Abstract This cross-sectional study investigated the association of SNPs rs670 (C>T) and rs693 (G>A) with parameters of lipid metabolism and endothelial activation in 167 subjects, including 86 COVID-19 outpatients and 81 healthy subjects (control group) matched for sex and age. Serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), non-high-density lipoprotein cholesterol (non-HDL-c), triglycerides (TG), apolipoproteins (Apo A-I and B), and vascular cell adhesion molecule-1 (VCAM-1) were determined. The SNPs were genotyped by quantitative polymerase chain reaction (qPCR). A p -value<0.05 was assumed. COVID-19 outpatients showed increases in TC (187.0±48.3 vs . 160.8±32.0 mg/dL), LDL-c (110.3±41.5 vs . 98.8±28.2 mg/dL), non-HDL-c (138.3±45.8 vs . 115.6±31.6 mg/dL), TG (139.7±80.3 vs . 84.9±35.1 mg/dL), and Apo A-I (149.5±40.0 vs . 133.3±20.9 mg/dL), along with a high frequency of hypercholesterolemia and hypertriglyceridemia. VCAM-1 levels were double those of the control (682.7±231.8 vs. 299.3±102.9 ng/mL) and a strong predictor of COVID-19 (AUC=0.946). Moreover, VCAM-1 correlated with TC (r = -0.223) and HDL-c (r = -0.225). The decrease in TG and VCAM-1 is predicted by the dominance of the T allele (rs670) and its codominance with the A (rs693) allele in COVID-19 outpatients. COVID-19 has been shown to be associated with dyslipidemias and endothelial activation, and apolipoprotein polymorphisms may influence this. crosssectional cross sectional rs rs67 C>T CT C (C>T rs69 G>A GA G (G>A 16 8 COVID19 COVID 19 COVID-1 group age TC, , (TC) highdensity density HDLc, HDLc HDL c (HDL-c) lowdensity low LDLc, LDLc LDL (LDL-c) nonhighdensity non nonHDLc, nonHDLc (non-HDL-c) TG, (TG) AI I B, B B) molecule1 molecule 1 molecule- VCAM1 VCAM (VCAM-1 determined qPCR. qPCR (qPCR) value<0.05 value005 value 0 05 -value<0.0 assumed 187.0±48.3 1870483 187 48 3 (187.0±48. 1608320 160 32 160.8±32. mg/dL, mgdL mg/dL mg dL mg/dL) 110.3±41.5 1103415 110 41 5 (110.3±41. 988282 98 28 2 98.8±28. 138.3±45.8 1383458 138 45 (138.3±45. 1156316 115 6 31 115.6±31. 139.7±80.3 1397803 139 7 80 (139.7±80. 849351 84 9 35 84.9±35. 149.5±40.0 1495400 149 40 (149.5±40. 1333209 133 20 133.3±20. hypertriglyceridemia VCAM- 682.7±231.8 68272318 682 231 (682.7±231. 29931029 299 102 299.3±102. ng/mL ngmL ng mL AUC=0.946. AUC0946 AUC AUC=0.946 946 (AUC=0.946) Moreover r 0.223 0223 223 -0.223 0.225. 0225 0.225 225 -0.225) (rs670 (rs693 this rs6 COVID1 COVID- (TC (HDL-c (LDL-c (non-HDL-c (TG (VCAM- (qPCR value<0.0 value00 -value<0. 187.0±48. 187048 18 4 (187.0±48 160832 160.8±32 110.3±41. 110341 11 (110.3±41 98828 98.8±28 138.3±45. 138345 13 (138.3±45 115631 115.6±31 139.7±80. 139780 (139.7±80 84935 84.9±35 149.5±40. 149540 14 (149.5±40 133320 133.3±20 682.7±231. 6827231 68 23 (682.7±231 2993102 29 10 299.3±102 AUC094 AUC=0.94 94 (AUC=0.946 0.22 022 22 -0.22 -0.225 (rs67 (rs69 (VCAM value<0. value0 -value<0 187.0±48 18704 (187.0±4 16083 160.8±3 110.3±41 11034 (110.3±4 9882 98.8±2 138.3±45 13834 (138.3±4 11563 115.6±3 139.7±80 13978 (139.7±8 8493 84.9±3 149.5±40 14954 (149.5±4 13332 133.3±2 682.7±231 682723 (682.7±23 299310 299.3±10 AUC09 AUC=0.9 (AUC=0.94 0.2 02 -0.2 (rs6 value<0 -value< 187.0±4 1870 (187.0± 1608 160.8± 110.3±4 1103 (110.3± 988 98.8± 138.3±4 1383 (138.3± 1156 115.6± 139.7±8 1397 (139.7± 849 84.9± 149.5±4 1495 (149.5± 1333 133.3± 682.7±23 68272 (682.7±2 29931 299.3±1 AUC0 AUC=0. (AUC=0.9 0. -0. (rs value< -value 187.0± (187.0 160.8 110.3± (110.3 98.8 138.3± (138.3 115.6 139.7± (139.7 84.9 149.5± (149.5 133.3 682.7±2 6827 (682.7± 2993 299.3± AUC=0 (AUC=0. -0 187.0 (187. 160. 110.3 (110. 98. 138.3 (138. 115. 139.7 (139. 84. 149.5 (149. 133. 682.7± (682.7 299.3 AUC= (AUC=0 - 187. (187 110. (110 138. (138 139. (139 149. (149 682.7 (682. 299. (AUC= (18 (11 (13 (14 682. (682 (AUC (1 (68 ( (6

