“The aim of this study was to


“The aim of this study was to Rabusertib chemical structure compare the Streamlined Liner of the Pharynx Airway (SLIPA (TM)) with the ProSeal Laryngeal Mask Airway (LMA-ProSeal (TM)) in mechanically ventilated paralyzed patients undergoing laparoscopic gynecologic surgery.\n\nOne hundred and one patients were allocated

randomly to SLIPA (n = 50) or to LMA-ProSeal (n = 51) treatment groups. After induction of general anesthesia and insertion of the assigned supralaryngeal airway (SLA) device, we made note of the occurrence of any gastric insufflation and perilaryngeal leakage. We then evaluated the anatomical fit of the SLA device using a fibreoptic bronchoscope, and we assessed the airway sealing pressure and respiratory mechanics with change in head position and during peritoneal insufflation. After surgery, we evaluated the severity of postoperative find more sore throat and the presence of blood or regurgitated fluid on the SLA device.\n\nThe insertion success rate, gastric insufflation, perilaryngeal leakage, anatomical fit, airway sealing pressure,

respiratory mechanics, severity of sore throat, and incidence of blood and regurgitated fluid on the device were similar between the two groups. The incidence of perilaryngeal leakage with changes in the patient’s head position was lower with the SLIPA group than with the LMA-ProSeal group (3/50 vs 11/51, respectively; P = 0.026). During peritoneal insufflation, perilaryngeal leakage did not occur with the SLIPA but occurred in four cases with the LMA-ProSeal (P = 0.045).\n\nBoth the SLIPA and the LMA-ProSeal can be used effectively and without severe complications in paralyzed patients undergoing laparoscopic gynecological surgery. However, WH-4-023 the SLIPA offers the advantage of less perilaryngeal gas leakage than the LMA-ProSeal with change in head position and during insufflation of the peritoneal cavity. This trial is registered with ANZCTR (ACTRN12609000914268).”
“Interleukin-12, a heterodimeric cytokine consisting of glycosylated subunits of 35 and 40 kDa, is

a central molecule in controlling innate as well as adaptive immunity. This study was aimed to investigate the role of IL12A and IL12B as candidate genes for immune competence in pigs. The porcine genes were screened for polymorphism and association analysis was carried out by mixed model analysis with parameters of innate immunity, in vitro haemolytic complement activity in the classical and alternative pathways, in vivo complement activation expressed as C3c serum concentration, and blood leucocyte proliferation measured in F2 animals of a pig resource population based on cross of Duroc and Berlin miniature pig (DUMI resource population). A single nucleotide polymorphism (SNP) in the promoter region (C > A) of IL12A was identified. Two SNPs were detected in intron 4 of IL12B at positions 192 (A > G) and 437 (C > T).

Since most literatures have focused on the rCBF changes of operat

Since most literatures have focused on the rCBF changes of operative hemisphere, we evaluated the hemodynamics of nonoperative side by xenon-enhanced computed tomography (Xe-CT) and acetazolamide challenge test in patients with MMD during a short time follow-up. Fifteen MMD patients with unilateral ischemic presentations who received direct revascularization on the symptomatic hemispheres

with complete hemodynamic evaluations by Xe-CT and acetazolamide challenge test were enrolled. Hemodynamic SN-38 research buy evaluations were performed 1, 3, and 6 months, postoperatively. The postoperative rCBF and cerebral vascular reserve (CVR) were recorded and correlated with clinical outcome. Angiography was performed if the patient had neurological deterioration or deficits. The average follow-up time was 8.5 +/- 3.5 months. Three months after the ipsilateral Oligomycin A order direct revascularization, the CVR of nonoperative hemispheres (25.8 +/- 8.1%) began to decrease significantly (P = 0.003). Six months later, the rCBF showed a downward trend in nonoperative hemispheres (47.4 +/- 8.0 ml center dot 100 g(-1) min(-1)) than the preoperative status, but the difference

was not significant (P = 0.053). Three patients presented with decreased rCBF and impaired CVR in the nonoperative hemispheres. Among them, two patients were symptomatic. Unilateral direct revascularization in symptomatic hemisphere for MMD patient could induce CVR selleck impaired in primary asymptomatic hemisphere during the short term after the surgery. Therefore, critical follow-up, especially the hemodynamic follow-up in the asymptomatic hemispheres should be performed in patients with MMD.”
“Few studies have been carried out on nitrification potential

