can be used (C) CQ415 How do we treat atrophic vaginitis? Answer

can be used. (C) CQ415 How do we treat atrophic vaginitis? Answer 1 Prescribe vaginal estriol tablet for symptomatic cases. (B) CQ416 How do we prevent postmenopausal osteoporosis, and what are the strategies for early detection and treatment? Answer 1 Advise the patients to exercise regularly and have adequate calcium intake to prevent osteoporosis. (B) CQ417 How should we treat mood-related disorders and non-specific medical complaints? Answer 1 Prescribe hormone replacement therapy for depressive mood and symptoms associated with menopause. (B) CQ418 How do we diagnose and manage premenstrual syndrome? Answer 1 The diagnosis

of premenstrual syndrome is made based on the period of onset, physical and psychological symptoms. (A) Diagnostic guidelines set up by the American College of Obstetrics and Gynecology are used. this website (C) CQ419 How do we diagnose urinary incontinence? Answer 1 The Akt inhibitor type of urinary incontinence is diagnosed by patient interview. (B) CQ420 How do we treat urinary incontinence? Answer 1 Perform pelvic floor muscle exercises as a behavioral therapy for stress incontinence.

(B) CQ421 How do we manage overactive bladder in an outpatient setting? Answer 1 Diagnose overactive bladder by asking the questions in the Overactive Bladder Symptom Score (OABSS). (B) CQ422 How do we manage pelvic organ prolapse (POP) in an outpatient setting? Answer 1 Start initial treatment for pelvic organ prolapse when the patient complains of discomfort from symptoms, such as sagging, vaginal bulging etc. (B) The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work. “
“The ‘Clinical Guidelines for Obstetrical Practice, 2011 edition’ were revised and published as a 2014 edition (in Japanese) in April 2014 by the Japan

Society of Obstetrics and Gynecology and the Japan Association of Obstetricians and Gynecologists. The aims of this publication include the determination of current standard care practices for pregnant women in Japan, the widespread use of standard care practices, the enhancement of safety in obstetrical practice, the reduction of burdens associated with medico-legal and medico-economical heptaminol problems, and a better understanding between pregnant women and maternity-service providers. The number of Clinical Questions and Answers items increased from 87 in the 2011 edition to 104 in the 2014 edition. The Japanese 2014 version included a Discussion, a List of References, and some Tables and Figures following the Answers to the 104 Clinical Questions; these additional sections covered common problems and questions encountered in obstetrical practice, helping Japanese readers to achieve a comprehensive understanding.

Recently, Skogedal et al2 demonstrated that caries can be succes

Recently, Skogedal et al.2 demonstrated that caries can be successfully prevented in patients with RDEB

by continuous follow-up aimed at dietary advice, oral hygiene habits, frequent professional cleaning, and fluoride therapy. 1)  To prevent and treat pain and infection. This is important considering that patients with oral pain will reduce their nutritional intake. The clinic must be of easy access for patients using wheelchairs and walking frames. Allow patients to accommodate on their own giving them enough time. Do not try to assist them if you are not aware of the areas where they have wounds. If the patient has to travel a long distance to attend the specialist dentist in the EB unit, a shared care Ion Channel Ligand Library screening approach can be arranged with a local dentist, who can provide more regular preventative care. Access to dental care can be a challenge for some patients. Even though in most developed countries it is guaranteed, it is still a privilege for many patients around the world. There is a lack of knowledge about the disease in the dental profession9 and other healthcare professionals. Dental care can be complicated by the fears of both the patient and the dentist10. Allow yourself plenty of time. Even the most simple procedures, such as an oral exam, takes longer because of the limited access, discomfort, or fear of developing blisters secondary to soft tissue manipulation. Members

of the multidisciplinary team should refer patients to the dentist before oral problems Nutlin-3a ic50 present, as early referral and close follow-up are the key to keeping patients as healthy as possible from the oral point of view (Image 1). Patients with EB should be Astemizole referred to the dentist for the first consultation at the age of 3–6 months. The first consultation should be aimed at: (a)  Education of the parents and caregivers: counselling on diet (including sugar-free medications), oral hygiene routines, fluorides, technical aids, and oral manifestations of EB. This preventative advice should be provided even before the teeth erupt (Image 2). Patients with EB should be referred to a dentist as early

as possible to identify any feature related to EB that needs special attention, for example, generalized enamel hypoplasia5,10-13. This enables dentists to start preventive programmes and reduces the risk of developing dental diseases14. Many case reports have shown that patients visit the dentist only when they already have several carious lesions or pain7,11,15,16. Although oral bullae, ulcers, and erosions are the most common oral feature of EB, there is only one published study of a therapy for these oral lesions. Marini et al.17 found that sucralfate suspension reduced the development and duration of oral mucosal blisters and ulcers, reduced the associated oral pain, and improved plaque and gingival inflammation indices17. Oral Hygiene.