Abstract Diabetes mellitus (DM) is a major cause of chronic kidney disease (CKD) and changes in lipoprotein. Literature data suggest that cholesterol associated with high-density lipoprotein (HDLc) plays a protective role against albuminuria and diabetic nephropathy. These factors are related with changes in serum apolipoproteins such Apo A-I. This work aims to evaluate the correlation of apolipoprotein A-I with renal function in diabetic outpatients. Samples were collected from 281 outpatients for analyses of glycated hemoglobin (HbA1c), serum creatinine (SCr), urea (BUN), cholesterol (TC), triglycerides (TG), HDL-cholesterol (HDLc) and estimation of glomerular filtration rate (eGFR). Urinary samples were obtained to assess urine albumin creatinine ratio (UACR). Triglyceride-glucose index (TyG) was calculated to estimate insulin resistance. The mean age was 61,5 ± 16,4 years. Most patients were female, Afro-Mestizo and over 50 years of age. Pearson's revealed negative correlation of creatinine with HDLc and Apo A-I. There was a correlation of eGFR with HbA1c, TG and HDLc. TyG presented a negative correlation with Apo A-I and HDLc. The highest quartiles of UACR presented the highest TyG and the lowest Apo A-I. In conclusion, Apo A-I indicated an association with insulin resistance and changes in renal function parameters, especially as a factor associated with the onset of albuminuria, with a better predictive potential than the HDLc. DM (DM CKD (CKD highdensity high density (HDLc nephropathy AI. AI A I. I 28 HbA1c HbAc , HbA c (HbA1c) SCr, SCr (SCr) BUN, BUN (BUN) TC, TC (TC) TG, (TG) HDLcholesterol HDL eGFR. . (eGFR) UACR. (UACR) Triglycerideglucose Triglyceride glucose (TyG 615 61 5 61, 164 16 4 16, female AfroMestizo Afro Mestizo Pearsons Pearson s conclusion parameters 2 (HbA1c (SCr (BUN (TC (TG (eGFR (UACR 6 1