of marsh soils in natural saline wetlands with high alkalinity. The nitrification potentials of a closed wetland and an open wetland were monitored by an aerobic incubation at 25 degrees C for 28 days. The relative nitrification index (RNI, NO(3)-N/NO(3)-N+NH(4)(+)-N) rapidly increased with time in both wetlands and decreased with depth in soil profiles in both wetlands within the first 21 days. Nitrification proceeded much faster in the closed wetland than in the open wetland. The higher rate of nitrogen removal in closed wetlands than open wetland was probably due to the fast nitrification followed by denitrification or leaching loss.”
“The purpose of this study was to assess whether intraoperative fluoroscopy assists in the restoration of the coronal limb alignment target in conventional total knee arthroplasty (TKA). One hundred and six patients undergoing conventional cemented TKA were randomly assigned to be operated on with or without intraoperative fluoroscopy. The image intensifier, together with customized manual instrumentation, was used for separately measuring the frontal alignment of the femoral and tibial resection surfaces.

We show that for warmer interglacial

periods the relation

We show that for warmer interglacial

periods the relationship between temperature and the isotopic signature varies among ice core sites, and that therefore the conversions must be nonlinear for at least some sites. Model results indicate that the isotopic composition of East Antarctic ice is less sensitive to temperature changes during warmer climates. We conclude that previous temperature estimates from interglacial BLZ945 cost climates are likely to be too low. The available evidence is consistent with a peak Antarctic interglacial temperature that was at least 6K higher than that of the present day -approximately double the widely quoted 3 +/- 1.5K (refs 5, 6).”
“It is widely accepted that infants begin learning their native language not by learning words, but by discovering features of the speech signal: consonants, vowels, and combinations of these sounds. Learning to understand words, as opposed to just perceiving their sounds, is said to come later, between 9 and 15 mo of age, when infants develop a capacity for interpreting others’ goals and intentions. Here, we demonstrate that this consensus about

the developmental sequence of human language learning is flawed: in fact, infants already know the meanings of several common words from the age of 6 mo onward. We presented 6- to 9-mo-old infants with sets of pictures to view while their parent named a picture PHA-739358 cost in each set.

Over this entire age range, infants directed their gaze to the named pictures, indicating their understanding of spoken words. Because the words were not trained in the laboratory, the results show that even young infants learn ordinary Sapitinib datasheet words through daily experience with language. This surprising accomplishment indicates that, contrary to prevailing beliefs, either infants can already grasp the referential intentions of adults at 6 mo or infants can learn words before this ability emerges. The precocious discovery of word meanings suggests a perspective in which learning vocabulary and learning the sound structure of spoken language go hand in hand as language acquisition begins.”
“Capacity is limited in the developing world to conduct cost-effectiveness analysis (CEA) of health interventions. In Thailand, there have been concerted efforts to promote evidence-based policy making, including the introduction of economic, appraisals within health technology assessment (HTA). This paper reviews the experience of this lower middle-income country, with an emphasis on the creation of the Health Intervention and Technology Assessment Program (HITAP), including its mission, management structures and activities.\n\nOver the past 3 decades, several HTA programmes were implemented in Thailand but not sustained or developed further into a national institute.

Drug-induced changes can be functional and/or associated with mor

Drug-induced changes can be functional and/or associated with morphological alterations in the normal heart histology. It is therefore crucial to understand VX-680 cost the normal variations in histology to discriminate test article-related changes from background lesions. Rodent progressive cardiomyopathy is probably the most commonly encountered change in control animals of nonclinical toxicity studies. A multisite study mimicking standard short-term toxicity studies using young male Sprague-Dawley

rats was performed to better characterize this finding. Using an enhanced sectioning method for this research study, it was observed that the incidence of background cardiomyopathy was 100%. The vast majority of the microscopic findings were inflammatory in nature, CAL-101 with associated necrotic changes (defined as necrosis/inflammatory cell infiltrate) and these changes were mainly located in the myocardium of the mid region of the ventricles (the left side being predominantly affected). The monitored environmental factors in this study (multiple facilities, study duration, handling) did not have an effect on the

