This is consistent with previous research demonstrating that administration of NO donors, such as nitroglycerin, induce cranial vasodilation,9 headache in healthy volunteers,11 and attacks of primary headaches such as tension-type headache,12 cluster headache13 and particularly migraine.9,14 The present results extend these observations by directly stimulating sGC with riociguat, bypassing upstream determinators of NO formation (Fig. 3)15,16,21 We thereby confirm that activation of this enzyme is sufficient to induce cranial vasodilation and headache. This evidence concerns the gene SGCB and Headache.