RESUMO
BACKGROUND: A potential option for the correction of presbyopia after cataract extraction or refractive lens exchange is the implantation of accommodative intraocular lenses (IOL). When evaluating these lenses, it is essential to differentiate between accommodative and pseudoaccommodative effects, as both may have a positive impact on near visual acuity and reading performance. Only in this way accommodation can be proved. MATERIAL AND METHODS: This article provides a brief overview on the principles of accommodation and presbyopia. Furthermore, different tests for testing near visual acuity, reading ability and accommodative processes are described, as well as options to perform these in a manner that allows the differentiation between accommodative and pseudoaccomodative effects. Against this background, the current literature has been reviewed regarding the results of potential accommodative IOLs. RESULTS: A differentiation between accommodative effects in clinical practice can be performed using defocus curves or better open field aberrometers or refractometers as well as IOL movement measurements under non-pharmacologically stimulated conditions. Reading charts are not suitable. Currently mainly 7 different potential accommodating IOLs can be found in clinical research literature (5 single-optics, 1 gel-optic and one dual-optic). All of them are based on the principle of using ciliary muscle contraction for moving the IOL or changing its thickness and/or surface radii during accommodation in order to change the ocular refractive power. A proof of principle of such lenses under physiological, non-pharmacologically stimulated conditions is still lacking. However, the evaluated implants show significant improvement in terms of visual acuity in near and especially intermediate distances. CONCLUSION: Using adequate testing procedures it becomes clear that the positive near vision effects achieved with accommodative intraocular lenses are due rather to pseudoaccommodative effects than to accommodative ones.
Assuntos
Acomodação Ocular , Lentes Intraoculares , Presbiopia/cirurgia , Desenho de Prótese , Aberrometria , Percepção de Distância , Humanos , Leitura , Refração Ocular , Acuidade VisualRESUMO
Centration and positional stability of intraocular lenses (IOLs) are crucial factors for optical quality and predictability of the result after IOL implantation. Continuous improvements of IOL design and materials, surgical techniques and measurement methods have contributed to an optimised correction of the presudophakic eye and to a better unterstanding of the effects of IOL positioning. With modern IOLs implanted into the capsular bag, positioning and stability comparable to the natural crystalline lens can be achieved.
Assuntos
Implante de Lente Intraocular/métodos , Análise de Falha de Equipamento , Humanos , Lentes Intraoculares , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Desenho de Prótese , Ensaios Clínicos Controlados Aleatórios como Assunto , Refração OcularRESUMO
BACKGROUND: Collagen cross-linking with administration of riboflavin and UV radiation may delay or halt the progression of keratoconus. This study examines the effects of the treatment on the corneal wavefront error. MATERIALS AND METHODS: Twenty eyes of 20 patients with keratoconus received collagen cross-linking with riboflavin administration and 30 min of UV radiation at a wavelength of 365 nm. Preoperatively as well as 1 and 6 months postoperatively, the corneal wavefront error was computed from axial keratometric topography data by Zernike decomposition over a pupil diameter of 6 mm. RESULTS: Preoperative mean keratometric astigmatism was 5.37 +/- 2.36 D. Six months postoperatively it was 5.29 +/- 2.73 D (p = 0.35). Total higher order aberrations were preoperatively 3.35 +/- 1.65 microm and after 6 months 3.31 +/- 1.79 microm (p = 0.116). Coma's root mean square was 2.94 +/- 1.47 microm preoperatively and 2.75 +/- 1.38 microm after 6 months (p = 0.047). CONCLUSION: Within the first 6 postoperative months, collagen cross-linking with riboflavin administration and UVA irradiation does not significantly increase or decrease corneal wavefront aberrations.