Previous studies with nonselective blockers suggested that ether-

Previous studies with nonselective blockers suggested that ether-à-go-go-related gene (ERG) K+ channels are functionally significant. Here, electrophysiology with selective chemical and peptide ERG channel blockers (E-4031 and rBeKm-1) and computational methods were used to define the contribution made by ERG channels to the firing properties of midbrain dopamine neurons in vivo and in vitro. Selective ERG channel blockade increased the frequency

of spontaneous activity as well as the response to depolarizing current pulses without selleckchem altering spike frequency adaptation. ERG channel block also accelerated entry into depolarization inactivation during bursts elicited by virtual NMDA receptors generated with the dynamic clamp, and significantly prolonged the duration of the sustained depolarization inactivation that followed pharmacologically evoked bursts. In vivo, somatic ERG blockade was associated

with an increase in bursting activity attributed to a reduction in doublet firing. Taken together, these results show that dopamine neuron ERG K+ channels play a prominent Selleckchem Atezolizumab role in limiting excitability and in minimizing depolarization inactivation. As the therapeutic actions of antipsychotic drugs are associated with depolarization inactivation of dopamine neurons and blockade of cardiac ERG channels is a prominent side effect of these drugs, ERG channels in the central nervous system may represent a novel target for antipsychotic drug development.


“Orexin (hypocretin) and melanin-concentrating hormone (MCH) neurons are unique to the lateral hypothalamic (LH) region, but project throughout the brain. These cell groups have been implicated in a variety of functions, including reward learning, responses to stimulants, and the modulation of attention, arousal and the sleep/wakefulness cycle. Here, we examined roles for LH in two aspects of Carbohydrate attention in associative learning shown previously to depend on intact function in major targets of orexin and MCH neurons. In experiments 1 and 2, unilateral orexin-saporin lesions of LH impaired the acquisition of conditioned orienting responses (ORs) and bilaterally suppressed FOS expression in the amygdala central nucleus (CeA) normally observed in response to food cues that provoke conditioned ORs. Those cues also induced greater FOS expression than control cues in LH orexin neurons, but not in MCH neurons. In experiment 3, unilateral orexin-saporin lesions of LH eliminated the cue associability enhancements normally produced by the surprising omission of an expected event. The magnitude of that impairment was positively correlated with the amount of LH damage and with the loss of orexin neurons in particular, but not with the loss of MCH neurons.

5 g/dL), acidemia, and repeated generalized convulsions, requirin

5 g/dL), acidemia, and repeated generalized convulsions, requiring critical care attention. Although comorbidity was present in this case, P. vivax may produce severe malaria mainly due to severe anemia, in a rate similar to the one we show in our study.31 Increasing check details evidence that P. vivax is not always a benign parasite, which can cause severe malaria,

even death,38–42 coupled with the emergence of drug resistant strains could pose a serious threat to global control of malaria. The mortality rate was similar to those referred in other studies.1,2,8,9,12,25 Six of the seven deaths occurred in foreign sailors who arrived on the island through the harbor. Severe and complicated malaria among them was highly present. Unfortunately, this group of patients has been poorly characterized in former studies.8 There are different reasons that could help to explain a higher lethality in these individuals: difficulties for health attention out at sea, with consequent diagnosis and treatment delay, and language barriers that impede detailed anamnesis. In our opinion, burden of malaria in sailors arriving in Gran Canaria is higher than we show here. An unknown number of malaria cases are treated in private sanitary centers, which do not usually declare the infection, even though malaria is a

notifiable disease to health authorities in Spain. African immigration to the Canary Islands is notably increasing. Often, Sotrastaurin order the Canary Islands are the first stop on their way to other European countries. During the last years, some of these immigrants are arriving crowded on boats called “pateras” or “cayucos.” Malaria diagnosis has not been a frequent finding in these people when they arrived;

