We have long known that GH release is stimulated by catecholaminergic mechanisms, among others. For almost 30 years now, different GH stimulation tests have been used to prove whether GH response in depressed patients differs from controls and subjects with other psychiatric diseases. Most revealed significant differences between patients with major depression and healthy subjects or patients with minor depression, using various specific substances to selleck Nutlin-3a challenge GH response. Patients with recurrent major depression exhibited a blunted GH Inhibitors,research,lifescience,medical response, which could be interpreted as cither decreased DA receptor sensitivity (challenge with apomorphine) or decreased α2-adrenoceptor sensitivity

(challenge with clonidine).80 It was further suggested that this blunted GH response to clonidine was Inhibitors,research,lifescience,medical a trait marker that persists in depressed patients following their recovery.81 -82 However,

as challenge with different α2-adrenoceptor-selective agents resulted in a normal GH response, an intrinsic abnormality in the GH system was also suggested as opposed to decreased a2-adrenoceptor sensitivity.83 Alterations in thyroid function have been Inhibitors,research,lifescience,medical repeatedly linked to depression and the administration of triiodothyronine (T3 ) seems to be an effective adjunctive treatment for many patients.84,85 The relationship between thyroid hormones and neurotransmitters have mainly focused on the noradrenergic and serotonergic selleckbio systems and it was shown that thyroid hormone application increases cortical serotonin release86 and may act as a cotransmitter to Inhibitors,research,lifescience,medical NE in the adrenergic nervous system.87 However, the exact mechanism of this interaction is not clear. Especially intriguing was the observation that 5-HT function was especially reduced in patients without hypothalamus-pituitary-thyroid

axis abnormalities, which suggests that mechanisms that are not serotonergic might be involved in the reduced secretion of thyroid-stimulating hormone (TSH).84 A further hint Inhibitors,research,lifescience,medical on the influence of hormones comes from the fact that the immediate postpartum period is a time of highly increased GSK-3 risk for the onset or relapse of depression.88 Several results underline the influence of estrogen and progesterone,89 thyroid hormones,90 or alterations in the HPA axis,91 but the direct mechanisms have not been clarified. In addition, recurrent depressive symptoms can be limited to the premenstrual period and more enduring depression is typically exacerbated premenstrually. These findings on possible disturbances in sex hormones could give an explanation for the increased incidence in women. Neuroimmune mediators The clinical course of depression is that of a variable disease with long periods of recovery between periods of depression in many patients, but it can also involve closely spaced episodes that finally lead to a severe and unremitting course.

It was rational to apply these techniques

to mild cognitive deficit, in order to characterize these states and identify predictors of progression to AD. Neuropathological studies have shown the hippocampus to be one of the earliest, affected structures in AD,71 and so it is a region of choice for neuroimaging studies. Although hippocampal atrophy, as measured by volumetric Inhibitors,research,lifescience,medical techniques is not entirely specific, it is now considered to be a hallmark of AD,72 and its absence in addition to minor or unilateral atrophy is believed to be strong evidence against the diagnosis. In mild cognitive deficit, several studies have shown lesser73-76 or similar77 hippocampal Inhibitors,research,lifescience,medical atrophy to that found in AD. Age transformation of combined hippocampal and amygdala volume increases the accuracy of classifying AD, MCI, and normal elderly subjects.78 MCI subjects

had hippocampal volume correlated with cognitive and performance measures79 and those who declined over time had also a greater annualized rate of hippocampal atrophy than nondeclincrs, close to that of AD patients.80 Atrophy of various regions at baseline, Inhibitors,research,lifescience,medical including hippocampus79, 81, 82 ERC,83-84 fusiform gyrus,85 caudal cingulate cortex,83 and medial temporal lobe,76 was found predictive of progression to AD. White matter lesions have been found to be associated with subjective cognitive decline,86 lowered attention and speed of mental processing,87 and progression to dementia.88 There Inhibitors,research,lifescience,medical is an agreement on the fact that established AD is characterized by altered cerebral blood flow (CBF) and metabolism in posterior parietal and temporal lobes as well as by, according to stage and neuropsychological Inhibitors,research,lifescience,medical profile, frontal cortex deficits, and hemispheric asymmetry.89 That functional imaging is able to detect selleckchem preclinical AD is suggested by positron emission tomography (PET) studies, which found regional cerebral glucose metabolism (rCMRGlu) alterations in nondemented subjects at risk of AD (ie, those carrying the apolipoprotein E type 4 allele [ ApoE ε4] and with familial