Abstract Changes in lipoprotein metabolism are among the main causes of hemodynamic impairment in renal function. COVID-19 is an multisystemic inflammatory disease, aggravating this situation. This cross-sectional study investigated the relationship of serum lipoprotein profile with inflammatory parameters and renal function in 95 COVID-19 outpatients in comparison with 173 with flu-like symptoms. Serum samples were collected for the determination of total cholesterol and fractions, apolipoproteins (Apo A-I and Apo B), urea (sUr) and creatinine (sCr). The glomerular filtration rate (eGFR) was calculated. Neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) ratios were calculated as inflammatory parameters derived from the blood tests. COVID-19 patients presented lower high-density lipoprotein cholesterol (HDL-c) (47.90 ± 1.543 vs. 51.40 ± 0.992) and higher PLR (190.9 ± 9.410 vs. 137.6 ± 5.534) and NLR (3.40 ± 0.22 vs. 2.80 ± 0.15). Both NLR and PLR correlated with each other (r = 0.639). Furthermore, the Apo B/Apo A-I ratio was correlated with PLR (r = 0.5818) and eGFR (r = -0.2630). COVID-19 patients classified as at high risk of developing acute myocardial infarction based on the Apo B/ Apo A-I ratio had higher values for sUr/sCr. Thus, serum apolipoproteins, PLR, and NLR could be related to renal dysfunction in COVID-19. COVID19 COVID 19 COVID-1 disease situation crosssectional cross sectional 9 17 flulike flu like symptoms fractions AI A I B, B , B) sUr (sUr sCr. sCr . (sCr) (eGFR Neutrophillymphocyte Neutrophil lymphocyte (NLR plateletlymphocyte platelet (PLR tests highdensity density HDLc HDL c (HDL-c 47.90 4790 47 90 (47.9 1543 1 543 1.54 vs 5140 51 40 51.4 0.992 0992 0 992 190.9 1909 190 (190. 9410 410 9.41 1376 137 6 137. 5.534 5534 5 534 3.40 340 3 (3.4 022 22 0.2 280 2 80 2.8 0.15. 015 0.15 15 0.15) r 0.639. 0639 0.639 639 0.639) Furthermore BApo 0.5818 05818 5818 0.2630. 02630 0.2630 2630 -0.2630) sUrsCr sUr/sCr Thus COVID19. 19. COVID1 COVID- (sCr 47.9 479 4 (47. 154 54 1.5 514 51. 0.99 099 99 190. (190 941 41 9.4 13 5.53 553 53 3.4 34 (3. 02 0. 28 8 2. 01 0.1 063 0.63 63 0.581 0581 581 0263 0.263 263 -0.2630 47. (47 1. 0.9 09 (19 94 9. 5.5 55 3. (3 06 0.6 0.58 058 58 026 0.26 26 -0.263 (4 (1 5. ( 0.5 05 -0.26 -0.2 -0. -0 -

Abstract Obesity and dyslipidemia are conditions often associated with cardiovascular risk, inflammation, oxidative stress, and death. Thus, a new approach has been highlighted to promote research and development of pharmacological tools derived from natural sources. Among the most widely studied groups of substances, polyphenols such as tyramine stand out. This study investigated hypolipidemic and anti-obesity properties of tyramine. Oral toxicity evaluation, models of dyslipidemia and obesity were used. To induce dyslipidemia, Poloxamer-407 (P-407) was administered intraperitoneally. In the hypercholesterolemic and obesity model, specific diet and oral tyramine were provided. After 24h of P-407 administration, tyramine 2 mg/kg (T2) decreased triglycerides (TG) (2057.0 ± 158.5 mg/dL vs. 2838 ± 168.3 mg/dL). After 48h, TG were decreased by T2 (453.0 ± 35.47 vs. 760.2 ± 41.86 mg/dL) and 4 mg/kg (T4) (605.8 ± 26.61 760.2 ± 41.86 mg/dL). T2 reduced total cholesterol (TC) after 24h (309.0 ± 11.17 mg/dL vs. 399.7 ± 15.7 mg/dL); After 48h, 1 mg/kg (T1) (220.5 ± 12.78 mg/dL), T2 (205.8 ± 7.1 mg/dL) and T4 (216.8 ± 12.79 mg/dL), compared to P-407 (275.5 ± 12.1 mg/dL). The treatment decreased thiobarbituric acid reactive substances and nitrite in liver, increased superoxide dismutase, reduced the diet-induced dyslipidemia, decreasing TC around 15%. Tyramine reduced body mass, glucose, and TC after hypercaloric feed. Treatment with 5 mg/L (0.46 ± 0.04 ng/dL) and 10 mg/L (0.44 ± 0.02 ng/dL) reduced plasma insulin (1.18 ± 0.23 ng/dL). Tyramine increased adiponectin at 5 mg/L (1.02 ± 0.02 vs. 0.83 ± 0.02 ng/mL) and 10mg/L (0.96 ± 0.04 ng/mL). In conclusion, tyramine has low toxicity in rodents, has antioxidant effect, reduces plasma triglycerides and cholesterol levels. However, further studies should be conducted in rodents and non-rodents to better understand the pharmacodynamic and pharmacokinetic properties of tyramine.