Assuntos
Ceratocone/tratamento farmacológico , Fotoquimioterapia/efeitos adversos , Erros de Refração/diagnóstico , Erros de Refração/etiologia , Riboflavina/administração & dosagem , Riboflavina/efeitos adversos , Terapia Ultravioleta/efeitos adversos , Adulto , Colágeno/química , Topografia da Córnea , Reagentes de Ligações Cruzadas/química , Feminino , Humanos , Ceratocone/complicações , Ceratocone/diagnóstico , Masculino , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Erros de Refração/prevenção & controle , Riboflavina/química , Resultado do Tratamento , Terapia Ultravioleta/métodosRESUMO
Accommodation is a dynamic change in the dioptric power of the eye. According to the widely accepted and experimentally confirmed theory of Helmholtz, it is achieved by release of zonular tension with contraction of the ciliary muscle and consecutive modelling of the shape of the crystalline lens by the elastic lens capsule. The ability to accommodate is gradually lost with age (presbyopia). Because of difficulties in examining the accommodative apparatus in vivo, many theories, in part contradictory, about the mechanism of accommodation and the origin of presbyopia have been developed. In recent years experimental studies have greatly increased the knowledge about the acommodative apparatus and suggest a multifactorial aetiology of presbyopia. A better understanding of the physiology of accommodation and presbyopia can contribute to the development of effective treatments.
Assuntos
Acomodação Ocular/fisiologia , Presbiopia/fisiopatologia , Tecido Elástico/fisiopatologia , Corpos Geniculados/fisiopatologia , Humanos , Cristalino/fisiopatologia , Músculo Liso/inervação , Músculo Liso/fisiopatologia , Nervo Óptico/fisiopatologia , Presbiopia/etiologia , Refração OcularRESUMO
There are two basic approaches for the surgical correction of presbyopia: increasing depth of focus (e.g. by means of multifocal laser abrasion of the cornea), Or restoring accommodation in the sense of a dynamic change in ocular refraction (accommodative intraocular lenses, scleral expansion). Pseudoaccommodative procedures are able to achieve satisfactory near vision, albeit at the price of lower performance in the intermediate range and decreased image quality. The restoration of accommodation remains problematic, partly because the mechanism of accommodation and the development of presbyopia are still not fully understood. Some surgical procedures are based on concepts, the validity of which is not confirmed or which even contradict experimental evidence. Thus, it is necessary to assess the results and presumed mechanisms critically and objectively.
Assuntos
Acomodação Ocular , Implante de Lente Intraocular/instrumentação , Implante de Lente Intraocular/métodos , Lentes Intraoculares , Presbiopia/diagnóstico , Presbiopia/cirurgia , Procedimentos Cirúrgicos Refrativos/instrumentação , Procedimentos Cirúrgicos Refrativos/métodos , Alemanha , HumanosRESUMO
In this overview, the current status of intraocular lens surgery to correct refractive error is reviewed. The interventions are divided into additive surgery with intraocular lens implantation without extraction of the crystalline lens (phakic intraocular lens, PIOL) or the removal of the crystalline lens with implantation of an IOL (refractive lens exchange, RLE). Phakic IOLs are constructed as angle-supported or iris-fixated anterior chamber lenses and posterior chamber lenses that are fixated in the ciliary sulcus. The implantation of phakic IOLs has been demonstrated to be an effective, safe, predictable and stable procedure to correct higher refractive errors. Complications are rare and differ for the three types of PIOL; for anterior chamber lenses these are mainly pupil ovalization and endothelial cell loss.
Assuntos
Câmara Anterior/cirurgia , Implante de Lente Intraocular/métodos , Cristalino , Lentes Intraoculares , Procedimentos Cirúrgicos Refrativos , Extração de Catarata , Seguimentos , Humanos , Iris/cirurgia , Lentes Intraoculares/efeitos adversos , Microscopia Eletrônica de Varredura , Refração Ocular , Rotação , Fatores de TempoRESUMO
PURPOSE: To report the clinical and confocal microscopic characteristics of reticular folds (mudcracks) in a cornea after laser in situ keratomileusis (LASIK). METHODS: A 30-year-old male showed reticular flap folds on slit-lamp examination 1 week after LASIK. In addition to slit-lamp biomicroscopy, confocal in vivo microscopy was performed. RESULTS: Examination with a confocal white-light slit-scanning microscope revealed distinct folds of Bowman's layer and underlying microfolds throughout the flap stroma. After flap re-lifting, no changes could be determined, either clinically or by confocal microscopy. At 12 months following the procedure, best spectacle-corrected visual acuity was slightly improved, but the folds, as imaged by confocal microscopy, still persisted. CONCLUSIONS: In the present case, reticular folds after LASIK involved the entire thickness of the flap. Simple flap lifting was not sufficient for smoothing out the folds.