however, we described seven cases, six of them in 2006. Malaria in travelers is a preventable disease, if adequate measures are taken. Adherence to chemoprophylaxis in travelers to endemic countries here described is similar learn more to that referred to by other authors,24 but there is also notable variability according to the different studies.2,18,23,24 Furthermore, it is possible that many of the cases ignored the need to have chemoprophylaxis during the journey. None of the patients who traveled to endemic regions to VFR were declared to have had any chemoprophylaxis. This fact heightens the necessity to encourage the use of preventive measures and chemoprophylaxis in VFR.29,36 We hope that travel health consulting at hospitals in Gran Canaria Island and availability of better antimalarial drugs for chemoprophylaxis will help to improve chemoprophylaxis adherence in travelers. Data on patients diagnosed from 2007 has not been made available for detailed investigation. To follow the trends and evaluate preventable measures that could be taken, notification of cases to the public health system is essential. The authors state that they have no conflicts of interest.

5 g/dL), acidemia, and repeated generalized convulsions, requirin

5 g/dL), acidemia, and repeated generalized convulsions, requiring critical care attention. Although comorbidity was present in this case, P. vivax may produce severe malaria mainly due to severe anemia, in a rate similar to the one we show in our study.31 Increasing UK-371804 evidence that P. vivax is not always a benign parasite, which can cause severe malaria,

even death,38–42 coupled with the emergence of drug resistant strains could pose a serious threat to global control of malaria. The mortality rate was similar to those referred in other studies.1,2,8,9,12,25 Six of the seven deaths occurred in foreign sailors who arrived on the island through the harbor. Severe and complicated malaria among them was highly present. Unfortunately, this group of patients has been poorly characterized in former studies.8 There are different reasons that could help to explain a higher lethality in these individuals: difficulties for health attention out at sea, with consequent diagnosis and treatment delay, and language barriers that impede detailed anamnesis. In our opinion, burden of malaria in sailors arriving in Gran Canaria is higher than we show here. An unknown number of malaria cases are treated in private sanitary centers, which do not usually declare the infection, even though malaria is a

notifiable disease to health authorities in Spain. African immigration to the Canary Islands is notably increasing. Often, MS-275 datasheet the Canary Islands are the first stop on their way to other European countries. During the last years, some of these immigrants are arriving crowded on boats called “pateras” or “cayucos.” Malaria diagnosis has not been a frequent finding in these people when they arrived;

however, we described seven cases, six of them in 2006. Malaria in travelers is a preventable disease, if adequate measures are taken. Adherence to chemoprophylaxis in travelers to endemic countries here described is similar these to that referred to by other authors,24 but there is also notable variability according to the different studies.2,18,23,24 Furthermore, it is possible that many of the cases ignored the need to have chemoprophylaxis during the journey. None of the patients who traveled to endemic regions to VFR were declared to have had any chemoprophylaxis. This fact heightens the necessity to encourage the use of preventive measures and chemoprophylaxis in VFR.29,36 We hope that travel health consulting at hospitals in Gran Canaria Island and availability of better antimalarial drugs for chemoprophylaxis will help to improve chemoprophylaxis adherence in travelers. Data on patients diagnosed from 2007 has not been made available for detailed investigation. To follow the trends and evaluate preventable measures that could be taken, notification of cases to the public health system is essential. The authors state that they have no conflicts of interest.

However, approximately one-third (317%; CI 260–396%) did not e

However, approximately one-third (31.7%; CI 26.0–39.6%) did not expect pharmacists to be available for consultation during rounds. Physicians’ experiences with pharmacists were

less favourable; whereas 77% (CI 70.2–81.5%) of the physicians agreed that pharmacists were always a reliable source of information, only 11.5% (CI 6.2–16.4%) agreed that pharmacists appeared to be willing to take responsibility for solving any drug-related problems. The present study showed that hospital physicians are more likely to accept traditional pharmacy services than newer clinical services for hospital-based pharmacists in the West Bank, Palestine. Pharmacists should therefore interact more positively and more frequently with physicians. This will close the gap between the