Cilengitide history of AD)90, 9190-91; those in the inferior parietal and posterior cingulate cortices correlated with later memory decline.92 Studies comparing CBF and rCMRGlu in normal and mildly impaired subjects found deficits in the latter, in various regions including bilateral parietal cortex,56 hippocampus,77 and posterior cingulate gyrus.93-95 Prediction of outcome was found for defects in parietal or temporoparietal cortex,56, 96 posterior cingulate gyrus,94, 95 and for temporoparietal asymmetry97 and lowered postcroanterior ratio89; others were predictive when combined with performance on specific cognitive tasks98, 99 and/or demographic selleck chem characteristics.99 Progress in functional imaging can come from activation studies.

Panel B shows another chronic HCV patient who had only a few scattered FGL2-positive cells (brown cells) in the explanted liver

and has not required any treatment for recurrent HCV infection. Figure 6. Increased expression of FGL2 in the explanted liver correlates with severity and recurrence of HCV infection. A: Chronic HCV patient with many FGL2-positive cells (brown cells) in the explant, who developed aggressive recurrent disease that did not respond … FGL2: MECHANISM OF ACTION Based upon the data collected to date, it has been shown that FGL2 is integral to both the innate and the adaptive Inhibitors,research,lifescience,medical immune responses. This is not surprising as FGL2 is a molecule that has been conserved through evolution from single-cell organisms such as the ameba to selleck kinase inhibitor higher primates. We propose a mechanistic model by which FGL2 exerts its immunoregulatory effects (Figure 7). Treg cells secrete FGL2, which then binds to the inhibitory FcγRIIB receptor expressed on DC. Binding of FGL2 to FcγRIIB down-regulates immune activation of DC as selleck indicated by inhibition of expression Inhibitors,research,lifescience,medical of the maturation markers CD80, CD86, and MHCII. This suppressive effect of FGL2 on DC was Inhibitors,research,lifescience,medical shown to be mediated through inhibition of NF-κB nuclear translocation.47 DC that are exposed to FGL2 would

be therefore less effective in inducing proliferation and effector function of helper and cytotoxic Inhibitors,research,lifescience,medical T lymphocytes. Suppression of helper T cell activation and DC maturation by FGL2 could lead indirectly to inhibition of T-dependent and T-independent B cell responses, respectively. As demonstrated

by our in vitro studies, FGL2 can also directly induce apoptosis in B cells upon binding to the inhibitory FcγRIIB receptor, which is known to be expressed on B cells. The indirect and direct suppressive activities of FGL2 result in inhibition of the immune response against the HCV, leading to viral persistence and chronic infection. Figure 7. A proposed Inhibitors,research,lifescience,medical model of FGL2 immunoregulatory activities. Treg production of FGL2 down-regulates adaptive immune responses through binding to the inhibitory Entinostat FcγRIIB receptor, which is expressed on antigen-presenting cells. The suppressive activities … CONCLUSIONS AND FUTURE DIRECTIONS HCV infection is a major world health problem and the leading cause of HCC worldwide. Disturbances in Treg cell function or number have now been shown to contribute to failure of clearance of HCV and the development of chronic hepatitis. FGL2 has been shown to be an important effector molecule of Treg cells and was demonstrated to play a key role in the pathogenesis of both experimental and human viral hepatitis. Measurement of levels of sFGL2 in plasma of patients appears to predict both the course of HCV disease and response to anti-viral therapy, and, as such, FGL2 as a biomarker may become an important diagnostic reagent in the management of HCV patients.