Assuntos
Doenças da Córnea/diagnóstico , Substância Própria/patologia , Ceratomileuse Assistida por Excimer Laser In Situ/efeitos adversos , Retalhos Cirúrgicos/patologia , Adulto , Doenças da Córnea/etiologia , Doenças da Córnea/cirurgia , Humanos , Masculino , Microscopia Confocal , Miopia/cirurgia , Reoperação , Acuidade VisualRESUMO
PURPOSE: To prospectively measure the scotopic pupil diameter in a normal population and to compare 2 infrared pupillometers for these measurements. SETTING: Johann Wolfgang Goethe-University, Department of Ophthalmology, Frankfurt am Main, Germany. METHODS: The Colvard infrared pupillometer was compared to the Video Vision Analyzer (VIVA) infrared pupillometer under scotopic light conditions in 33 participants (aged 19 to 55 years). Reliability was assessed by 2 independent examiners (E1, E2). Statistical analysis was performed using a comparison method by Bland and Altman. RESULTS: Mean pupil diameter was 6.16 mm +/- 1.20 (SD) (range 3.20 to 9.00 mm) with all measurements taken under scotopic illumination. The mean scotopic pupil diameter was 6.08 +/- 1.16 mm (range 3.2 to 8.4 mm) with the Colvard pupillometer and 6.24 +/- 1.28 mm (3.5 to 9.0 mm) with the VIVA pupillometer. The mean differences between the Colvard and VIVA were -0.27 mm (E1) and -0.05 mm (E2). Limits of agreement ranged from 1.4 (Colvard) to 2.4 (VIVA). The coefficients of repeatability ranged from 0.7 (Colvard) to 1.1 (VIVA). CONCLUSIONS: A mean scotopic pupil diameter of 6.15 mm with a maximal pupil size of 9.00 mm can be expected in a normal population; this should be considered in refractive corneal and refractive lens surgery. Measurements with the Colvard pupillometer were more reliable and precise than those with the VIVA pupillometer.
Assuntos
Adaptação à Escuridão/fisiologia , Técnicas de Diagnóstico Oftalmológico/instrumentação , Raios Infravermelhos , Pupila/fisiologia , Gravação em Vídeo , Adulto , Envelhecimento/fisiologia , Desenho de Equipamento , Cor de Olho , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estudos Prospectivos , Valores de ReferênciaRESUMO
The secondary and tertiary amines morpholine, aminopyrine and cimetidine as well as their nitroso products were examined for mutagenicity with the Ames Salmonella typhimurium microsome test (strains TA1535 and TA100) and the host-mediated assay. The formation of mutagenic nitroso compounds from morpholine and aminopyrine in the presence of nitrite could be demonstrated in artificial gastric juice and was confirmed in the stomach of mice in vivo. In contrast, the positive response of the chemical nitrosation in vitro with cimetidine did not match with the mammalian host-mediated assay results. To enhance sensitivity the role of modifiers of nitrosation, such as ascorbic acid and thiocyanate as well as the influence of biotransformation were studied.
Assuntos
Aminas/metabolismo , Nitritos/metabolismo , Compostos Nitrosos/metabolismo , Animais , Feminino , Masculino , Camundongos , Modelos Biológicos , Testes de Mutagenicidade , Ratos , Salmonella typhimurium/genéticaRESUMO
Paracetamol (acetaminophen) has been examined for mutagenic potential in numerous studies: gene mutation tests consistently gave negative results while in vitro chromosomal aberration tests showed equally consistently positive effects. In vivo studies for chromosome breaking activity gave clearly negative, equivocal or weakly positive results. In particular two reports have indicated that human volunteers taking a maximum daily dose of paracetamol (3 x 1000 mg over 8 h) exhibited significantly elevated frequencies of chromatid breaks in their peripheral lymphocytes 24 h later. In the one study evaluating the time course, levels returned to normal between 3 and 7 days later. We performed a carefully controlled double-blind study in which volunteers were pre-screened for normal liver function, they all were non-smoking and their diet and environmental exposures were controlled during the study. Cell-cycle kinetics were monitored and paralleled and a placebo group was included. Although a larger number of cells than in the other studies was analysed we were unable to reproduce their findings. No significant increases in structural chromosome aberrations (CA) were found either when the paracetamol group (male, female or both) post-dosing values were compared with pre-dosing values, or when treated groups at any sampling time were compared with the placebo groups. There was not even any evidence that individuals responded to the clastogenic potential of paracetamol or that a group response may have been masked by non-responders. In conjunction with the recently published results of the NTP bioassay, showing no carcinogenic activity in mice and no carcinogenic activity in rats except an increase of mononuclear cell leukaemia in female rats which is of doubtful relevance, the study presented here argues that paracetamol does not pose an unacceptable (if any) genotoxic/carcinogenic risk to man.
