I love my Ruger SR22. Fun and comfortable to hold. If I HAD to pick something I didn't like, the only thing would be the safety. You flick it DOWN for safe, UP to fire. This isn't a big deal for me since my other gun is a Glock, but it would be bothersome to me if I had another gun with the opposite safety switching. Yes, when the safety is off it exposes a red indicator showing so. However, I would think it would be quite an issue to have "muscle memory" the opposite way (thinking up is safe) and jeopardizing your own safety.
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