The c-fos upregulation pattern produced by http://www.selleckchem.com/products/Dasatinib.html quetiapine resembles

clozapine. Quetiapine blocks dopamine- and serotonin-induced animal behaviors in laboratory testing and fails to induce catalepsy at clinically relevant doses.50 Efficacy in chronic psychoses Quetiapine has a significantly greater antipsychotic action than placebo according to several controlled trials at doses of 150 to 750 mg/day.51 Moreover, it has actions equivalent to haloperidol and risperidone on positive and negative symptoms. Several Inhibitors,research,lifescience,medical studies also document a positive effect of quetiapine on cognitive dysfunction in schizophrenia, especially attention and working memory. This effect will need to be documented as a distinct action from the antipsychotic effects, and such studies are now under way. Quetiapine has been tested

in mania, but not in multisite controlled trials. Nonetheless, in open clinical use, quetiapine Inhibitors,research,lifescience,medical seems to have the usual antipsychotic action in mania as reported for other agents.52 Moreover, it is safe and apparently effective in adolescent mania.53 In the area of behavioral disruption/agitation in dementia, quetiapine requires Inhibitors,research,lifescience,medical further study with systematic evaluation. However, because other agents have been tested and found effective in the psychosis and agitation of the elderly with dementia, quetiapine has been similarly applied. Open results indicate Inhibitors,research,lifescience,medical that the drug is effective and well tolerated in elderly dementia and should be further and rigorously tested.54 Drug side effects and human pharmacokinetics Quetiapine has a benign side-effect profile. It fails to induce motor side effects in excess of placebo. No akathisia is apparent. Reported side effects include sedation, selleck inhibitor somnolence, and headache. Mild weight gain does occur, but at lower levels than with clozapine. The report of cataracts in animals developing during drug treatment have failed to show extension to humans, and hence no cataract risk

currently exists for humans and slit-lamp examinations are not necessary. The plasma Inhibitors,research,lifescience,medical half-life of quetiapine is approximately 6 h. The kinetics arc linear up to 600 mg. Drug clearance is reduced in the elderly, and so lower doses should be used in this population. Ziprasidone Dacomitinib Ziprasidone is a drug designed to have a high ratio of serotonin (5-HT2) to dopamine receptor affinity. In addition, it has some unique properties, one of which is to block serotonin and norepinephrine reuptake blockade; this is a rather potent, action on the reuptake proteins, though related advantages have not been adequately explored as yet. Its approval by the Food and Drug Administration (FDA) was delayed because the drug was shown to produce QTc prolongation, consistent with potential cardiac arrhythmias. Additional studies were required for ziprasidone to rule out added cardiac risk.

From the possible direct requirement for ATP in degradation of proteins in bacteria, it was not too unlikely to assume a similar direct mechanism in the degradation of cellular proteins in eukaryotes. Supporting this notion was the description of the cell-free proteolytic system in reticulocytes,28,29 a cell that lacks lysosomes, which indicates that energy is probably required directly for the proteolytic process, although here, too, the underlying mechanisms had remained enigmatic at the time. Yet, the description of the cell-free system paved the road Inhibitors,research,lifescience,medical for detailed selleck screening library dissection of the underlying mechanisms

involved. THE UBIQUITIN-PROTEASOME SYSTEM The cell-free proteolytic system from reticulocytes28,29 turned Inhibitors,research,lifescience,medical out to be an important and rich source for the purification and characterization of the enzymes that are involved in the ubiquitin-proteasome system. Initial fractionation of the crude reticulocyte cell extract on the anion exchange resin diethylaminoethyl cellulose yielded two fractions which were both required to reconstitute the energy-dependent proteolytic activity that is found in the crude extract: the unadsorbed, flow-through material was denoted fraction I, and the Inhibitors,research,lifescience,medical high-salt eluate of the adsorbed proteins was denoted fraction II (Table 1).38 This was an important

observation and a lesson for the future dissection of the system. For one it suggested that the system was not composed of a single “classical” protease that has evolved evolutionarily to acquire energy dependence (although such energy-dependent proteases, Inhibitors,research,lifescience,medical the mammalian 26S proteasome Inhibitors,research,lifescience,medical (see below) and the prokaryotic Lon gene product have been described later) but that it was made of at least

two components. This finding of a two-component, energy-dependent protease left the researchers with no paradigm to follow, and, in attempts to explain the finding, they suggested, for example, that the two fractions could represent an inhibited protease and its activator. Second, learning from this reconstitution experiment and the essential dependence between the two active components, we continued to reconstitute activity from resolved fractions whenever we encountered Drug_discovery a loss of activity along further purification steps. This biochemical “complementation” approach resulted in the discovery of additional enzymes of the system, all required to be present in the reaction mixture in order to catalyze the multistep http://www.selleckchem.com/products/Imatinib(STI571).html proteolysis of the target substrate. We chose first to purify the active component from fraction I. It was found to be a small, ~8.5 kDa, heat-stable protein that was designated ATP-dependent proteolysis factor 1 (APF-1).