Assuntos
Acetaminofen/efeitos adversos , Aberrações Cromossômicas , Linfócitos/efeitos dos fármacos , Acetaminofen/sangue , Adulto , Ciclo Celular/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/fisiologia , Linfócitos/ultraestrutura , Masculino , Pessoa de Meia-IdadeRESUMO
Nineteen coded chemicals were tested in an international collaborative study for their mutagenic activity. The assay system employed was the Ames II Mutagenicity Assay, using the tester strains TA98 and TAMix (TA7001-7006). The test compounds were selected from a published study with a large data set from the standard Ames plate-incorporation test. The following test compounds including matched pairs were investigated: cyclophoshamide, 2-naphthylamine, benzo(a)pyrene, pyrene, 2-acetylaminofluorene, 4,4'-methylene-bis(2-chloroaniline), 9,10-dimethylanthracene, anthracene, 4-nitroquinoline-N-oxide, diphenylnitrosamine, urethane, isopropyl-N(3-chlorophenyl)carbamate, benzidine, 3,3'-5,5'-tetramethylbenzidine, azoxybenzene, 3-aminotriazole, diethylstilbestrol, sucrose and methionine. The results of both assay systems were compared, and the inter-laboratory consistency of the Ames II test was assessed. Of the eight mutagens selected, six were correctly identified with the Ames II assay by all laboratories, one compound was judged positive by five of six investigators and one by four of six laboratories. All seven non-mutagenic samples were consistently negative in the Ames II assay. Of the four chemicals that gave inconsistent results in the traditional Ames test, three were uniformly classified as either positive or negative in the present study, whereas one compound gave equivocal results. A comparison of the test outcome of the different investigators resulted in an inter-laboratory consistency of 89.5%. Owing to the high concordance between the two test systems, and the low inter-laboratory variability in the Ames II assay results, the Ames II is an effective screening alternative to the standard Ames test, requiring less test material and labor.
Assuntos
Cooperação Internacional , Testes de Mutagenicidade/normas , Mutagênicos/toxicidade , Salmonella typhimurium/genéticaRESUMO
Head lettuce plantlets (Lactuca sativa L. var. capitata) were potted, treated with vinclozolin at the six-leaf stage according to application standards and allowed to dry for 24 h. The potted plantlets were then placed in either growth chambers with controlled temperature (20 and 25 degrees C, respectively) or in a greenhouse (approximately 12 degrees C), together with untreated spinach (Spinacia oleracea L.) and standardized grass cultures (Lolium multiflorum Lam. ssp.) While the treated lettuce pots remained in the respective growing compartments until the end of the experiments, spinach and grass were exposed to the compartment air for 24 h and their shoot material was analyzed for vinclozolin by GC-ECD and GC-high resolution mass spectrometry. Exposure and analysis of untreated spinach and grass were carried out at two- or three-day intervals during the course of the experiments. Also, air samples were taken from the compartments at intervals and analyzed for vinclozolin. Maximum vinclozolin concentration in the growth chamber air was about 330 ng m(-3) while vinclozolin contamination of the untreated plants ranged from 50 to 200 microg kg(-1) FW (fresh weight). In the greenhouse atmospheric vinclozolin concentration reached approximately 15 ngm(-3) and maximum contamination of spinach and grass were 30-40 microg kg(-1) FW. Our data clearly show that unintended contamination of plants growing in the vicinity of vinclozolin-treated plants can occur even if the fungicide layer is completely dry. Implications for safety testing and food plants are discussed.