Abstract Hypertriglyceridemia is associated with several metabolic diseases. The triglycerides (TG) disrupt the cholesterol reverse transport and contribute to increased levels of low-density lipoprotein (LDL). High-density lipoprotein (HDL) acts in cholesterol reverse transport as an anti-inflammatory and antioxidant. This study aims to investigate the role of hypertriglyceridemia in the functionality of HDL. Individuals were divided into 4 groups based on high or low HDL-c and triglycerides levels. Biochemical and anthropometric analysis were performed. This study demonstrated that triglycerides promote dysfunctions on HDL, increasing the cardiovascular risk. Blood pressure was higher in subjects with low HDL. Women presented higher levels of HDL-c and low percentage of fat mass. The highest levels of triglycerides were observed in older age. In addition, high levels of triglycerides were associated with higher total cholesterol and LDL-c levels, non-HDL-c, non-esterified fatty acids, and blood glucose, increasing in the ratio of non-HDL-c/HDL-c and ApoB/ApoA-I. The increase of triglycerides levels progressively impairs the antioxidant capacity of HDL, probably due to a higher occurrence of fatty acid peroxidation in individuals with hypertriglyceridemia. Patients with high HDL and low TG levels increased the Lag Time. Furthermore, a positive correlation was found between TG versus HDL particle size, variables that depend on age and anthropometric parameters. diseases (TG lowdensity density LDL. LDL . (LDL) Highdensity High (HDL antiinflammatory anti inflammatory HDLc c performed risk mass addition LDLc nonHDLc, nonHDLc non c, non-HDL-c nonesterified esterified acids glucose nonHDLc/HDLc nonHDLcHDLc c/HDL ApoB/ApoAI. ApoBApoAI ApoB/ApoA I. ApoB ApoA I ApoB/ApoA-I Time Furthermore size parameters (LDL cHDL ApoAI ApoB/ApoAI ApoBApoA

As complicações cardiovasculares apresentam relevância devido à sua freqüência e gravidade no contexto da hipertensão. Estudos referem que a prestação do Cuidado Farmacêutico (CF) é capaz de reduzir a taxa de risco cardiovascular (%RCV) em hipertensos. Esse trabalho objetivou investigar, com um ensaio clínico randomizado, a influência da prestação do CF na %RCV em hipertensos atendidos em uma unidade de atenção primária à saúde de Fortaleza-Ceará. Formarm-se dois grupos de estudo: i. Grupo Intervenção (GI), que recebeu orientações sobre tomada dos medicamentos, ações visando prevenir/resolver interações medicamentosas e reações adversas e intervenções não-farmacológicas por 9 meses e ii. Grupo Controle (GC), que recebeu assistência tradicional da unidade e foi monitorado durante o mesmo período. Observou-se redução estatisticamente significativa nas %RCV (10,76 to 7,86; p=0,04) e nos níveis de pressão arterial sistólica (PAS) (137,69 to 131,54; p<0,01) no GI, enquanto no GC, não houve alteração significativa. Identificaram-se 151 Problemas Relacionados com Medicamentos (PRM) e foram realizadas 124 intervenções farmacêuticas, das quais, 89,2% resultaram em solução/prevenção dos problemas. Nossos achados indicaram que a inclusão do serviço de CF na assistência ao paciente hipertenso foi mais eficaz na redução da %RCV e níveis de PAS em comparação à assistência tradicional.

Cardiovascular complications are relevant due to their frequency and severity on the hypertension scenario. Studies refer Pharmaceutical Care (PC) as capable of decreasing cardiovascular risk rate (%CVR) on hypertensive patients. This study aimed to investigate, through a randomized clinical assay, the influence of PC service on the %CVR of hypertensive patients assisted in a health primary care unit from Fortaleza-Ceará. Two study groups were formed: i. Intervention Group (IG), which received orientation about taking medicines, actions aiming to prevent/solve medicine interactions and adverse effects and non-pharmacological interventions for 9 months and, ii. Control Group (CG), which received traditional assistance of the unit and was monitored during the same period. It was observed a statistically significant reduction on %CVR (10.76 to 7.86; p=0.04) and systolic blood pressure levels (SBP) (137.69 to 131.54; p<0.01) in the IG, while, in the CG, there was no significant alteration. 151 Drug Related Problem (DRP) were identified and it was realized 124 pharmaceutical interventions, with 89.2% of them resulting on solution/prevention of the problem. Our findings indicated that the inclusion of the PC service in the hypertensive health assistance was more effective at the %CVR and the SBP reduction in comparison to the traditional assistance offered.