physicians’ commonly held perceptions of what they expect pharmacists to do and EPZ015666 supplier what pharmacists can actually do, and gain support for an extended role of hospital-based pharmacists in future patient therapy management. “
“Feasibility of pharmacist delivered motivational interviewing (MI) to methadone patients has been demonstrated, but its efficacy is untested. This study aimed to determine whether pharmacists trained in MI techniques can improve methadone outcomes. A cluster randomised controlled trial by pharmacy, with community pharmacies across Scotland providing supervised methadone to >10 daily patients, aged >18 years, started on methadone <24 months. Pharmacies were randomised to intervention or control. Intervention pharmacists received MI training and a resource pack. Crizotinib Control pharmacists continued with normal practice. Primary outcome was illicit heroin use. Secondary outcomes were treatment retention, substance use, injecting behaviour, psychological/physical health, treatment satisfaction and patient feedback. Data were collected via structured interviews at baseline

and 6 months. Seventy-six pharmacies recruited 542 patients (295 intervention, 247 control), mean age 32 years; 64% male; 91% unemployed; mean treatment length 9 months. No significant difference in outcomes between groups for illicit heroin use (32.4% cf. 31.4%), although within-groups use reduced (P < 0.001); treatment retention was Carbohydrate higher in the intervention group but not significantly (88% cf. 81%; P = 0.34); no significant difference between groups in treatment satisfaction, although this improved significantly in intervention (P < 0.05). More intervention than control patients said pharmacists had ‘spoken more,’ which approached statistical significance (P = 0.06), and more intervention patients found this useful (P < 0.05). Limited intervention delivery may have reduced study power. The intervention did not significantly reduce heroin use, but there are indications of positive benefits from increased communication and treatment satisfaction. Methadone is the most commonly prescribed opiate replacement treatment in Scotland.

In keeping with BHIVA standards for HIV clinical care, patients n

In keeping with BHIVA standards for HIV clinical care, patients needing inpatient care for HIV-related disease should ordinarily be admitted to an HIV centre or the relevant tertiary service in liaison with the HIV centre. “
“The aim of the study was to identify and describe the characteristics of persons born in the UK who acquire HIV infection abroad. Analyses using case reports and follow-up data from the national HIV database held at the Health Protection Agency were performed. Fifteen per cent Sotrastaurin order (2066 of 13 891) of UK-born adults diagnosed in England, Wales and Northern

Ireland between 2002 and 2010 acquired HIV infection abroad. Thailand (534), the USA (117) and South Africa (108) were the countries most commonly reported. As compared

with UK-born adults acquiring HIV infection in the UK, those acquiring HIV infection abroad were significantly (P < 0.01) more likely to have acquired it heterosexually (70% vs. 22%, respectively), to be of older age at diagnosis (median 42 years vs. 36 years, respectively), and to have reported sex with a commercial sex worker (5.6% vs. 1%, respectively). Among men infected in Thailand, 11% reported sex with a commercial sex worker. A substantial number of ABT-263 cell line UK-born adults are acquiring HIV infection in countries with generalized HIV epidemics, and in common holiday destinations. Of particular concern is the high proportion of men infected reporting sex with a commercial sex worker. We recommend HIV prevention and testing efforts be extended to include travellers abroad, and that sexual health advice be provided routinely in travel health consultations and in occupational health travel advice packs, particularly to those travelling to high HIV prevalence areas and destinations for sex tourism. Safer sex messages should include an awareness of the potential detrimental health and social impacts of the sex industry. In 2010, UK residents made an estimated 55 million visits abroad [1]. Some of these residents will have had sex, often unprotected, with people they met while abroad Protein kinase N1 [2, 3]. Persons who have new sexual partners abroad [3], and/or engage in high-risk sexual behaviours while abroad [4], are likely to have higher risk

sexual lifestyles more generally [3, 4], and an above average number of sexual partners at home [5]. Furthermore, persons travelling specifically for sex are more likely to engage in unprotected sex and have multiple partnerships while abroad than they normally would at home [6]. Increased sexual mixing while abroad brings with it an associated risk of acquiring a sexually transmitted infection, including HIV infection [7]. This risk is likely to be highest among persons engaging in unprotected sex with local partners in countries where the prevalence of sexually transmitted infections is elevated [8], particularly among ‘sex tourists’ (persons travelling for commercial sex) [7], the majority of whom are men [9] and are of older age [7, 9, 10].