Assuntos
Poluentes Atmosféricos/análise , Fungicidas Industriais/química , Oxazóis/química , Cromatografia Gasosa , Monitoramento Ambiental , Contaminação de Alimentos , Fungicidas Industriais/análise , Lactuca , Lolium , Oxazóis/análise , Segurança , Spinacia oleracea , VolatilizaçãoRESUMO
BACKGROUND: Diffuse lamellar keratitis (DLK) is a sterile inflammation after lamellar corneal surgery. A clinical staging for DLK was recently set up. In this observational case series, the clinical and confocal microscopic findings of stages 1-3 are reported. METHODS: Six eyes of six patients (three eyes with DLK stage 1, two eyes with DLK stage 2, and one eye with DLK stage 3) were examined by slit lamp biomicroscopy and confocal microscopy. RESULTS: In all cases, confocal microscopy showed an infiltration of inflammatory cells into the anterior stroma and the flap interface. The number of cells varied between the eyes with DLK stage 1, and both stage 2 corneas had dense infiltrates. In the eye with stage 3 DLK, an aggregation of decayed cells, most likely granulocytes, was noticed clinically and by confocal microscopy. CONCLUSIONS: The DLK stages represent different clinical intensities of interface inflammation after LASIK. While stages 1 and 2 have a similar confocal microscopic appearance, stage 3 is a result of aggregation of a high amount of inflammatory cells.
Assuntos
Ceratite/etiologia , Ceratomileuse Assistida por Excimer Laser In Situ/efeitos adversos , Microscopia Confocal , Adulto , Feminino , Humanos , Ceratite/diagnóstico , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Acuidade VisualRESUMO
BACKGROUND: A prospective, randomized study was performed to evaluate intra-individually the biocompatibility of foldable, highly refractive silicone and hydrophobic acrylic intraocular lenses (IOL). MATERIALS AND METHODS: We studied 35 patients who underwent phacoemulsification using a self-sealing tunnel incision. In a randomized fashion one eye received a 6-mm optic IOL made of high-refractive index silicone (Allergan SI40NB) and the other eye a hydrophobic acrylic 6-mm optic IOL (Alcon AcrySof MA60BM). All patients were examined 7 days, 1-3 and 6 months, and 1 year postoperatively. RESULTS: The mean best-corrected visual acuity (BCVA) was 0.9 +/- 0.12 vs. 0.89 +/- 0.13 (SI40NB vs. MA60BM) after 1-3 months. One-year postoperatively BCVA was still 0.9 +/- 0.12 vs. 0.87 +/- 0.14. The flare values (photon counts/ms) increased slightly 7 days after surgery (14.2 +/- 8.68 vs. 15.49 +/- 7.2, n.s.). Three months after surgery these values were again in the normal range. The mean IOL decentration was 0.29 +/- 0.14 vs. 0.3 +/- 0.15 mm 1 year postoperatively. Scheimpflug slit photography showed 40% of MA60BM IOLs to have "glistenings." No significant difference regarding posterior capsular opacification was found. CONCLUSION: One year after implantation of foldable, highly refractive silicone and hydrophobic acrylic IOLs using a self-sealing tunnel incision and phacoemulsification, no significant functional or morphological differences between the two IOL types were observed.
Assuntos
Acrilatos , Materiais Biocompatíveis , Lentes Intraoculares , Silicones , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Complicações Pós-Operatórias/etiologia , Estudos ProspectivosRESUMO
PURPOSE: The results of photorefractive/photoastigmatic refractive keratectomy (PRK/PARK) were compared between two patient groups treated consecutively with either broad-beam or scanning-spot technology. PATIENTS AND METHODS: PRK/PARK was performed with a broad-beam excimer laser VISX 20/20 in 46 eyes and with the scanning-spot laser system Keracor 217 in 49 eyes. Preoperative spherical equivalent (subjective manifest refraction) was < or =-6.0 diopter in both groups. Safety, efficacy, predictability, stability, and complications were investigated after 1,4 and 12, months postoperatively. RESULTS: In the broad-beam laser group no eye lost two or more lines of best-corrected visual acuity;in the scanning-spot laser group one eye lost two lines 12 months postoperatively. Efficacy, predictability, and stability were comparable between the two groups. CONCLUSIONS: Both the broad-beam and the scanning-spot laser provided good results after PRK/PARK for low myopia and myopic astigmatism. This study found no fundamental differences between the two laser systems.