incidence or severity of the spontaneous cardiomyopathy. In addition, cardiac-specific serum troponin levels were measured and were within the published control range.”
“BACKGROUND: Experimental and clinical observations show that proinflammatory cytokines and oxidative stress are involved in the development of local and particularly systemic complications in acute pancreatitis (AP) patients. There are often pulmonary complications in such patients. The mechanisms through which lung injury is induced in AP are not fully clear.\n\nMETHODS: In order to assess the role of activated neutrophils, pro- and anti-inflammatory cytokines and adhesion molecules at the onset and development of respiratory complications and respiratory

failure, we measured the serum levels of pro-inflammatory (IL-1 beta, IL-6, IL-8, IL-18, TNF-alpha) and Selleckchem JIB 04 anti-inflammatory (IL-Ira, IL-10) cytokines in 51 AP patients who had been diagnosed with pancreatitis-associated lung injury with and without the development of organ dysfunction.\n\nRESULTS: When admitted to the hospital, severe AP patients had increased concentrations of IL-1 beta, IL-6, IL-8, IL-18, and TNF-alpha. The concentration of IL-18 alone was considerably increased in the patients who later developed respiratory failure. The onset of acute respiratory distress syndrome in the AP patients was accompanied by an increase in the level of anti-inflammatory cytokines’ especially IL-10. It was noted that in severe lung injury, myeloperoxidase activity in the blood increased significantly, but still reflected the processes taking place in the lung parenchyma.

The primary endpoints were change in best-corrected visual

The primary endpoints were change in best-corrected visual SBE-β-CD nmr acuity (BCVA) at 12 months for CNTF3 and change in visual field sensitivity at 12 months for CNTF4. Patients had the choice of retaining or removing the implant at 12 months for CNTF3 and 24 months for CNTF4.\n\nRESULTS: There were no serious adverse events related to either the encapsulated cell implant or the surgical

procedure. In CNTF3, there was no change in acuity in either ciliary neurotrophic factor- or sham-treated eyes at 1 year. In CNTF4, eyes treated with the high-dose implant showed a significant decrease in sensitivity while no change was seen in sham- and low dose-treated eyes at 12 months. The decrease in sensitivity was reversible upon implant removal. In both studies, ciliary neurotrophic factor treatment resulted in a dose-dependent increase in retinal thickness.\n\nCONCLUSIONS: Long-term intraocular delivery of ciliary

neurotrophic factor is achieved by the encapsulated cell implant. Neither study showed therapeutic benefit in the primary outcome variable. (C) 2013 by Elsevier Inc. All rights reserved.”
“Nausea is a universal human experience. It evolves slowly over time, and brain mechanisms underlying find more this evolution are not well understood. Our functional magnetic resonance imaging (fMRI) approach evaluated brain activity contributing to and arising from increasing motion sickness. Subjects rated transitions to increasing nausea, produced by visually induced vection within the fMRI environment. We evaluated parametrically increasing brain activity 1) precipitating increasing

nausea and 2) following transition to stronger nausea. All subjects demonstrated visual stimulus-associated GW4869 molecular weight activation (P < 0.01) in primary and extrastriate visual cortices. In subjects experiencing motion sickness, increasing phasic activity preceding nausea was found in amygdala, putamen, and dorsal pons/locus ceruleus. Increasing sustained response following increased nausea was found in a broader network including insular, anterior cingulate, orbitofrontal, somatosensory and prefrontal cortices. Moreover, sustained anterior insula activation to strong nausea was correlated with midcingulate activation (r = 0.87), suggesting a closer linkage between these specific regions within the brain circuitry subserving nausea perception. Thus, while phasic activation in fear conditioning and noradrenergic brainstem regions precipitates transition to strong nausea, sustained activation following this transition occurs in a broader interoceptive, limbic, somatosensory, and cognitive network, reflecting the multiple dimensions of this aversive commonly occurring symptom.”
“This work describes a simple method to immobilize heparin by covalent bonding to the surface of poly(lactic acid) film with the aim of showing improved hemocompatibility.