[15,16]This may be due to the high rate of co-morbidities among this relatively elderly population. Palliative care provision should be according to need. Referral criteria and care pathways for this patient population need to take account of the complexities of prognostication and incidence of sudden death. [17] Palliative care planning that takes account of preferences and family support may reduce the number of unplanned admission among Inhibitors,research,lifescience,medical CHF patients (an internal audit [unpublished data] found that within the Hospital 22% of discharged heart failure patients

were readmitted within 30 days). Conclusion We propose referral criteria based on this data, mindful that referrals should not rely on end-of-life or terminal stages, as earlier intervention may optimise quality of life. Our proposed criteria are reproduced Inhibitors,research,lifescience,medical in Figure ​Figure22. Figure 2 Proposed referral criteria to palliative care for patients with Chronic Heart Failure. Our conservative measurement of the magnitude of need suggests that 4.4% of medical, vascular surgical and care of the elderly hospital inpatients have clinically diagnosed CHF and require palliative care, therefore adequate generalist and specialist skills are required within the acute setting. We propose the present criteria as a means

to Inhibitors,research,lifescience,medical ensure optimal quality of life for patients with CHF according to need rather than disease progression. Competing interests The authors declare that they have no competing interests. Authors’ contributions RH designed the study, secured funding, managed data collection/analysis and drafted the manuscript. TB neverless assisted design, secured funding, recruited subjects, Inhibitors,research,lifescience,medical assisted in interpretation and commented on drafts. FH was a selleck chem Palbociclib member of the project group, recruited patients, assisted in interpretation and commented on drafts. EC was a member of the project group, Inhibitors,research,lifescience,medical recruited patients, assisted in interpretation and commented on drafts. MK was a member of the project group, participated in interpretation and commented

on drafts. LS was a member of the project group, participated in interpretation and commented on drafts. IH was a member Drug_discovery of the project group, assisted design, assisted in interpretation and commented on drafts. All authors read and approved the final manuscript. Pre-publication history The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1472-684X/8/8/prepub Acknowledgements We are grateful to all the clinical staff that assisted us in conducting this study. We thank Guy’s & St Thomas’ Charitable Foundation for supporting this study with a service development grant.
GPs refer relatively few patients from these migrant groups to home care. They often find it difficult to assess the needs of these patients and their families.

05, 95% CI: 0.94 to 1.17; P=0.409). Table 2 Univariate demographic analysis of stroke mortality in Southern Iran Figure 1 Stratified analysis of age and sex associated with hospital mortality in patients with all types of stroke in Southern Iran Table 3 Covariates associated with hospital mortality based on multiple logistic regression analysis Trends of Mortality Over Time During the study period, the percentage of all types of stroke admissions Inhibitors,research,lifescience,medical to Nemazee Hospital decreased from 5% (95% CI: 4.9% to 5.1%) in 2001 to 4.5% (95% CI: 4.4% to 4.6%) in 2010 (P<0.001). However, the mortality rate among the hospitalized stroke patients (figure 2)

increased from 17.7% (95% CI: 16.7% to 18.7%) to 22.2% (95% CI: 21.6% to 23.4%) (P<0.001). This observation was made in both genders. Figure 2 Trend of overall Inhibitors,research,lifescience,medical mortality associated with all types of stroke in southern Iran between 2001 and 2010 Discussion Four important observations can be made from this analysis. First is the higher in-hospital mortality (20%) in comparison to developed countries.1 Our result chimes in with the reported case fatality rate from any stroke in central Iran

(24.6%).6 Furthermore, mortality rates in central and southern Iran are higher than those reported from the nearby states. Thirty-day case fatality rate for stroke in Arab Inhibitors,research,lifescience,medical middle-eastern and North African countries, where socioeconomic characteristics of the population are generally similar to Iran, falls between 10% and 17.3%.11 Several factors may have contributed to these results, including absence of health institution infrastructure such as specialized stroke units and underutilization of thrombolysis, both of which are known to positively Inhibitors,research,lifescience,medical influence outcomes in acute ischemic stroke.12 Moreover, stroke Inhibitors,research,lifescience,medical awareness is lacking among most of the Iranian general population.13