The cell densities were adjusted to 10 units of optical density

The cell densities were adjusted to 1.0 units of optical density at 620 nm (OD620 nm) and used to determine the CSH by the CRB and SAT assays. The curli-producing E. coli

MC4 100 strain, grown on blood agar at 37 °C for 24 h, was used as a reference strain for CSH using CRB assay. Y-27632 purchase L. crispatus LMG12005a Pregnant woman, vagina L. crispatus LMG 12003 L. crispatus LMG 18199 L. gasseri LMG 9203 Unknown human source L. gasseri LMG 13134 L. gasseri LMG 18177 L. johnsonii LMG 18175 Human unknown source L. rhamnosus LMG 18243a (LGG) L. rhamnosus LMG 23534 Healthy human (adult), faeces L. gasseri CCUG 44034 L. johnsonii CCUG 44519 L. reuteri DSM 20016 L. reuteri DSM 17983 Healthy human (adult), faeces E. coli MC4 100 30 °C Lineage of E. coli K-12 E. coli MC4 100 37 °C The CSH was also determined by SAT as previously described (Lindahl et al., 1981). A 10-μL aliquot of a fresh cell suspension in PBS was mixed on a glass-slide with 10 μL of ammonium CAL-101 molecular weight sulphate (pH 6.8) of various molarities (0.02, 0.2, 0.8, 1.6, 3.2 and 4 M). The formation of cell aggregates was observed

after 1 min by visual reading. The molarity at which the cells caused aggregation was recorded as a positive result. CR binding was performed using CR-MRS agar (MRS with 0.01% CR, which was autoclaved separately). Washed agar- and broth-cultured cells were plated on CR-MRS agar and all plates were incubated at 37 °C for 72 h. CR-bound cells produced intense red colonies and non-CRB cells produced

colourless colonies on CR-MRS agar (Qadri et al., 1988). A quantitative CRB assay was performed as described by Qadri et al. (1988) with slight modifications for the broth- and agar-cultured cells grown at 30 and 37 °C. 6-phosphogluconolactonase Briefly, washed cell suspensions were adjusted to 1.0 units of OD620 nm and incubated with 100 μg mL−1 of CR in PBS in a total assay volume of 1 mL and incubated at 37 °C for 10 min and centrifuged at 9000 g for 30 min. The amount of dye remaining in the supernatant was quantified by measuring absorbance at OD480 nm. The concentration of CR in the supernatants was determined using the CR standard curve. From these data, CR bound by each strain was calculated using the following formula: Results were expressed as per cent CR bound. A high percentage of CR binding implies a high CSH of the strains. Escherichia coli MC4 100 was used as the reference strain for CRB assay. The effect of pH (3–8), ionic strength of the PBS (with/without 0.85% NaCl) and cholesterol (100 μg mL−1) of CRB of lactobacilli was also determined. The effect of proteinase K (100 μg mL−1, pH 8) and pronase E (100 μg mL−1, pH 8) treatment of the cells on CRB was determined by incubating 1.0 units of OD620 nm of the cell suspension with the above enzymes at 37 °C for 1 h. CRB was then determined as mentioned above after inactivating the proteolytic enzymes with 1 mM PMSF. Exponentially grown lactobacilli cells (0.

faecalis V583 (Table 1) They also show similarity to similar gen

faecalis V583 (Table 1). They also show similarity to similar genes of other phages, such as the holin of Lactococcus phage φAM2 and the endolysins of Streptococcus phage φCP-L9, Lactococcus phages ul and TP901-1, and Leuconostoc phage 10MC (Table 1). Following phage assembly, holin proteins assemble to form pores in the cellular membrane, allowing the digestive enzymes (presumably PHIEF11_0026, PHIEF11_0028, and PHIEF11_0030) access to the surrounding peptidoglycan

(Young et al., 2000). The PHIEF11_0027 protein contains Seliciclib nmr a C-terminal domain that is homologous with a family of phage proteins that are autolysin regulatory proteins (ArpU). These transcriptional regulators are believed to control the expression of the lysin genes, which, in the φEf11 genome, surround PHIEF11_0027. The amidase (PHIEF11_0028) belongs to a peptidase family of (zinc) metallo endopeptidases that lyse bacterial cell wall peptidoglycans at gly–gly linkages. Similar peptidases are known to lyse the cell walls of other bacteria as a mechanism of ecological antagonism. The deduced PHIEF11_0028 gene product shows identity to the amidases of numerous other phages including

