality salience on reckless driving: a test of terror management mechanisms. Journal of Personality and Social Psychology 76, 35-45], adapted for truck drivers for this study. It was expected that non-professional, as compared to professional (truck) drivers, would be more permissive regarding reckless driving, since driving risks are less prominent in their daily driving experience. An ANOVA performed on mean reckless-driving scores yielded significant results. The post hoc Schéffe test indicated significantly higher reckless-driving scores for automobile drivers as compared to both mixer-truck driver scores and tip-truck driver scores. In addition, the reckless-driving scores for mixer-truck drivers were significantly higher than the tip-truck driver scores. We discuss various explanations for the findings and consider possible implications for training strategies in organizations as well as for media campaigns focused on mutual safe road use of truck drivers and private vehicle drivers.


Assuntos
Condução de Veículo , Automóveis , Veículos Automotores , Saúde do Trabalhador , Assunção de Riscos , Adulto , Análise de Variância , Comportamentos Relacionados com a Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Estatística como Assunto , Inquéritos e Questionários
11.
Accid Anal Prev ; 41(2): 241-5, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19245881

RESUMO

This study examined self-reported driving behaviors in 120 (Israeli) male drivers as a function of trait anxiety (TA). TA was assessed through the TA scale of the State-Trait Anxiety Inventory. For the analysis of driving behaviors, the present study used the Driver Behavior Questionnaire (DBQ) and adopted previous distinctions between four classes of behaviors within the DBQ: errors, lapses, ordinary violations and aggressive violations. Regression analyses revealed that level of TA had a significant direct positive effect on all dependent variables, suggesting riskier driving behaviors among high-anxious individuals. Significant logarithmic effects for all measures indicate that these aberrant driving behaviors increase more at increasing LTA-, than at increasing HTA-values. Consistent with the general adverse effects of anxiety on performance effectiveness, the present findings as well, are interpreted in the framework of theories which suggest that worries occupy the capacities of working memory, at the expense of the task to be performed. The positive relation between aggressive violations and TA is sought to reflect low levels of emotional adjustment among high-anxious individuals.


Assuntos
Ansiedade , Condução de Veículo/psicologia , Assunção de Riscos , Adulto , Estudos Transversais , Humanos , Masculino , Escala de Ansiedade Manifesta , Pessoa de Meia-Idade , Adulto Jovem
12.
Accid Anal Prev ; 40(6): 1919-24, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19068295

RESUMO

Following a previous study that revealed the disobedience of Ultra-Orthodox citizens, as compared to secular citizens, of traffic lights at crosswalks, the present study examined the road habits of 995 Ultra-Orthodox and secular pedestrians in neighboring Ultra-Orthodox and secular cities. Using an observation grid designed specially for this study, the pedestrians were observed at two crosswalks--one in an Ultra-Orthodox city and one in a secular city--as far as similar traffic parameters, using a logistic regression. The tendency to cross on a red light was assessed as a function of estimated age, gender, religiosity, location (religious/secular), the duration of the red light, the number of vehicles crossing and the number of pedestrians waiting at the curb. Ultra-Orthodox pedestrians committed more violations than secular pedestrians did, and there were more road violations in the Ultra-Orthodox location than there were in the secular location. Fewer traffic violations were committed by "local" pedestrians (Ultra-Orthodox pedestrians in the Ultra-Orthodox location and secular pedestrians in the secular location) than by "foreigners" (Ultra-Orthodox pedestrians in the secular location and secular pedestrians in the Ultra-Orthodox location). The odds of crossing on a red light decreased as a function of both the number of people waiting at the curb and the number of vehicles. Consistent with previous research, males crossed on red much more than females did, regardless of religiosity and location. Our discussion focuses on theoretical and practical explanations of the findings.


Assuntos
Judaísmo , Gestão da Segurança/legislação & jurisprudência , Caminhada/legislação & jurisprudência , Acidentes de Trânsito/prevenção & controle , Adolescente , Adulto , Criança , Estudos Transversais , Feminino , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Veículos Automotores/legislação & jurisprudência , Assunção de Riscos , Fatores Sexuais , Adulto Jovem
13.
Accid Anal Prev ; 40(2): 697-703, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18329423

RESUMO

The present study examined in 224 individuals whether an advanced driving training aimed at recognizing, avoiding and handling risks in demanding driving situations, affected perceived risk of driving situations (measured by a questionnaire). The training, which involved both experience and feedback on real performance, specifically intended to emphasize the dangers in loss of control of a vehicle. With that emphasis, it was hypothesized that perceived risk would increase after as compared to before the training. In addition, this study examined whether risk perception was dependent on gender or on age. A mixed ANOVA performed on mean scores on the questionnaire yielded significant main effects for training (before/after), gender, and age. Higher levels of perceived risk were reported after the training as compared to before it, by females than by males, and by older adult drivers than by younger adult drivers. An analysis of the data of a smaller sample showed that the increment in perceived risk was still present 2 months after the training, and that it did not decrease significantly as compared to immediately after the training. These results are discussed in relation to relevant methodological issues and future research.


Assuntos
Condução de Veículo/psicologia , Automóveis , Percepção Visual/fisiologia , Adolescente , Adulto , Condução de Veículo/educação , Coleta de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Assunção de Riscos , Fatores Sexuais , Inquéritos e Questionários
14.
Accid Anal Prev ; 39(6): 1296-301, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17920854

RESUMO

The present study examined whether performance in practical driving tests differed when individuals were tested with and without the presence of another testee. In addition, this study examined whether such differences were dependent on the sex of the tested person, on that of the observer testee, and on the order of tests. It was found that for both males and females, a greater proportion of drivers who were tested alone passed the test as compared to drivers who were tested in pairs. Additionally, proportionately more males than females passed the driving test. Only for males was performance also dependent on the gender of the other tested individual. A greater proportion of males who were tested with an accompanying female passed the test than males who were tested with an accompanying male. These results are discussed in relation to social facilitation, gender differences in driving performance, and differences in testing procedures.


Assuntos
Logro , Exame para Habilitação de Motoristas , Adolescente , Adulto , Fatores Etários , Estudos de Coortes , Feminino , Humanos , Relações Interpessoais , Israel , Licenciamento , Masculino , Reprodutibilidade dos Testes , Fatores Sexuais , Análise e Desempenho de Tarefas
15.
J Safety Res ; 38(3): 283-8, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17617237

RESUMO

INTRODUCTION: Through observations this study sought to examine the effects of road familiarity on driving performance. METHOD: Severe and minor traffic violations, dangerous behaviors, and speeding were assessed in well known and in less familiar locations. RESULTS: As compared to less known locations, drivers in well known locations performed more severe and minor violations, more dangerous behaviors, and they drove above the speed limit more often. DISCUSSION: The results are discussed in the context of Theory of Risk Homeostasis (later re-labeled as Target Risk Theory), the psychological effect of familiarity on driving performance, and the phenomenon of automatic driving. Presenting the risk of driving in familiar locations would assist to elevate safe driving.


Assuntos
Condução de Veículo/legislação & jurisprudência , Comportamento , Adulto , Condução de Veículo/psicologia , Feminino , Humanos , Pessoa de Meia-Idade , Inquéritos e Questionários , Estados Unidos
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