(c) 2010 Elsevier B V All rights reserved “
“Objectives To

(c) 2010 Elsevier B.V. All rights reserved.”
“Objectives. To describe the effect of fatigue on the strength of the bracket-adhesive-enamel complex and characterize the fatigue behavior of the materials tested.\n\nMethods. Upper central incisor brackets (Discovery

(R), Dentaurum) were bonded with a light-curing (Transbond XT (TM), 3M Unitek) and a chemically-curing GDC-0994 cost adhesive (Concise (TM), 3M Unitek) on bovine teeth embedded in cylindrical resign bases and stored in water at 37(+/- 2) degrees C for 24 (+/- 2) h. The first 15 specimens were tested with a universal testing machine ZMART.PRO (R) (Zwick GmbH & Co. KG, Ulm, Germany) for ultimate shear bond strength according to the DIN-13990-2-standard. The remaining three groups of 20 specimens under-went fatigue staircase testing of 100, 1000 and 3000 cycles at 1 Hz with a self-made testing machine. The survived specimens were subjected to shear strength testing.\n\nResults. The fatigued specimens showed decreased shear strength with both adhesives at all cycle levels. The shear strength after fatigue for 100, 1000 and 3000 cycles was in the Concise (TM)-groups 34.8%, 59.0%, 47.3% and in the Transbond (TM) XT-groups

33.6%, 23.1%, 27.3% relative to the ultimate shear strength. The fatigue life of the Concise (TM)-groups decreased with increasing stress and Transbond (TM) XT showed lower fatigue ratio with no obvious trend. Quisinostat solubility dmso The specimens bonded with Transbond (TM) XT showed typically favorable fracture modes in contrary to Concise (TM).\n\nSignificance. Fatigue of the bracket-adhesive-enamel complex decreased its shear strength. The staircase method can provide a standardized experimental protocol for fatigue studies, however testing at various cycle numbers is recommended.

(C) 2013 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.”
“Exercise selleckchem has repeatedly been shown to improve glycemic control as assessed by glycated hemoglobin. However, changes in glycated hemoglobin do not provide information regarding which aspects of glycemic control have been altered. The purpose of this systematic review was to examine the effect of exercise as assessed by continuous glucose monitoring systems (CGMS) in type 2 diabetes. Databases (PubMed, Medline, EMBASE) were searched up to February 2013. Eligible studies had participants with type 2 diabetes complete standardized exercise protocols and used CGMS to measure changes in glycemic control. Randomized controlled trials, crossover trials and studies with pre-post designs were included. Average glucose concentration, daily time spent in hyperglycemia or hypoglycemia, and fasting glucose concentration were compared between exercise and control conditions. Eleven studies met the inclusion criteria and were included in the review.

The H(2)S donor, NaSH (100 mu M-10mM),

inhibited BK(Ca) c

The H(2)S donor, NaSH (100 mu M-10mM),

inhibited BK(Ca) channels in a concentration-dependent manner with an IC(50) of ca. 670 mu M. In contrast to the known effects of CO donors, the H(2)S donor maximally decreased the open state probability by over 50% and shifted the half activation voltage by more than +16 mV. In addition, although 1 mM KCN completely suppressed CO-evoked channel activation, it was without effect on the H(2)S-induced channel inhibition, suggesting that the effects of CO and H(2)S were non-competitive. RT-PCR showed that mRNA for both QNZ molecular weight of the H(2)S-producing enzymes, cystathionine-beta-synthase and cystathionine-gamma-lyase, were expressed in HEK 293 cells and in rat carotid body. Furthermore, immunohistochemistry was able to localise cystathionine-gamma-lyase to glomus cells, indicating that the carotid body has the endogenous capacity to produce H(2)S. In conclusion, we have shown that H(2)S and CO have opposing effects on BK(Ca) channels, suggesting that these gases

have separate CBL0137 modes of action and that they modulate carotid body activity by binding at different motifs in the BK(Ca)alpha subunit.”
“Intraguild predation (IGP) among predatory species can influence many plant-arthropod associations. However, the relevance of IGP is poorly understood for truly omnivorous species such as those that can complete development on both animal and plant diets. Here we test the hypothesis that IGP among two omnivorous mirids is more common when extraguild food is either absent or not suitable. Laboratory experiments were performed in experimental

cages in order https://www.selleckchem.com/screening/stem-cell-compound-library.html to determine the effect of intraguild prey densities and diet availability on direction and intensity of IGP between Dicyphus tamaninii and Macrolophus caliginosus (Heteroptera: Miridae). Intraguild predation was symmetrical between the two mirid species in the absence of alternative food. Increasing densities of intraguild prey enhanced drastically the incidence of IGP. Intraguild predation was reduced when mirids were in the presence of green or red tomato fruits, but the presence of any other extraguild resources had no impact on IGP level. However, when given before the experiments, all resources with the exception of tomato leaves significantly reduced IGP. A second experiment was performed on live plants to compare the results of the previous trials with that obtained in a more natural setting. No IGP was observed when both mirid species were present on a plant. However, development of the intraguild prey (the more vulnerable strage) was hindered by the presence of the intraguild predator. The potential of such results is discussed from community ecology and biological control perspective.