Assuntos
Astigmatismo/cirurgia , Miopia/cirurgia , Ceratectomia Fotorrefrativa/instrumentação , Adulto , Feminino , Seguimentos , Humanos , Lasers de Excimer , Masculino , Pessoa de Meia-Idade , Refração Ocular , Resultado do TratamentoRESUMO
PURPOSE: Recently laser-in-situ-keratomileusis (LASIK) has been increasingly used to correct refractive errors. The purpose of this investigation was to evaluate the safety, efficacy, predictability, stability and complications using the scanning spot excimer LASIK technology. PATIENTS AND METHODS: The results of 100 consecutive LASIK operations carried out between 2/1998 and 2/1999 on 60 patients (mean age 37 years, range 20-55 years) have been evaluated. The Hansatome microkeratome with a superior hinge (flap diameter: 9.5 mm) and a scanning spot excimer laser (Technolas C-Lasik 217) were used in all cases. The mean spherical equivalent of the subjective manifest refraction was -6.96 +/- 2.87 diopters (D), the mean sphere was -6.47 +/- 2.71 D and the mean astigmatism was -0.98 +/- 0.94 D. In 6% of the eyes preoperative visual acuity was not better than 20/40. Examinations were performed preoperatively, after 1 and 7 days, after 1,4 and 12 months. Safety, efficacy, predictability, stability and complications were calculated using the datagraph software (version 1.11). RESULTS: All 100 eyes were examined after 1 day and 1 week, 96 after 1 month, 95 after 4 months and 92 after 1 year. Following 1 year none of the eyes lost 2 or more lines of best corrected visual acuity, 99% were within +/- 1 line and 1% gained 2 lines (safety index 1.03). In 92% of all eyes an uncorrected visual acuity of > or = 0.5 was reached, in 77% > or = 0.8 and in 51% > or = 1.0 (efficacy index 0.89). For 60 eyes (65.21%) a refractive correction of +/- 0.5 D was necessary, for 82 eyes (89.13%) +/- 1.0 D and for 91 eyes (98.91%) +/- 2.0 D. The mean spherical equivalent after 1 year was -0.15 +/- 1.31 D. Between 1 and 12 months a mean regression of -0.14 D occurred. On the request of the patients, 5 eyes were retreated during the study period for under- or over-correction. Complications due to the microkeratome did not occur. Corneal infections were not observed, a diffuse lamellar keratitis (DLK) was seen in 12 cases, but all cases healed with no loss of visual acuity. In 7 eyes a slight decentration of the ablation was observed using corneal topography, which in one case caused an increase in glare sensitivity. CONCLUSIONS: LASIK with superior hinge and scanning spot excimer photoablation is suitable for the correction of myopia (up to a maximum of -12 D) and for myopic astigmatism (up to a maximum of -5 D). The refractive results showed a high stability during the 12-month study period but there is still room for improvement of the predictability.
Assuntos
Astigmatismo/cirurgia , Ceratomileuse Assistida por Excimer Laser In Situ , Miopia/cirurgia , Adulto , Fatores Etários , Seguimentos , Humanos , Complicações Intraoperatórias , Ceratomileuse Assistida por Excimer Laser In Situ/efeitos adversos , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Prospectivos , Fatores de TempoRESUMO
BACKGROUND: High myopia phakic intraocular lenses (IOL) have become an established means of surgical correction for high ametropia. Scheimpflug photography is one of the methods which are frequently applied for postoperative examination of the implants. MATERIAL AND METHODS: Results from published studies employing Scheimpflug photography for examination of anterior chamber angle-fixated, iris-fixated and sulcus-fixated phakic IOLs were evaluated. RESULTS: In several published studies Scheimpflug photography was used to examine the position of the implant and opacification of the crystalline lens. The results provided valuable evidence for the improvement of phakic IOL design. CONCLUSION: Scheimpflug photography offers an easy to use, rapid non-contact examination of phakic IOLs.