This can lead to the referral of stroke patients in late stages and increased mortality. Post-stroke care has been another issue which may have influenced outcome. Surveys of Iranian stroke survivors suggested AV-951 that the social, financial, and rehabilitative support for stroke was inadequate.14 Unlike developed countries, nursing facilities are not available in Iran; consequently, most stroke survivors are discharged home.6 The lack of organized rehabilitation care and the nonsystematic nature of family care can lead to lengthy recovery, probable readmissions, and perhaps higher mortality.15 The second observation from this analysis is noted differences in epidemiological characteristics of the stroke population in Iran. Our results suggest that a higher proportion of stroke occurs in young adults and children (14% of all stroke cases occurred in those younger than 45). These rates are comparable to those reported in the nearby countries such as Qatar (18%) and Libya (19.

6,9 In this regard, the population of COMPERA are considered to be at selleck product intermediate risk for worse outcome (WHO function class III in 75% of patients, mean 6 minutes walk test of 294 m; mean right atrial pressure of 8.8 mmHg and mean cardiac output index of 2.2 L/min/m2). Another point to be considered is how early anticoagulant therapy should be initiated in PAH patients. Introduction of anticoagulant therapy at an early stage of the disease may carry the possible advantage of slowing the progression of

luminal narrowing in PAH. However, this strategy may be associated with increased life-time exposure to anticoagulant therapy with increased bleeding risk. Alternatively, the use of anticoagulant therapy in patients in an advanced stage of the disease is expected to offer more protection, since these patients have low cardiopulmonary reserve that cannot withstand further arterial obstruction. Nevertheless, these patients may be also at increased bleeding risk related to hepatic and gastrointestinal

congestion. Risk of bleeding Bleeding in PAH patients is important for two reasons: it occurs in relatively higher rates compared with other diseases; and it may be associated with serious sequelae. In a retrospective single centre study, major bleeding ranged from 2.4 per 100 patient-years for chronic thromboembolic pulmonary hypertension and 5.4 per 100 patient-years for idiopathic PAH,

to 19 per 100 patient-years for PAH associated with connective tissue disease. 10 These rates are considered high compared to the reported rates of major bleeding in patients with atrial fibrillation receiving oral anticoagulants (2.0 per 100 patient-years). 11–12 The occurrence of an otherwise mild bleeding can be a catastrophic event in PAH patients. These patients are volume sensitive and acute blood loss may induce a fatal vicious circle of cardiopulmonary decompensation that leads to irreversible cardiogenic shock. Chronic blood loss will impair cardiopulmonary reserve and in severe anemia both tissue hypoxia and lactic acidosis contribute to increase pulmonary GSK-3 artery pressure. A number of factors should be considered to assess risk of bleeding in these patients. [4] Type of PAH: bleeding risk is increased in 3 groups of patients with PAH: (a) patients with connective tissue diseases, specially patients with scleroderma in whom the risk of gastrointestinal bleeding is increased due to the presence of luminal telangiectasia 13 ; (b) patients with PAH related to congenital heart disease and (c) patients with portopulmonary hypertension with increased risk for gastrointestinal bleeding owing to the presence of varices and abnormal coagulation profile.

3.2.2. Antibodies Immunowww.selleckchem.com/products/Rapamycin.html liposomes are liposomes coupled with antibodies which can be used to target cell-specific antigens. In the case of phagocyte targeting, the use of nonspecific and monoclonal antibodies can lead to liposome opsonisation and uptake by macrophages. In vivo liposomes interact with a wide variety of serum proteins including immunoglobulins, Inhibitors,research,lifescience,medical apolipoproteins, and complement proteins [42, 53] and may also activate complement leading to enhanced uptake by the MPS. However, protein interaction, complement activation, and opsonisation depend greatly on the physicochemical properties of the liposomes such as size, surface charge, cholesterol content, and

lipid composition [42, 53]. For example, some studies Inhibitors,research,lifescience,medical have reported complement activation to be greater with increasing liposome size [53] although observed activation has not always been of significance [24]. Immunoglobulins (Igs) are recognised by Fc receptors on the surface of phagocytic cells which are involved in phagocytosis as well as antigen presentation [21] (Figure 1). Interest has focused on the Inhibitors,research,lifescience,medical FcγRI receptor as a target which recognises IgG and is expressed by monocytes, macrophages,