Pediatrics 2012;130:585-586″
“Primary objective: To extend p

Pediatrics 2012;130:585-586″
“Primary objective: To extend previous research on alternative stimulus preference assessment (SPA) modalities to individuals with severe ABI by evaluating the effects of pictorial, verbal and tangible item presentation.\n\nResearch design: Paired-stimulus procedure used for SPA sessions with the order of modalities counterbalanced across participants.

Reinforcer assessments (RAs) were experimentally evaluated using an alternating treatments design. A progressive-ratio procedure was used for reinforcer assessment (RA) sessions.\n\nMethods and procedures: Six adults with severe ABI. The Assessment of Basic Learning Abilities was conducted to assess discrimination skills; the Reinforcer Assessment for Individuals GSI-IX price with Severe Disabilities structured interview was administered see more to identify items for subsequent evaluations. Three SPA sessions-one of each stimulus modality-were conducted with each participant. Subsequent RAs were conducted using the stimuli ranked as the most highly preferred for each participant.\n\nMain outcomes and results: Each modality identified a different food item with the highest selection percentage

for three participants, while three participants had highly consistent SPA results. Subsequent RAs demonstrated that all modalities made valid predictions of foods that would function as reinforcers for programming.\n\nConclusions: Use of the different direct-observation methods to identify reinforcers for reductive and skill acquisition programming would likely be a useful addition to rehabilitation settings.”
“Limited information is available on the time-dependent or dosage-dependent cariostatic efficacy of highly concentrated fluoride compounds. This good clinical practice-conforming, double-blind, placebo-controlled,

crossover in situ study tested the hypothesis that a 1.0% amine fluoride fluid is superior to a 0.5% amine fluoride fluid regarding fluoride retention and mineral change in initial caries enamel lesions over a period of 28 d. Fluoride retention was significantly higher after application of the two fluoride fluids compared with placebo but had decreased in both groups to similar levels after only 1 wk. Mineral gain was significantly higher for both verum groups compared with placebo. The use JQ-EZ-05 solubility dmso of 1% fluoride fluid resulted in significantly higher remineralization compared with the use of 0.5% fluoride fluid. For both fluoride fluids mineral gain followed a linear relationship with time during the experimental period, indicating a possible further uptake of mineral, even after 4 wk.”
“Butanolic extract of seeds from 2 different Lathyrus species (Lathyrus ratan [commercial variety] and L. aphaca [wild variety]), were investigated for their in vitro antibacterial activity. The antibacterial activity against plant and human pathogenic bacteria was evaluated on the basis of inhibition zones (IZs) measured by disc diffusion method.

The complete genome sequence of bacteriophage EC1-UPM was analyse

The complete genome sequence of bacteriophage EC1-UPM was analysed and compared with other closely related N4-like phage groups to assess their genetic similarities and differences.\n\nResults: Bacteriophage EC1-UPM displays a very similar codon usage profile with its host and does not contain any tRNA gene. Comparative genomics analysis reveals close resemblance of bacteriophage EC1-UPM to three N4-like bacteriophages namely vB_EcoP_G7C, IME11 and KBNP21 with a total of 44 protein coding genes shared at 70% identity threshold. The genomic region coding for

the tail fiber protein was found to be unique in bacteriophage EC1-UPM. Further annotation of the tail fiber protein using HHpred, a highly sensitive homology detection tool, reveals the presence of protein structure homologous to various polysaccharide processing proteins in its C-terminus. Leveraging on the availability of multiple N4-like bacteriophage genome sequences, CCI-779 mw GSK2879552 order the core genes of N4-like bacteriophages