Onze derivados da ftalimida foram avaliados quanto a sua atividade antiproliferativa em células tumorais e normais e possíveis efeitos tóxicos. Avaliou-se a citotoxicidade contra tumores murinos (células de Sarcoma 180 e B-16/F-10) e células mononucleares do sangue perférico (CMSP) usando os ensaios de MTT e Alamar Blue. Em seguida, a investigação de citotoxicidade foi executada por citometria de fluxo e potencial antitumoral e toxicológico por meio de métodos in vivo. As moléculas 3b, 3c, 4 e 5 revelaram citotoxicidade in vitro contra Sarcoma 180, B-16/F-10 e PBMC. Uma vez que o composto 4 foi o derivado mais efetivo, ele foi escolhido para detalhar o mecanismo de ação após 24, 48 e 72h de exposição (22.5 e 45 µM). Células de Sarcoma 180 tratadas com o composto 4 mostraram desintegração de membrana, fragmentação de DNA e despolarização mitocondrial de maneira tempo e concentracão dependente. Os compostos 3c, 4 e 5 (50 mg/kg/dia) não inibiu o crescimento tumoral in vivo. Os animals tratados com o composto 4 exibiram aumento do total de leucócitos, linfócitos e no peso relativo do baço, diminuição de neutrófilos e hiperplasia da polpa branca esplênica. Os animais tratados apresentaram alterações histológicas reversíveis. A molécula 4 tem ação antiproliferativa in vitro provavelmente por ativação de apoptose, efeitos tóxicos reversíveis e exibiu propriedades imunoestimulantes que podem ser exploradas para atacar células neoplásicas.

Eleven phthalimide derivatives were evaluated with regards to their antiproliferative activity on tumor and normal cells and possible toxic effects. Cytotoxic analyses were performed against murine tumors (Sarcoma 180 and B-16/F-10 cells) and peripheral blood mononuclear cells (PBMC) using MTT and Alamar Blue assays. Following, the investigation of cytotoxicity was executed by flow cytometry analysis and antitumoral and toxicological potential by in vivo techniques. The molecules 3b, 3c, 4 and 5 revealed in vitro cytotoxicity against Sarcoma 180, B-16/F-10 and PBMC. Since compound 4 was the most effective derivative, it was chosen to detail the mechanism of action after 24, 48 and 72 h exposure (22.5 and 45 µM). Sarcoma 180 cells treated with compound 4 showed membrane disruption, DNA fragmentation and mitochondrial depolarization in a time- and dose-dependent way. Compounds 3c, 4 and 5 (50 mg/kg/day) did not inhibit in vivotumor growth. Compound 4-treated animals exhibited an increase in total leukocytes, lymphocytes and spleen relative weight, a decreasing in neutrophils and hyperplasia of spleen white pulp. Treated animals presented reversible histological changes. Molecule 4 had in vitro antiproliferative action possibly triggered by apoptosis, reversible toxic effects on kidneys, spleen and livers and exhibited immunostimulant properties that can be explored to attack neoplasic cells.

Objetivou-se com este trabalho avaliar a influência de diferentes dietas líquidas sobre os perfis dos metabólitos séricos relacionados ao status proteico e energético de bezerros até 60 dias de idade. Foram utilizados 24 bezerros mestiços, distribuídos em delineamento inteiramente casualizado com quatro tratamentos e seis repetições: leite integral (controle); 50% leite integral + 50% de soro de queijo in natura; 50% leite integral + 50% de soro de queijo in natura + um ovo integral in natura; 50% leite integral + 50% de soro de queijo in natura + um ovo integral in natura + biotina. A adaptação dos animais às dietas compreendeu os dez dias que antecederam o início da pesquisa. Os animais tiveram à disposição concentrado farelado, feno de capim Tifton-85 (Cynodon sp.) e água ad libitum. Semanalmente, foram coletadas amostras de sangue por punção da veia jugular externa, no período da manhã, antes do fornecimento da dieta líquida e duas horas após a ingestão desta. As concentrações médias de glicose, ureia, creatinina, proteínas séricas totais e albumina mostraram-se dentro dos limites normais para bezerros e, apenas os valores de ureia diferiram estatisticamente entre os tratamentos, sem prejudicar, porém, o desempenho normal dos animais. Assim, pôde-se utilizar o soro em substituição ao leite integral, na proporção de 50%, sem adição de ovo ou biotina, uma vez que os mesmos também não acarretaram alterações nas concentrações séricas dos metabólitos estudados.