E. faecalis phage φEF24C, Streptococcus agalactiae prophage Lambda SA1, and S. pyogenes phage 315.3 (Table 1). The PHIEF11_0029 protein has Ipilimumab order eight predicted transmembrane helix motifs along its length. In addition, it shows similarity to a membrane protein of Lactococcus lactis ssp. cremoris MG1363 (Table Thymidine kinase 1) and a hypothetical protein of L. casei 334, which in turn shows similarity to membrane proteins of E. faecalis OG2RF and TX0204 (NCBI accessions ZP_03056680 and ZP_0394962, respectively). Taken together, this evidence suggests that PHIEF11_0029 codes for a membrane protein. Because holin proteins function through disruption

of the host cell membrane, it is possible that as a membrane protein, the PHIEF11_0029 product contributes to this action. PHIEF11_0030 contains a LysM domain detected in chromosomal locus EF2795 of E. faecalis V583 (Table 1). The LysM domain is found in a variety of enzymes involved in bacterial cell wall degradation, and may have a general peptidoglycan-binding function. Consequently, the product of PHIEF11_0030 is also likely to be involved in host cell lysis. This arrangement of lysis-related genes is unusual in several aspects. First, there appears to be more genes concerned with host cell lysis in the φEf11 genome than is found in most other bacteriophages. Typically, there is one holin gene and one lysin gene present in each phage genome. Here, the φEf11 genome appears to contain at least four (and perhaps five) genes that code for proteins that participate in host cell lysis.

These indexes were calculated as follows: alerting–no cue minus d

These indexes were calculated as follows: alerting–no cue minus double cue; orienting–previous center cue minus previous spatial cue; executive (conflict)–incompatible targets minus targets. We used statistica 11 (StatSoft, Tulsa, USA) and Prism 6 (GraphPad, La Jolla, USA) software for data analysis. First, we ran goodness-of-fit analysis (Kolmogorov–Smirnov test for normality of data distribution). We used repeated measures analyses of variance (anovas), followed by Tukey Honestly Significant Difference (HSD) post hoc tests. In the analysis of the letter recall part of the ABT, the between-subjects

factor was group (PD vs. controls) and the within-subjects factors were time (baseline vs. follow-up) and stimulus type (target vs. distractor letters). In the analysis of the scene recognition part of the ABT, the between-subjects factor was group (PD vs. controls), Lumacaftor supplier and the within-subjects factors were time (baseline vs. follow-up) and stimulus type (scenes associated with targets, distractors and scenes alone). In the ANT, we ran separate anovas for mean response time and error rate, response time indexes, and error rate indexes with the group as the between-subjects factor and time as the within-subjects factor. The same anova design was used for the analysis of rating scales (HAM-D and BIS-11). In the replication sample, time was not a within-subjects factor because it was

a cross-sectional study. To explore the relationship between changes in ABT and rating BI 2536 molecular weight scales, we calculated Pearson’s product www.selleck.co.jp/products/erastin.html moment correlation coefficients, corrected for multiple comparisons with the Bonferroni method. Demographic parameters were compared with two-tailed t-tests and chi-square tests. The level of statistical significance was α < 0.05.

Table 1 depicts the clinical and demographic characteristics of the patients with PD and control individuals. One patient with PD had specific phobia. None of the other patients and controls exhibited DSM-IV Axis I disorders at baseline and follow-up. MIDI/SOGS revealed no impulse control disorders at baseline and follow-up. Patients with PD and control individuals did not differ in age, gender, education, IQ and socioeconomic status. Patients with PD scored higher than controls on the HAM-D scale at baseline but not at follow-up. Patients with PD and controls did not differ significantly in BIS-11 scores, although patients with PD achieved higher scores at follow-up relative to baseline (Table 1). Patients with PD and control volunteers displayed similar letter detection performances at baseline and follow-up (anova, P > 0.5). As expected, letter detection performance for targets was higher than that for distractors (P < 0.0001; Fig. 2). Figure 3 depicts the results from the scene recognition test. The anova revealed significant main effects of group (F1,49 = 7.0, P < 0.05, η2 = 0.