were identified and used to perform a multilocus phylogenetic analysis which enabled the construction of a phylogenetic tree with higher confidence than phylogenetic trees based on single genes.\n\nConclusion: We report for the first time the complete genome sequence of a N4-like bacteriophage which is lytic against avian pathogenic Escherichia coli O78:K80. A novel 928 amino acid residues tail fiber protein was identified in EC1-UPM which may be useful to further the understanding of phage-host specificity. Multilocus phylogenetic analysis using core genes of sequenced N4-like phages showed that the evolutionary relationship correlated well with the pattern of host specificity.”
“Background Tissue factor (TF) encryption this website plays an important role in regulating TF coagulant activity. Potential differences in experimental cell model systems and strategies hampered

our understanding of the TF encryption mechanisms.\n\nObjective To characterize the procoagulant activity status of TF in different cell types, and to determine whether increased TF procoagulant activity following the activation stems from transformation of the cryptic TF to the active form.\n\nMethods Simultaneous kinetic analyses of TF-FVIIa activation of FX and FVIIa binding to cell surface TF were performed under identical experimental conditions in fibroblast (WI-38), cancer cell (MDA-231), endothelial cell (HUVEC) and monocytic cell (THP-1) model systems. These data were then utilized to estimate TF coagulant-specific activity and percentages of active and cryptic TF present in these cell types.\n\nResults MDA-231 and WI-38 cells express 10 to 100 times more TF on their cell surfaces compared with perturbed HUVEC and THP-1 cells. TF-specific activity on cell surfaces of MDA-231, WI-38 and THP-1 cells was very similar. Nearly 80-90% of the TF in MDA-231, WI-38 and THP-1 cells was cryptic.

The novel complementary approach was able to determine the stoich

The novel complementary approach was able to determine the stoichiometry in all tested cases. The major benefit of this method compared to the standard Job’s approach seems to be its capability to reveal a reaction stoichiometry OICR-9429 in chelators with moderate affinity to iron.\n\nIn conclusion, using this complementary method may explain several previous contradictory data and lead to a better understanding of the

underlying mechanisms of chelator’s action. (C) 2013 Elsevier Inc. All rights reserved.”
“Physicochemical properties provide reliable guidance in optimization of pharmacological efficiency and ADME profile of small chemical compounds. Their high-throughput determination is regularly based on application of HPLC techniques. In this study CHI and CHI IAM of 32 4-hydroxycoumarin analogs were measured by HPLC with methanol gradient at pHs 2.8 and 7.0. Results were analyzed by PCA in terms of computed descriptors in order to identify space for optimization of their phospholipids affinity and lipophilicity for which predictive software failed to produce reliable estimations. The chromatographic behavior of studied 4-hydroxycoumarins was typical of acidic compounds.

The CHI2.8, CHI7.0, CHI IAM(2.8) and CHI IAM(7.0) values were all considerably cross-correlated in accordance with their prevailing lipophilic character. Structure-retention relationship (SRR) analysis furthermore revealed https://www.selleckchem.com/products/Cediranib.html that H-bond accepting capacity and dipolar interactions with methanol generally shorten their retention times. However, deviations from the linear trends were noticed for R3/R5-substituted derivatives able to form intramolecular contacts with the 4-O(H) group and characterized by more uniform electron density at 2-O and 4-O atoms and quite different acidity/H-bond donating capacity than the rest of derivatives. Thus, CHI and CHI IAM determinations and SRR analysis are fast and efficiently pointed to ways of modifying biological activities of 4-hydroxycoumarins. (c) 2012 Elsevier B.V. All rights reserved.”
“A catalytic Mannich reaction of a simple ester with no activating functionality at the alpha-position GDC 973 via a product-base

mechanism was reported. The desired Mannich adducts were obtained in high yields using a catalytic amount of KH. This is a rare example of a Bronsted base-catalyzed Mannich reaction of unactivated esters as substrates.”
“Intracerebral recordings of neuronal activity in patients undergoing deep brain stimulation have revealed characteristic movement-related desynchronization at frequencies <30 Hz and increased activity in the gamma band (similar to 30-100 Hz) in the basal ganglia and thalamus. Thalamic gamma activity is also found during arousal. Here, we explore oscillatory gamma band activity recorded from the ventralis intermedius nucleus of the thalamus during motor performance in a Go/noGo task in 10 patients with essential tremor after implantation of deep brain stimulation electrodes.