activated neutrophils, and DCs [21]. Opsonisation is generally Fc-receptor mediated and has previously been shown to significantly enhance liposome uptake by monocytes and macrophages [32]. Opsonisation of non-immunoliposomes by immunoglobulins, Inhibitors,research,lifescience,medical for example, IgM and IgG, can also occur in vivo leading to enhanced uptake by macrophages [53]. Antibodies have been coupled to the surface of liposomes or distally via their Fc-region to liposome-attached PEG [31, 32]. Koning et al. showed increased Inhibitors,research,lifescience,medical Kupffer cell uptake with greater antibody surface density [31, 32]. Dendritic cells have been targeted with histidine-tagged antibody fragments attached to a novel chelator lipid, 3(nitrilotriacetic acid)-ditetradecylamine (NTA3-DTDA), incorporated into stealth liposomes via the DC receptors DEC-205 and CD11c [21]. 3.2.3.

Lectins Immune cells including alveolar macrophages, peritoneal macrophages, monocyte-derived dendritic cells, and Kupffer cells constitutively express high levels of the mannose receptor (MR). Macrophages and DCs can therefore be targeted via mannosylated nanoparticles (Figure 1). The MR is a C-type lectin 175-kD type I transmembrane protein [62, 63] whose ligands possess a terminal Batimastat nonreducing sugar such as mannose, glucose, N-acetylglucosamine, and fucose [64, 65]. These receptors play numerous roles in immune function including antigenic recognition, endocytosis, and antigen presentation, and are critically involved in homeostatic maintenance, inflammation and immune responses [66, 67]. Hence MR can identify and engulf pathogens such as Mycobacterium tuberculosis and Leishmania obviously donovani via surface sugar antigens.

Indeed, the final aim is the use of a single laser for all the micromachining operations.Figure 2.Schematic set-up for femtosecond laser micromachining. Multilevel irradiation followed by selective chemical etching is used to perform microcuts through the whole sample thickness. Direct waveguide writing can also be performed by using a lower intensity …The microcuts are fabricated by a two-step process: femtosecond laser irradiation followed by chemical etching in HF solution. For the irradiation the laser beam is focused inside the sample by a 0.3 numerical aperture (NA) 20�� microscope objective and the sample is translated along directions transversal to the beam path, with a speed of 1mm/s. The scanning of the laser focus produces exposed areas while the surrounding material remains unaltered. The scanning is repeated multi
Since 1988 China and Brazil have carried out a joint space program called China-Brazil Earth Resources Satellite (CBERS), specially dedicated to environmental data assessment. In the beginning, the CBERS program included two remote selleck Ganetespib sensing satellites (named CBERS-1 and CBERS-2) with three different sensors onboard: the Wide Field Imager (WFI), the High Resolution CCD Camera (CCD) and the Infrared Multispectral Scanner (IRMSS). CBERS-1 and CBERS-2 were launched in October, 1999 and November, 2003, respectively. The relative success of these two satellites in both engineering and application terms encouraged Chinese and Brazilian governments to expand the cooperation and to include five new satellites in the CBERS program: CBERS-2B (2007), CBERS-3 (2009), CBERS-4 (2011), CBERS-5 (2013) and CBERS-6 (2015).Considering the four years between the end of CBERS-2 lifetime (2005) and CBERS-3 launching (2009) it was decided to launch the CBERS-2B satellite in order to guarantee the continuity of several environmental monitoring programs in both countries.CBERS-2B payload is composed by the CCD, the WFI and by a new camera, named High Resolution Camera (HRC), flying for the first time onboard a CBERS satellite. In spite of the expected new possibilities to be explored with this improvement in nominal spatial resolution (2.36 m) aspect, main attention is still expected to the CCD data quality, since at least among the Brazilian remote sensing users, there are a lot of researches (academia) and application initiatives (government and private companies) that depend on its data. Some of these research projects and general applications have been based on the conversion of digital numbers (DN) to physical unities like radiance or reflectance.Taking into account well succeeded remote sensing programs in the world, all of them have been characterized by a continuous concerning to properly inform the users about the relationship between DN values and the effective in-flight radiance (Top of the Atmosphere �C TOA radiance) measured by the sensor [1].