This study was conducted to evaluate the influence of the liquid diet on the blood metabolites profile related to the protein and energy status of calves receiving different liquid diets. Twenty-four calves of Holstein x Gir breed were distributed in a completely randomized design with four treatments and six replications: Whole milk (Control); 50% whole milk + 50% of whey of cheese in natura; 50% whole milk + 50% of cheese whey in natura + one egg in natura; 50% whole milk + 50% of cheese whey in natura + one egg in natura + of biotin. The adaptation of the animals to the experimental diets occurred ten days before the beginning of the treatments. The animals received concentrate, Tifton-85 (Cynodon sp.) hay and water ad libitum from the birth to wean. Samples of blood were weekly collected in the morning, before the supply of the liquid diet and two hours after the ingestion. The concentrations of glucose, urea, creatinin, total proteins and albumin found in the serum of the calves, between liquid diets tested, were within normal limits when compared to reference levels in the literature. Only the values of urea differ significantly between treatments, but without harming the performance of the animals, soon it can be used the cheese whey in substitution to the whole milk, in the proportion of 50%, without egg or biotin addition, for a redution on the production cost.

Crotalaria retusa é uma planta encontrada no Nordeste brasileiro, pertence ao gênero Crotalaria e à família Leguminosae, e possuem mais de seissentas espécies no mundo e mais de quarenta no Brasil. As variedades tóxicas mais conhecidas são C. spectabilis, C. crispata, C. retusa, C. dura e C. globifera. Plantas do gênero Crotalaria são de interesse porque são usadas na medicina popular. Esses gêneros são ricos em alcaloides pirrolizidínicos (AP), que são as principais toxinas e apresentam efeitos pneumotóxicos, nefrotóxicos, cardiotóxicos, fetotóxicos, carcinogênicos, inflamação, hemorragia e fibrose. A monocrotalina é o principal alcaloide pirrolizidínico encontrado nessas plantas e é ativamente oxidada in vivo pelo citocromo P450 no fígado, formando intermediários altamente reativos tipo pirrólicos que são responsáveis pela ligação cruzada do DNA-DNA e DNA-proteína. O presente trabalho teve como objetivo fazer um levantamento bibliográfico via internet, utilizando bancos de dados, programas de pesquisa científica e pesquisa em livros relacionados, acerca da atividade farmacológica e do mecanismo de ação da monocrotalina extraída de plantas do gênero Crotalaria, ressaltando desde os aspectos botânicos da planta, estrutura química dos alcaloides pirrolizidínicos, exemplos experimentais de toxicidade e provável mecanismo de ação.

Crotalia retusa is a plant found in Brazilian Northeast and belongs to the genus Crotalaria and the family Leguminosae, which comprises more than 600 species throughout the world and more than forty in Brazil. The most known toxic species are C. spectabilis, C. crispata, C. retusa, C. dura and C. globifera. Plants of the Crotalaria genus are of great interest because they are used by humans for folk medicine. These plants are rich in pyrrolizidine alkaloids (PA), which are the main toxins that cause effects such as pneumotoxic, nefrotoxic, cardiotoxic, fetotoxic, carcinogenic, inflammation, hemorrhage and fibrosis. Monocrotaline is the main pirrolizidinic alkaloid found in plants and is actively oxidated in vivo by the cytochrome P450 in the liver, yielding highly reactive pyrrolic type intermediates, which are responsible for DNA-DNA and DNA-protein cross-links reaction. The aim of this work is to make a bibliographic survey via internet, using databases, scientific research programs and related books, about pharmacological activity and mechanism of action of monocrotaline extracted from plants of Crotalaria genus, emphasizing plant botanical aspects, chemical structure of pirrolizidinic alkaloid, experimental examples of toxicity and probable action mechanism.